WO2025153714A1 - Pla2g15 inhibitors for use in the treatment of lysosomal storage diseases, hiv, alzheimer's disease or parkinson's disease - Google Patents

Abstract

The current invention provides inhibitors of a PLA2G15 protein for use in the treatment of lysosomal storage diseases, Alzheimer's disease or Parkinson's disease.

Description

PLA2G15 INHIBITORS FOR USE IN THE TREATMENT OF LYSOSOMAL STORAGE DISEASES, HIV, ALZHEIMER'S DISEASE OR PARKINSON'S DISEASE

Field

The current invention relates to inhibitors of a PLA2G15 protein for use in the treatment of lysosomal storage diseases, HIV, Alzheimer's disease and Parkinson's disease. In particular, It relates to Niemann-Pick disease type

C or a neuronal ceroid lipofuscinosis or Batten disease such as CLN3 disease, CLN5 disease, or GRN frontotemporal dementia.

Background of the invention

Lysosomal dysfunction is a hallmark of rare and common neurodegenerative diseases, metabolic disease and cancer, including neuronopathic lysosomal storage disorders (LSD) such as Niemann-Pick disease type C (NP-C) as well as Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementia (FTD) (1). Indeed, heterozygous carriers of well-known LSD causing mutations in genes like NPC1, GRN or GBA carry increased risk of developing AD, FTD or PD, respectively, highlighting a mechanistic link between rare lysosomal storage diseases and more common neurodegenerative diseases (42, 10, 43). Therefore, counteracting lysosomal dysfunction is considered of potential therapeutic benefit not only to lysosomal storage diseases, but also more common neurodegenerative diseases like AD, PD or FTD.

It is an objective of the invention to provide a treatment for these diseases.

Summary of the invention

The invention provides an inhibitor of a PLA2G15 protein for use in the treatment of Niemann-Pick disease type

C, wherein the inhibitor does not induce lysosomal phospholipid accumulation exceeding levels observed in wildtype cells, as determined by a fluorescence-based assay measuring intracellular lipid accumulation.

In another aspect, the invention provides an inhibitor of a PLA2G15 protein for use in the treatment of a Neuronal ceroid lipofuscinosis selected from CLN3 and CLN5.

In a further aspect, the invention provides an inhibitor of a PLA2G15 protein for use in the treatment of a lysosomal storage disease selected from Niemann-Pick disease, preferably of type C, a Neuronal ceroid lipofuscinosis preferably selected from CLN3, CLN5, and CLN11, and a condition caused by mutations in the GRN gene, Alzheimer's disease, HIV, or Parkinson's disease.

In preferred embodiments, the inhibitor does not induce lysosomal phospholipid accumulation exceeding levels observed in wildtype cells, as determined by a fluorescence-based assay measuring intracellular lipid accumulation.

In a preferred embodiment, the lysosomal storage disease is Niemann-Pick disease type C caused by a mutation in an NPC1 gene or an NPC2 gene, preferably in an NPC1 gene. In another preferred embodiment, the administration of the inhibitor or composition restores or partially restores lysosomal bis(monoacylglycero)phosphate (BMP) levels. In a further preferred embodiment, the administration of the inhibitor results in the alleviation of at least one of the following symptoms: cerebellar ataxia, dysarthria, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and dementia. The invention further provides an inhibitor of a PLA2G15 protein for use in a condition susceptible to being improved or prevented by an increase in levels of bis(monoacylglycero)phosphate. In another aspect, the inhibitor reduces levels of glycolipids, preferably sphingolipids. In a preferred embodiment, the PLA2G15 protein is represented by an amino acid sequence having 90% sequence identity with SEQ ID NO: 1 or 2. Preferably, the inhibitor does not specifically inhibit other phospholipases than the PLA2G15 protein. In a further preferred embodiment, the inhibitor has a half-maximal inhibitory concentration (IC50) of 50 µM or less for the PLA2G15 protein, as determined in enzymatic assays. Preferably, the IC50 value is less than 40, 30, 20, 10, 5, 4, 3, 2, 1, 0.5, 0.1, 0.03, or 0.01 µM. In a preferred embodiment, the inhibitor is a small molecule, an antibody, an antibody fragment, an aptamer, or a nucleic acid. The invention further provides a composition for use in the treatment of a lysosomal storage disease, HIV, Alzheimer’s disease, or Parkinson’s disease comprising the inhibitor as defined above, and a pharmaceutically acceptable excipient. In another aspect, the invention provides a method for screening and selecting PLA2G15 inhibitors suitable for the treatment of in lysosomal storage disorders, metabolic diseases, liver and kidney diseases, HIV, cancers, and neurodegenerative disorders. The method comprises: a. Contacting a candidate compound with PLA2G15 protein in vitro; b. Optionally determining the binding affinity of the candidate compound to the PLA2G15 protein, wherein a compound is selected if it demonstrates a binding affinity with a half maximal inhibitory concentration (IC50) of 50 µmol/L or less for the PLA2G15 protein, as determined by an enzymatic activity assay; c. Optionally testing the candidate compound for enzymatic activity by measuring the ability of the compound to inhibit PLA2G15 enzymatic activity in an assay where the hydrolysis of a substrate by PLA2G15 is quantified; d. Optionally assessing the effect of the candidate compound on phospholipid accumulation by: i. Treating cultured cells with the candidate compound; ii. Staining the treated cells with a dye to detect phospholipid content; iii. Quantifying the phospholipid levels in the treated cells using fluorescence microscopy, flow cytometry or a fluorescence plate reader; e. Selecting the candidate compound based on the results of steps b, c, and d, wherein the candidate compound: i. If step b is performed, demonstrates a binding affinity with an IC50 of 50 µmol/L or less for the PLA2G15 protein, and ii. If step c is performed, shows inhibition of PLA2G15 enzymatic activity, and iii. If step d is performed, does not cause an increase in phospholipid accumulation in treated cells compared to control cells, wherein at least one of steps b or c is performed. Preferably, both steps b and c are performed. Preferably, all of steps b, c, and d are performed. In preferred embodiment, the effect of the candidate compound on cholesterol accumulation is assessed using a fluorescence-based cholesterol accumulation assay, comprising the steps of: a. Treating cultured cells, with the candidate compound for a period of 24 to 72 hours; b. Staining the treated cells with a lysosomal marker and a cholesterol-specific probe, such as Alexa-647 labeled recombinant perfringolysin O (PFO); c. Quantifying the cholesterol accumulation in lysosomal compartments by measuring fluorescence intensity in lysosomal puncta preferably using high-resolution imaging, flow cytometry or a fluorescence plate reader; and d. Selecting the candidate compound if it reduces lysosomal cholesterol accumulation in a disease model cell, such as a NPC1-deficient cell, compared to an untreated control. In a preferred embodiment, the substrate is 4-nitrophenyl butyrate. Preferably, the dye to detect phospholipid content is selected from the group consisting of Nile Red, BODIPY, and Oil Red O. Preferably, the cultured cells are human microglial or phagocytic cells. Preferably, the phospholipid levels are quantified using fluorescence detection, including fluorescent microscopy and a fluorescence plate reader. Preferably, the candidate compound is a small molecule, an antibody, an antibody fragment, an aptamer, or a nucleic acid. Preferably, the IC50 value is determined using a dose-response curve. Preferably, the cultured cells are treated with the candidate compound for a period ranging from 24 to 72 hours. Preferably, the candidate compound is further evaluated for cytotoxicity in the cultured cells. The invention further provides a compound selected by the method according to the invention.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 – Cerebellar ataxia measured with rotarod, for the indicated genotypes. Data shown as average, error bar represents the standard deviation; each data point is an average of 3 trials, 12 mice per genotype. Figure 2 – Kaplan-Meier survival curves of the mice. Data from 12 mice per genotype. Figure 3 – Neurofilament light chain (NF-l) concentration in plasma (left) and cerebrospinal fluid (CSF, right) at post-natal day 56. Average data from 6 mice per genotype, error bar is the standard deviation. ** P < 0.01, *** P < 0.001 vs HOM/KO, one-way ANOVA with Bonferroni correction. Figure 4 – Levels of sphingolipids in mouse brain measured with untargeted lipidomics. Data are shown as average mol percentage (mol%), error bar is standard deviation. Data from 6 mice per genotype. Figure 5 – Levels of sphingolipids in mouse liver measured with untargeted lipidomics. Data are shown as average mol percentage (mol%), error bar is standard deviation. Data from 6 mice per genotype. Figure 6 – Levels of hexosylceramides in cultured HMC3 WT and NPC1 KO cells. Compounds were added at 25 μM for 38 hours. Left graph shows average abundance as mol%, right the log2(fold change) over the WT condition. Figure 7 - PLA2G15 catalyzes hydrolysis of PG, LPG and BMP. Purified PLA2G15 WT or S198A was mixed with the indicated lipids, and the formation of free oleic acid was used as a measure of lipid hydrolysis. Data are shown as average ± standard deviation from two technical replicates. Figure 8 - Enzymatic activity of PLA2G15 controls BMP levels in HAP1 cells. HAP1 cell pellets were subjected to lipidomics to measure BMP levels. BMP levels are expressed as percentage of total measured lipid level, average ± standard deviation. Statistical differences are measured with ANOVA and post-hoc test using Bonferroni correction, comparing WT against each genotype. Data are from 3 replicates. Figure 9 - Knockout of PLA2G15 increases BMP levels in mouse tissues. Tissues of Pla2g15 knockout (KO) and wild-type (WT) littermates were subjected to untargeted lipidomics. BMP levels are shown as percentage of total measure lipids (mol%), average ± standard deviation. Statistical difference was measured using a Student’s t- test. Data are from 5 biological replicates per genotype. Figure 10 - Discovery of potent inhibitors of PLA2G15 activity. Human PLA2G15 was mixed with the indicated amount of inhibitor, and enzymatic activity was measured with a 4-nitrophenyl butyrate assay. Data are from 2 technical replicates, and shown as average ± standard deviation. IC50 values are shown in μM. Figure 11 - Small molecule inhibitors for PLA2G15 induce an elevation of BMP in HMC3 cells. HMC3 cells were exposed to 25 μM of inhibitor, harvested at the indicated time points and subjected to targeted lipidomics. Data are from 4 replicates per condition, shown as average ± standard deviation. Dotted line indicates BMP level from control (DMSO-treated) cells. Figure 12 - Inhibition of PLA2G15 induces an elevation of BMP in mouse tissues. Top: experimental design; mice were injected with 100 mg/kg SC-3865 1-3 times at 12 h intervals. Bottom shows average BMP concentration in lung after 0, 1, 2 or 3 injections with SC-3865. Figure 13 - IC50 curves for SC-003512p2, SC-004395, SC-003863, SC-003865, SC-004611 and fosinopril from cellular inhibition assay using TAMRA in HAP1 cells. Figure 14 – Plasma levels of aspartate transaminase (AST) and alanine transaminase (ALT) at day 56 across the genetic models. Data from 6 animals, dots indicate levels in individual samples. Error bars represent standard deviation. Figure 15 Average neurological composite score across time for different genetic models. Composite score was measured once a week, starting at 6 weeks of age. Error bars represent standard error of the mean. Gene order for the genotypes: Npc1/Pla2g15. HOM/WT is the NPC1 disease model, HOM/KO the disease model with Pla2g15 knock out. Figure 16 shows PFO spot intensity in HMC3 NPC1-ko, NPC1/PLA2G15-dko and wild type microglial cells. Figure 17 shows PFO spot intensity in HMC3 NPC1-ko and NPC1/PLA2G15-dko microglial cell treated with DMSO or with 10 µM of the PLA2G15 inhibitor SC-003863. Figure 18 shows the levels of multiple species of Bis(monoacylglycerol)phosphate (BMP) in cultured retinal pigment epithelial cell line ARPE19 with wildtype, CLN3ko or CLN5ko genotype. Cells were grown to confluency for 4 days before treatment with cell cycle inhibitor mitomycin C for 2h. After mitomycin C treatment cells were incubated for 7 days. Where indicated compounds were added at 10µM for the 11-day duration of the experiment. DESCRIPTION OF THE INVENTION PLA2G15 inhibitors for use in the treatment of diseases characterized by lysosomal dysregulation One of the characteristics of lysosomal dysregulation is that levels of bis(monoacylglycero)phosphate (BMP) are dysregulated. BMP is a lysosomal/late endosomal lipid that stimulates key lysosomal functions: it activates enzymatic activity mediating lipid degradation, controls cholesterol distribution to extra-lysosomal compartments and is involved in endosomal/lysosomal trafficking dynamics to allow cellular homeostasis (3). The central and limiting role of BMP in regulating lysosomal function is well understood in (glyco)sphingolipid breakdown: it also plays a structural role as a docking station for activating co-factors like GM2A, saposin A-D or the heat shock protein HSP-70 in complex with lysosomal enzymes mediating degradation of (glyco)sphingolipids (34, 37). Some of these BMP dependent enzymes are well known targets of genetic LSDs. Metabolic dysregulation may result in increased or decreased levels of BMP. Increased BMP levels in brain have been linked to several well-studied LSDs including NP-C, GM1 gangliosidosis [3], and Gaucher disease [34]. Increased BMP levels were also observed in an AD mouse model carrying the APO4 risk allele (41), while BMP levels were low in Batten CLN3 and CLN5 (14, 17) or FTD caused by granulin haploinsufficiency (10). Neuronal ceroid lipofuscinosis variants caused by mutations in the CLN5 gene show a near absence of BMP, while mutations in the CLN3 gene reduce BMP levels. Disorders caused by mutations in the GRN gene, including FTD and neuronal ceroid lipofuscinosis 11, also show reduced BMP levels. It has been reported that treatments that raise BMP levels alleviate cellular symptoms (10,21). Cellular treatments to increase BMP levels have been shown to correlate with reduced intracellular biogenesis of HIV viral particles and may therefore present novel therapeutic strategies in HIV treatment (47). In NP-C, defects in lysosomal cholesterol trafficking are accompanied by an elevation of BMP levels, and further increase of BMP levels was shown to lessen multiple cellular defects, including cholesterol accumulation and clearance of autophagic materials (21). The related disorders Niemann-Pick type A and B diseases are caused by accumulation of sphingomyelin due to mutations in the lysosomal enzyme acid sphingomyelinase and also display enhanced levels of BMP. As BMP stimulates acid sphingomyelinase activity, a further increase in BMP may be beneficial by enhancing hydrolysis of lysosomal sphingomyelin. Increased levels of BMP in lysosomal storage disease are not merely considered a secondary storage phenotype but rather an active cellular response to increase BMP-dependent lysosomal functions and counteract lysosomal pathology (17). Thus, insufficient BMP levels are considered a pathological factor and restoring balanced BMP expression in lysosomes is considered an attractive therapeutic approach in multiple human disorders. Indeed, therapeutic interventions leading to increased levels of BMP have been shown to correlate with therapeutic efficacy, including in preclinical models of NP-C (21, 22, 7) and PD (36). Therefore, increasing BMP levels in a wide range of diseases as outlined above is expected to have a beneficial therapeutic impact. In the present invention, surprisingly, inhibitors of PLA2G15 were found to restore BMP regulation. Herein, it is demonstrated that BMP and its precursor lysophosphatidylglycerol (LPG) are elevated in multiple tissues of mice that lack expression of the Pla2g15 gene or after in vivo pharmacological inhibition of PLA2G15. Similarly, BMP and LPG levels are elevated in cell lines when the Pla2g15 gene is deleted or after inhibition with specific PLA2G15 inhibitors (see example 4). Furthermore, it is shown that PLA2G15 activity mechanistically controls efficacy of the BMP biosynthetic pathway by hydrolyzing both the precursor LPG and the product BMP in vitro, consistent with the in vivo and cellular findings in genetic and pharmacological models. In addition, an assay was performed to demonstrate the effect of PLA2G15 inhibitors on lysosomal cholesterol level to quantify intracellular cholesterol levels. The results show that treatment with PLA2G15 inhibitors effectively reduces lysosomal cholesterol accumulation in cells with impaired NPC1 function. This reduction is specifically dependent on PLA2G15 activity, as no effect is observed in cells lacking both NPC1 and PLA2G15. These findings confirm the role of PLA2G15 inhibition in restoring lysosomal cholesterol homeostasis and underscore its therapeutic potential in addressing NPC pathology. Furthermore, these results align with the proposed mechanisms of BMP regulation and lysosomal function, providing strong support for targeting PLA2G15 in NPC and related lysosomal storage diseases. In a first aspect, the invention provides an inhibitor of a PLA2G15 protein for use in the treatment of a disease characterized by lysosomal dysregulation. Such inhibitors are referred to in the current application as inhibitors according to the invention. This term implies the use of the inhibitor in the treatment of said disease. Wherever an inhibitor is mentioned in this application, reference is made to an inhibitor according to the invention, unless explicitly mentioned otherwise. Said diseases include neuronopathic lysosomal storage disorders (LSD), AD, PD, FTD, neurodegenerative diseases, metabolic diseases, HIV, a kidney or a liver diseases and cancer. In one embodiment, said disease is an LSD. LSDs are inherited metabolic diseases characterized by lysosomal dysfunction and, most often, neurodegeneration. The term LSD defines a group of approximately 70 disorders, typically due to single gene defects: deficiency of specific enzymes that are normally required for the breakdown of lysosomal glycosaminoglycans (GAGs), glycosphingolipids or glycoproteins, which thus accumulate in the lysosomes of the cell. This accumulation disrupts the cell's normal functioning and gives rise to the clinical manifestations of LSDs. Neurological impairment and neurodegenerative processes are most often associated with lysosomal dysfunction and represent a predominant feature in many LSDs. Neuropathology can occur in multiple brain regions (e.g., thalamus, cortex, hippocampus, and cerebellum) and involves unique temporal and spatial changes, which often entail early region-specific neurodegeneration and inflammation. As an example, Purkinje cells degenerate in many of these diseases leading to cerebellar ataxia. Herein, we demonstrate a reduction of the ganglioside GM3 and lactosylceramide in the brain of NPC1/PLA2G15 double knock-out (dKO) mice compared to NPC1 KO mice. Similarly, we show a reduction of the gangliosides GM1, GM2 and GM3 as well as di-hexosylceramides, hexosylceramides and sphingosine in liver of NPC1/PLA2G15 dKO mice compared to NPC1 KO mice. In addition, we detect a reduction in levels of sphingomyelin (SM) and sulfatide (SM4) in liver of NPC1/PLA2G15 dKO mice compared to NPC1 KO mice. These findings indicate that PLA2G15 contributes to the accumulation of sphingomyelin and glycosphingolipids known to occur in primary or secondary sphingolipidoses. Inhibitors of PLA2G15 can help reducing sphingomyelin and glycosphingolipids. PLA2G15 inhibition is therefore expected to have broad therapeutic benefit across this class of diseases. In a specific embodiment, said disease is a sphingolipidosis. Sphingolipidosis is characterized by a disturbance of the sphingolipid metabolism. Errors in sphingolipid metabolism represent a major class of lysosomal storage diseases (2). Mutations in key enzymes mediating lysosomal degradation of (glyco)-sphingolipids have been identified across the catabolic pathways of this lipid class and give rise to so-called primary sphingolipidoses, including GM1 gangliosidosis, Tay– Sachs disease (B variant), Sandhoff disease, GM2AP deficiency, sialidosis, Fabry disease, Gaucher disease, Niemann-Pick disease type A/B, Krabbe disease, metachromatic leukodystrophy, Farber disease (35). In addition, secondary sphingolipidoses like NP-C disease and others occur where no mutations in the catabolic enzymes mediating (glyco)sphingolipid degradation is detected, yet pathologic accumulation of so-called secondary storage lipids of the (glyco)sphingolipid class is detected (44). Primary storage products like cholesterol and sphingomyelin in Niemann-Pick diseases type C and A/B, respectively, are thought to perturb lysosomal activity by counteracting the stimulatory activity of BMP on the (glyco)sphingolipid degradation pathway in the lysosome, as exemplified with ganglioside degradation by HexA (45). Therefore, restoring the balance between BMP expression in the late endosomal compartment and primary or secondary storage lipids like cholesterol or sphingomyelin is expected to have a positive therapeutic impact on a wide class of LSDs, including sphingolipidoses. Niemann-Pick disease types A and B (NPD-A and NPD-B) are lysosomal storage disorders caused by mutations in the SMPD1 gene, leading to deficient activity of acid sphingomyelinase (ASM) and subsequent accumulation of sphingomyelin in lysosomes. NPD-A primarily affects the central nervous system and is characterized by severe neurodegeneration with early onset, while NPD-B is a non-neuropathic form predominantly affecting visceral organs such as the liver, spleen, and lungs. BMP, a critical lysosomal lipid, plays a key role in regulating ASM activity by enhancing the hydrolysis of sphingomyelin. Reduced BMP levels in lysosomes may exacerbate sphingomyelin accumulation and contribute to disease pathology in NPD-A and NPD- B. Therapeutic strategies that increase BMP levels have the potential to restore ASM activity, thereby improving lysosomal sphingomyelin metabolism and alleviating the pathological accumulation of sphingomyelin in both neuronal and non-neuronal tissues. PLA2G15 inhibition, which has been shown to increase BMP levels in lysosomes, represents a promising approach to address the lysosomal dysfunction underlying NPD-A and NPD- B. By restoring BMP levels, PLA2G15 inhibitors may partially compensate for ASM deficiency, enhancing sphingomyelin hydrolysis and reducing the lysosomal lipid burden. This therapeutic mechanism aligns with the observed effects of BMP in enhancing lysosomal enzyme activity and supporting lysosomal homeostasis. While the potential impact of PLA2G15 inhibition on the central nervous system in NPD-A remains to be fully elucidated, its ability to target visceral lysosomal dysfunction in NPD-B provides a strong rationale for therapeutic exploration. Therefore, in an embodiment, said lysosomal storage disease is NPD-A or NPD-B. In a preferred embodiment, said disease is a sphingolipidosis, including Niemann-Pick diseases, type A an B , NP-C , Gaucher disease , metachromatic leukodystrophy , Krabbe disease and Farber disease. In a preferred embodiment, said sphingolipidosis is a mucopolysaccharidosis (MPS), including, MPS I (Hurler syndrome, MPS II (Hunter syndrome) , MPS IIIA (Sanfilippo syndrome) , MPS-IIIB (Sanfilippo syndrome) , MPS IIIC (Sanfilippo syndrome), MPS IIID (Sanfilippo syndrome), MPS VI (Maroteaux–Lamy syndrome), MPS VII (Sly syndrome). In a preferred embodiment, said sphingolipidosis is a mucolipidosis, including mucolipidosis II (I-cell disease), mucolipidosis III (pseudo-Hurler polydystrophy) and mucolipidosis IV. In a preferred embodiment, said disease is glycoproteinosis, including galactosialidosis, mannosidosis, sialidosis. In a preferred embodiment, said sphingolipidosis is a neuronal ceroid lipofuscinosis (NCL), including NCL 3 (Batten disease), NCL 10 and Hereditary spastic paraplegia (HSP). In a preferred embodiment, said disease is Alzheimer‘s disease. In a preferred embodiment, said disease is Parkinson’s disease. In preferred embodiments said condition is selected from neuronal ceroid lipofuscinosis (NCL), CLN3 Batten, CLN5 Batten, GRN, frontotemporal dementia and Niemann-Pick disease, preferably of type C. Therapeutic Potential of PLA2G15 Inhibitors in Batten Disease The neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease, are a group of lysosomal storage disorders caused by mutations in one of 13 genes (CLN1-CLN13). These mutations lead to diverse cellular dysfunctions but share a common pathology, including lysosomal impairment. A hallmark of the most prevalent form, CLN3 Batten disease, is a significant reduction in bis(monoacylglycero)phosphate (BMP) levels (Kollmann et al., 2013). Similarly, CLN5 Batten disease, caused by mutations in the CLN5 gene, results in almost absent BMP levels due to the loss of BMP-synthesizing enzymatic activity by the CLN5 gene product. In CLN11 Batten disease, caused by homozygous mutations in the GRN gene encoding progranulin, reduced BMP levels are also observed. Reduced BMP levels correlate with diminished lysosomal enzyme activity, as evidenced by the restoration of activity following exogenous BMP supplementation in GRN-deficient macrophages (Logan et al., 2021). Together, these findings establish BMP restoration as a disease-modifying strategy for Batten disease. Studies were conducted to evaluate the therapeutic potential of PLA2G15 inhibitors in restoring BMP levels in cellular models of Batten disease. Treatment with PLA2G15 inhibitors increased BMP levels in cells deficient in CLN3 or CLN5 (see Figure 18). These findings indicate that PLA2G15 inhibitors can partially restore BMP levels, addressing a key biochemical defect in Batten disease. BMP restoration is critical for lysosomal function, highlighting this therapeutic intervention as a promising approach for disease modification in Batten disease. Additionally, reduced BMP levels observed in CLN11 Batten disease share pathology with GRN-associated frontotemporal lobar dementia (FTLD). Frontal lobe tissues from FTLD patients with heterozygous GRN mutations exhibit diminished BMP levels (Boland et al., 2022), paralleling observations in CLN11 cell models. This overlap underscores the therapeutic relevance of BMP restoration via PLA2G15 inhibition in lysosomal disorders, including Batten disease and GRN-mediated conditions. Preferred Embodiments of Batten Disease and GRN-Mediated Conditions In a preferred embodiment, the invention provides an inhibitor of a PLA2G15 protein for use in the treatment of Batten disease and GRN-mediated conditions. Preferably, said Batten disease and GRN-mediated conditions include: • CLN3 Batten Disease: The most common form of neuronal ceroid lipofuscinosis, caused by mutations in the CLN3 gene and characterized by reduced BMP levels, lysosomal dysfunction, and accumulation of ceroid lipofuscin. • CLN5 Batten Disease: A subtype of neuronal ceroid lipofuscinosis caused by mutations in the CLN5 gene, resulting in almost absent BMP levels due to the loss of BMP-synthesizing enzymatic activity, accompanied by lysosomal impairment and neurodegeneration. • CLN10 Batten Disease: CLN10 Batten Disease is caused by mutations in the CTSD gene, encoding the lysosomal protease cathepsin D. These mutations result in impaired lysosomal proteolysis, which disrupts cellular homeostasis and leads to neurodegeneration. Unlike other forms of Batten disease, BMP levels are elevated in CLN10, which reflects a compensatory mechanism to enhance lysosomal function. Inhibition of PLA2G15, which degrades BMP, may stabilize and further elevate BMP levels to enhance lysosomal function. • CLN11 Batten Disease: A form of neuronal ceroid lipofuscinosis caused by homozygous mutations in the GRN gene, leading to severe BMP deficiency, lysosomal dysfunction, and early-onset neurodegeneration. • Frontotemporal Lobar Degeneration (FTLD): A neurodegenerative disorder associated with heterozygous mutations in the GRN gene, characterized by progranulin haploinsufficiency, diminished BMP levels, and TDP-43 proteinopathy. Other Lysosomal Storage Disorders with GRN Deficiency In a preferred embodiment, other lysosomal storage disorders with GRN deficiency include conditions caused by heterozygous or homozygous mutations in the GRN gene, resulting in progranulin insufficiency and associated lysosomal dysfunction. These disorders include: • GRN-Associated Frontotemporal Lobar Degeneration (FTLD-TDP): A neurodegenerative condition characterized by progranulin haploinsufficiency, TDP-43 protein inclusions, reduced BMP levels, and lysosomal impairment. Symptoms include behavioral and cognitive decline, primarily affecting the frontal and temporal lobes. • GRN-Related Neuronal Ceroid Lipofuscinosis Type 11 (CLN11): A severe lysosomal storage disorder caused by homozygous GRN mutations, leading to early-onset neurodegeneration, reduced BMP levels, and accumulation of lysosomal storage material, including ceroid lipofuscin. • GRN-Linked Neuroinflammatory Disorders: Conditions where progranulin deficiency exacerbates chronic inflammation due to impaired lysosomal function, potentially contributing to neurodegeneration and systemic inflammation. • GRN Deficiency-Associated Lysosomal Dysfunction in Alzheimer’s Disease: Emerging evidence suggests that progranulin haploinsufficiency and BMP dysregulation contribute to lysosomal dysfunction and neuroinflammation in certain forms of Alzheimer’s disease. • Parkinsonian Syndromes Associated with GRN Mutations: Atypical Parkinsonian disorders linked to progranulin deficiency, where impaired lysosomal function may contribute to disease pathology. In specific embodiments, said condition is selected from the diseases listed in Table 1. Disease BMP Levels, Side Chain Disease prevalence Composition and Tissue implicated in (Births) Localization Significantly elevated in spleen and liver, as well as Acid Niemann-Pick plasma in patients with NPA and 1:248,000 sphingomyelinase diseases type A and B NPB. Di-18:1 BMP and di-18:2 BMP were the predominant side chains in plasma . Di-18:1 BMP is significantly Acid-beta- elevated in plasma samples Gaucher disease 1:57,000 glucosidase from patients with Gaucher disease Significantly elevated in spleen and liver, as well as Niemann-Pick NPC1 and NPC2 1:211,000 plasma in NP-C patients. BMP disease type C di-18:1 was the most prevalent side chain in plasma. GM1-beta- GM1 1_:384,000 ^{Significantly elevated in} galactosidase gangliosidosis human brain samples from postmortem patients with GM1 gangliosidosis. BMP di-22:6, di- 18:0 and di-18:1 were the most abundant species. No significant elevation in plasma but significant elevation in urine observed, however, PG Metachromatic Arylsulfatase A 1:92,000 and BMP were undifferentiated leukodystrophy in the study’s Mass Spectrometry analysis, so BMP confirmation is unclear Significantly elevated in cultured skin fibroblasts from Alpha-galactosidase patients with Fabry disease, Fabry disease 1:117,000 A with di-22:6 BMP then di-18:1 BMPs as the most abundant species. B2GP1 (Beta-2- Antiphospholipid 1:2,000 NA glycoprotein-1) syndrome IGF2/MPR (insulin like growth Antiphospholipid 1:2000 NA factor/mannose-6- syndrome phosphate receptor) Di-22:6 BMP and BMPs with ABCA4 (ATP-binding C20:4 side chains were cassette, sub family A, Stargardt disease 1:9000 significantly elevated in human member 4) retina tissues from patients with Stargardt disease. In a preferred embodiment, said disease is NP-C. NP-C is a rare autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. Classically, children with NP-C demonstrate progressive neurological dysfunction with cerebellar ataxia (an inability to coordinate balance, gait, extremity and eye movements), dysarthria (difficulty speaking), vertical gaze palsy (ability to move eyes in the vertical direction), dysmetria, dysphagia (trouble swallowing), psychotic episodes, and dementia (preferably progressive dementia). Affected individuals often experience progressive decline in intellectual function and about one-third have seizures. NP-C is caused by mutations in the genes NPC1 or NPC2. NP-C is an autosomal recessive disorder occurring at a frequency of 1:100,000 live births. The gene products of NPC1 and NPC2 mediate redistribution of endocytic cholesterol from the late endosomal/lysosomal compartment to other cellular compartments like the endoplasmic reticulum and plasma membrane. Consequently, a hallmark of NP-C is the cellular storage of cholesterol in the lysosomal compartment (38). While a small subset of early infantile cases will die within their first six months of life from liver or respiratory failure, most patients will develop progressive and neurological complications and typically die between the ages of 10 to 25. The neurological symptoms typically present as cerebellar ataxia, dysarthria, dysmetria, dysphagia, and progressive dementia, and the majority of cases show a characteristic vertical supranuclear gaze palsy (VSGP) (38). In both patients and animal models of NP-C, progressive degeneration of the cerebellum and increased circulation of neurodegeneration biomarkers like neurofilament light chain can be detected (40). NP-C is characterized by the secondary accumulation of (glyco)sphingolipids and therefore considered a member of a group of LSDs called sphingolipidoses (35). In specific embodiments, said LSD is characterized by progressive neurological symptoms tied to accumulation of lipid species. In specific embodiments, such condition is characterized by defects in lysosomal cholesterol and sphingolipid trafficking. In specific embodiments, such condition is characterized by an increased level of cellular BMP. In other specific embodiments, said condition is characterized by a decreased level of cellular BMP. In preferred said cellular BMP level is elevated in the spleen, liver, brain, skin and/or plasma. In specific embodiments, said condition is characterized by cholesterol accumulation and lack of clearance of autophagic materials. In specific embodiments, the treatment according to the invention results in the stabilization of cellular BMP levels. In other specific embodiments, the treatment according to the invention results in the increase of cellular BMP levels. In other specific embodiments, the treatment according to the invention results in enhancing hydrolysis of lysosomal sphingomyelin, glycosphingolipids and/or gangliosides. In preferred said cellular BMP level is elevated in the spleen, liver, brain, skin and/or plasma. In other specific embodiments, the treatment according to the invention results in the formation of free oleic acid from PG, LPG and BMP. In specific aspects, NP-C is caused by mutation in an NPC1 gene (chromosome location 18q11) or an NPC2 gene (chromosome location 14q24.3), preferably in an NPC1 gene. NP-C caused by mutation in an NPC1 gene or an NPC2 gene may be called Niemann-Pick disease type C1 (NPC1) or Niemann-Pick disease type C2 (NPC2), respectively. Both the NPC1 gene and the NPC2 gene are involved in the efflux of lipids, particularly cholesterol, from late endosomes and lysosomes. The NPC1 gene encodes a protein that is located in the limiting membrane of endosomes and lysosomes, and is involved in the movement of cholesterol and lipids within cells. The NPC2 gene on the other hand encodes a protein that binds and transports cholesterol. NP-C is biochemically, genetically and clinically distinct from Niemann–Pick disease types A and B. In types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. Without being bound to this theory, in NP-C, NPC1, the protein encoded by the NPC1 gene, is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules such as cholesterol and sphingolipids through the cell. NPC2, the protein encoded by the NPC2 gene, more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting water- insoluble molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycosphingolipids in lysosomes. Hence, in NP-C, significant amounts of unesterified cholesterol accumulate in lysosomes, leading to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The mutations in the NPC1 gene and/or the NPC2 gene comprised in a subject suffering from NP-C may result in a decrease of NPC1 protein and/or NPC2 protein expression levels, respectively, and/or the expression of a fully or partially dysfunctional NPC1 protein and/or NPC2 protein, respectively. In the context of this application, a normal NPC1 or NPC2 protein expression level is defined as the NPC1 or NPC2 protein expression level in a healthy subject. A decreased NPC1 or NPC2 protein expression level means a NPC1 or NPC2 protein expression level lower than a normal NPC1 or NPC2 protein expression level, preferably decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01. In the context of this application, a dysfunctional NPC1 or NPC2 protein is an NPC1 or NPC2 protein whose cellular activity is decreased, preferably decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 relative to an NPC1 or NPC2 protein expressed in a healthy subject, or no longer comprises such cellular activity. In specific aspects, an inhibitor of the invention is able to induce one or more of the following changes when said inhibitor is introduced in a subject suffering from NP-C: — a restored or partially restored intralysosomal cholesterol concentration, preferably wherein the intralysosomal cholesterol concentration is decreased after introduction of the inhibitor, more preferably wherein the intralysosomal cholesterol concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and/or — a restored or partially restored endosomal, preferably late-endosomal cholesterol concentration, preferably wherein the endosomal, preferably the late-endosomal, cholesterol concentration is decreased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late-endosomal, cholesterol concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and/or — a restored or partially restored intralysosomal glycolipid, preferably glycosphingolipid concentration, preferably wherein the intralysosomal glycolips, preferably glycosphingolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the intralysosomal glycolipid or glycosphingolipid concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and/or — a restored or partially restored endosomal, preferably late-endosomal, glycolipid or glycosphingolipid concentration, preferably wherein the endosomal, preferably the late-endosomal, glycolipid or glycosphingolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late-endosomal, glycolipid or glycosphingolipid concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and/or — a restored or partially restored intralysosomal glycosphingolipid concentration, preferably wherein the intralysosomal glycosphingolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the intralysosomal glycosphingolipid concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and/or — a restored or partially restored endosomal, preferably late-endosomal, glycosphingolipid concentration, preferably wherein the endosomal, preferably the late-endosomal, glycosphingolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late-endosomal, glycosphingolipid concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; — a restored or partially restored or increased BMP concentration, preferably wherein the endosomal, preferably the late-endosomal, BMP concentration is increased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late-endosomal, BMP concentration is increased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; wherein a partially restored concentration means that the concentration is significantly closer to that in a corresponding healthy subject after introduction of said inhibitor, preferably by the factors described above, wherein a restored concentration means that the concentration is essentially the same as that in a corresponding healthy subject. In specific aspects, administration of an inhibitor according to the invention to a subject in need thereof results in one of the effects described above, particularly in a reduction of the intralysosomal cholesterol concentration and/or the intralysosomal glycosphingolipid concentration. NP-C shows a wide range of clinical symptoms. Affected individuals may have an enlargement of spleen (splenomegaly) and/or liver (hepatomegaly). Progressive neurological disease is the hallmark of NP-C. Classically, children with NP-C may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia). Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, dementia (preferably progressive dementia), progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor. In specific aspects, an inhibitor of the invention is able to alleviate or stabilize at least one of the following symptoms when said inhibitor is introduced in a subject suffering from NP-C: splenomegaly, hepatomegaly, hepatosplenomegaly, cerebellar ataxia, dysarthria, dysphagia, tremor, epilepsy, vertical supranuclear palsy, sleep inversion, gelastic cataplexy, dystonia, spasticity, hypotonia, ptosis, psychosis, dementia (preferably progressive dementia), progressive hearing loss, bipolar disorder, major and psychotic depression, hallucinations, delusions, mutism, and stupor. The alleviation or stabilization of a symptom is generally acknowledged by a skilled person (and in particular, by the treating physician) as a worthwhile clinical objective. In specific aspects, administration of an inhibitor according to the invention to a subject in need thereof results in the alleviation or stabilization of at least of the following symptoms: cerebellar ataxia, dysarthria, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and dementia (preferably progressive dementia). Structure of PLA2G15 proteins A PLA2G15 protein, which may also be called a phospholipase A2 group XV (protein), a lysophospholipase 3 (protein) or LYPLA3, is a protein encoded by a PLA2G15 gene. Other alternative names for the PLA2G15 protein include: LLPL, LPLA2, ACS, lysosomal phospholipase A and acyltransferase. Herein, all human variants and isoforms, and species homologues and their variants and isoforms are encompassed. In the context of this application, a PLA2G15 or a LYPLA3 refer to a PLA2G15 protein, unless explicitly mentioned otherwise. In specific aspects, a PLA2G15 gene is located at the open reading frame UNQ341/PRO540. In this context, a PLA2G15 (protein) may also be called a UNQ341/PRO540 (protein). In specific aspects, a PLA2G15 protein is represented by an amino acid sequence having at least 75%, 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%, 80.5%, 81%, 81.5%, 82%, 82.5%, 83%, 83.5%, 84%, 84.5%, 85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%, 89.5%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 100% sequence identity with SEQ ID NO: 1 or 2, preferably with SEQ ID NO:1. In specific aspects, a PLA2G15 protein is represented by an amino acid sequence having at least 75%, 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%, 80.5%, 81%, 81.5%, 82%, 82.5%, 83%, 83.5%, 84%, 84.5%, 85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%, 89.5%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 100% sequence similarity with SEQ ID NO: 1 or 2, preferably with SEQ ID NO:1. In specific aspects, a PLA2G15 protein comprises an amino acid sequence represented by SEQ ID NO: 1 or 2, preferably SEQ ID NO: 1. In more specific aspects, a PLA2G15 protein consists of an amino acid sequence represented by SEQ ID NO: 1 or 2, preferably SEQ ID NO: 1. In specific aspects, a PLA2G15 protein has a length from 322 up to 502 amino acids, or from 332 up to 492 amino acids, or from 342 up to 482 amino acids, or from 352 up to 472 amino acids, or from 362 up to 462 amino acids, or from 372 up to 452 amino acids, or from 382 up to 442 amino acids, or from 392 up to 432 amino acids, or from 402 up to 422 amino acids, or from 403 up to 421 amino acids, or from 404 up to 420 amino acids, or from 405 up to 419 amino acids, or from 406 up to 418 amino acids, or from 407 up to 417 amino acids, or from 408 up to 416 amino acids, or from 409 up to 415 amino acids, or from 410 up to 414 amino acids, or from 411 up to 413 amino acids, preferably wherein the PLA2G15 protein is represented by an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1, more preferably wherein the PLA2G15 protein is represented by an amino acid sequence comprising SEQ ID NO: 1. In specific aspects, a PLA2G15 protein has a length from 218 up to 418 amino acids, or from 228 up to 408 amino acids, or from 238 up to 398 amino acids, or from 248 up to 388 amino acids, or from 258 up to 378 amino acids, or from 268 up to 368 amino acids, or from 278 up to 358 amino acids, or from 288 up to 348 amino acids, or from 298 up to 338 amino acids, or from 308 up to 328 amino acids, or from 309 up to 327 amino acids, or from 310 up to 326 amino acids, or from 311 up to 325 amino acids, or from 312 up to 324 amino acids, or from 313 up to 323 amino acids, or from 314 up to 322 amino acids, or from 315 up to 321 amino acids, or from 316 up to 320 amino acids, or from 317 up to 319 amino acids, preferably wherein the PLA2G15 protein is represented by an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2, more preferably wherein the PLA2G15 protein is represented by an amino acid sequence comprising SEQ ID NO: 2. In specific aspects, a PLA2G15 protein has a length of 412 amino acids, or 318 amino acids. In specific aspects, a PLA2G15 protein is expressed in or is derived from a vertebrate, more preferably a mammal, even more preferably a rat, a mouse, a rabbit, monkey, dog or a human, most preferably a human. In this context, a PLA2G15 protein derived from a specific animal may be a recombinant protein expressed in a host organism. Activity of PLA2G15 proteins An inhibitor according to the invention is able to inhibit (i.e. decrease) an activity of a PLA2G15 protein. In this context, an inhibitor according to the invention may also be called a compound able to inhibit an activity of a PLA2G15 protein. Herein, decreasing an activity may mean inhibiting an activity of said PLA2G15 protein via direct or indirect contact between said inhibitor and said PLA2G15 protein, and/or decreasing the level of expression of said PLA2G15 protein thereby decreasing the total activity of said PLA2G15 protein. In specific aspects, decreasing an activity means inhibiting an activity of said PLA2G15 protein via direct or indirect contact between said inhibitor and said PLA2G15 protein. In specific aspects is provided an inhibitor according to the invention, wherein said inhibitor is able to decrease a catalytic activity of a PLA2G15 protein. In this context, a PLA2G15 protein may be called an enzyme and a catalytic activity may be called a enzymatic activity. It is understood that a catalytic activity of a PLA2G15 protein or enzyme means that said PLA2G15 protein increases the rate of a reaction, preferably by a factor of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000, relative to the rate of a corresponding reaction performed in a corresponding environment (e.g. similar cellular conditions, pH, salt concentrations, enzyme concentrations, etc.) and under corresponding conditions (e.g. same temperature, etc.) wherein said PLA2G15 protein is not present. Preferably, said rate increase of said reaction is defined under physiological conditions. In the context of this application, “a catalytic activity of a PLA2G15 protein, wherein said catalytic activity comprises a reaction”, “a reaction catalysed by a PLA2G15 protein” or similar phrases mean that the rate of said reaction is increased by said PLA2G15 Protein, as explained above. In specific aspects, decreasing a catalytic activity means decreasing the rate of a reaction catalysed by said PLA2G15 protein, more preferably by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001, relative to the rate of a corresponding reaction performed in a corresponding environment (e.g. similar cellular conditions, pH, salt concentrations, PLA2G15 concentration, other enzyme concentrations, etc.) and under corresponding conditions (e.g. same temperature, etc.) wherein said inhibitor according to the invention is not present. Preferably, said rate decrease of said reaction is defined under physiological conditions. As explained above, decreasing the rate of a reaction catalysed by a PLA2G15 protein may be the result of inhibiting a catalytic activity of said PLA2G15 protein via direct or indirect contact between said inhibitor and said PLA2G15 protein, and/or decreasing the level of expression of said PLA2G15 protein thereby decreasing the total catalytic activity of said PLA2G15 protein. Preferably, decreasing the rate of a reaction catalysed by a PLA2G15 protein is the result of inhibiting a catalytic activity of said PLA2G15 protein via direct or indirect contact between said inhibitor and said PLA2G15 protein. The rate of a reaction catalysed by a PLA2G15 protein may be measured or assessed by any suitable methods well-known in the art. In specific aspects, the rate of a reaction catalysed by a PLA2G15 protein is measured or defined at pH 4.5 and under otherwise physiological conditions. More preferably, said reaction takes place in an organelle, a cell fraction, a cell, a tissue, an organ or a subject, most preferably in a vertebrate, mammalian or human cell. Preferably, an organelle is a lysosome or an endosome. Preferably, an endosome is a late endosome. Without being limited to any specific explanation, mechanism or hypothesis, an inhibitor as used in the invention is capable, in a suitable assay or model and/or upon administration to a subject, of decreasing in specific aspects a catalytic activity of an PLA2G15 protein that originates from, is caused by or is linked to a catalytic triad comprised in said PLA2G15 protein, in particular a catalytic triad consisting of a histidine, a aspartic acid and a serine residue, and more in particular the catalytic triad that consists of His-359, Asp-327 and Ser-165. In specific aspects, a catalytic activity of a PLA2G15 protein comprises the cleavage of a fatty acid residue from a compound, which may also be called a deacylase activity. More preferably, said compound is a lipid and said catalytic activity may be called a lipase activity. Even more preferably, said lipid is a phospholipid and said catalytic activity may be called a phospholipase activity. Most preferably, said phospholipase activity is a phospholipase A1 activity or a phospholipase A2 activity, preferably a phospholipase A2 activity. In specific aspects, a phospholipid in the aspects above is a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylglycerol, or a phosphatidylserine. In specific aspects, a phospholipid in the aspects above is an oxidized phospholipid, preferably wherein said oxidized phospholipid comprises short fatty acid chains (e.g. comprising less than 10 carbon atoms) and/or a free carboxyl or formyl group at the sn-2 position. In specific aspects, a phospholipid in the aspects above is not a phosphatidylinositol or a sphingomyelin. In specific aspects, a catalytic activity of a PLA2G15 protein comprises a transfer of a fatty acid residue from a donor compound to an acceptor compound, which may also be called a transacylase activity. A transacylase activity thus comprises a deacylase activity, to which the preferences above apply. In specific aspects, a catalytic activity of a PLA2G15 protein comprises a transacylase activity, wherein said acceptor compound is N-acetyl-sphingosine. In specific aspects, an activity of a PLA2G15 protein comprises a catalytic activity during lipid metabolism. Herein, it is understood that lipid metabolism comprises lipid anabolism and lipid catabolism. Structure of inhibitors In specific aspects, an inhibitor according to the invention is able to decrease an activity of a PLA2G15 protein by inhibiting an activity of said PLA2G15 protein via direct or indirect contact between said inhibitor and said PLA2G15 protein. More preferably, said direct contact is non-covalent or covalent binding between said inhibitor and said PLA2G15 protein. In specific aspects, an inhibitor according to the invention is a small molecule, an antibody fragment, an antibody, an aptamer or a nucleic acid, more preferably a small molecule, an antibody fragment or an aptamer. In specific aspects, an inhibitor according to the invention is a small molecule. Examples of inhibitors which are able to decrease an activity of a PLA2G15 protein are described in (46). In specific aspects, a small molecule is a cationic amphiphilic molecule or a fluorophosphonate. In specific aspects, a cationic amphiphilic molecule is able to bind the PLA2G15 protein, wherein the binding disrupts electrostatic charge interaction with cationic residues comprised in the PLA2G15 protein. In specific aspects, an inhibitor according to the invention is able to specifically bind the PLA2G15 protein, but does not specifically bind other phospholipases. Without being exhaustive, other phospholipases include group I phospholipases (PLA2G1B), group II phospholipases (PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E, PLA2G2F), group III phospholipases (PLA2G3), group IV phospholipases (PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F), group V phospholipases (PLA2G5), group VI phospholipases (PLA2G6), group VII phospholipases (PLA2G7), group X phospholipases (PLA2G10) and group XII phospholipases (PLA2G12A, PLA2G12B). A skilled person in the art can identify suitable inhibitors by testing its inhibitory effect on the PLA2G15 enzymatic activity with an inhibition assay, preferably the 4-nitrophenyl butyrate assay as disclosed herein. In specific aspects, a cationic amphiphilic molecule is amiodarone ((2-{4-[(2-butyl-1-benzofuran-3- yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine) or D-threo-1-phenyl-2-decanoylamino-3-morpholino-1- propanol (PDMP). In specific aspects, a fluorophosphonate is a suicide inhibitor able to specifically and covalently bind a catalytic serine residue comprised in the PLA2G15 protein. Without being bound to this theory, the covalent binding essentially results in an irreversible enzyme-inhibitor complex and an inactive PLA2G15. In specific aspects, a fluorophosphonate is methoxy arachidonyl fluorophosphonate or isopropyl dodecylfluorophosphonate. An antibody refers to polyclonal antibodies, monoclonal antibodies, humanized antibodies, single-chain antibodies, and fragments thereof such as Fab F(ab)2, Fv, VHH and other fragments that retain the antigen binding function of the parent antibody. As such, an antibody may refer to an immunoglobulin or glycoprotein, or fragment or portion thereof, or to a construct comprising an antigen-binding portion comprised within a modified immunoglobulin-like framework, or to an antigen-binding portion comprised within a construct comprising a non-immunoglobulin-like framework or scaffold. A fragment of an antibody refers to a part of an antibody that retain the antigen binding function of said antibody. An antigen in the context of the current invention is preferably a PLA2G15 protein. In specific aspects, an antibody or a fragment thereof is an intrabody. An intrabody is defined herein as an antibody that performs its antigen binding function intracellularly by binding to an intracellular antigen. More preferably, the intrabody is expressed in the cell wherein said antigen binding function takes place. Most preferably, the intrabody is expressed from a sequence which has been introduced by means of a viral vector into the cell. In specific aspects, an inhibitor according to the invention is a competitive inhibitor of said PLA2G15 protein, wherein said inhibitor is able to specifically bind an active site of said PLA2G15 protein associated with said activity of said PLA2G15 protein. In specific aspects, an inhibitor according to the invention is a non-competitive or allosteric inhibitor of said PLA2G15 protein, wherein said inhibitor is able to specifically bind a part of said PLA2G15 protein which is not an active site associated with said activity of said PLA2G15 protein. In this context, said binding site which is not an active site maybe called an allosteric site. In specific aspects, an inhibitor according to the invention is able to decrease an activity of a PLA2G15 protein by decreasing the level of expression of an active form of said PLA2G15 protein, preferably said expression is in a vertebrate, more preferably in a mammal, even more preferably in a rat, a mouse, a rabbit or a human, most preferably in a human. In vitro assays can be performed with representative animal models, to determine if an inhibitor according to the invention exerts the desired effect of decreasing the level of expression of said active form of said PLA2G15 protein. Preferably, the level of expression can be correlated with the concentration of the active form in lysosomes in said vertebrate. Preferably, the level of expression of said active form of said PLA2G15 protein is decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01. In these aspects, it is understood that an active form a PLA2G15 protein may have undergone post-translational modifications. In specific aspects, an inhibitor according to the invention is a nucleic acid, preferably wherein the nucleic acid is able to decrease an activity of a PLA2G15 protein by decreasing the level of expression of said PLA2G15 protein. In specific aspects, an inhibitor according to the invention is a double-stranded RNA molecule, a small inhibitory RNA (siRNA) molecule, or an inhibitory RNA molecule (RNAi), a guideRNA (gRNA). More preferably, an inhibitor according to these specific aspects are able to decrease an activity of a PLA2G15 protein by decreasing the level of expression of said PLA2G15 protein. In other words, these inhibitors preferably do not bind a PLA2G15 protein but lead to a decreased concentration of PLA2G15 proteins in an organelle (preferably a lysosome), a cell fraction, a cell, tissue, organ or subject when they are introduced therein. Most preferably, the concentration of said PLA2G15 protein is decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 upon introduction in said organelle (or lysosome), cell fraction, cell, tissue, organ or subject. In specific aspects, an inhibitor according to the invention leads to a knockout of a PLA2G15 gene when introduced in an organelle (preferably a lysosome), a cell fraction, a cell, tissue, organ or subject. More preferably, a knockout of a PLA2G15 gene means level of expression of said PLA2G15 gene is decreased by a factor equal to or lower than 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01. The terms level of expression of a gene, its corresponding RNA transcripts and its corresponding polypeptides and proteins may be used interchangeable in the context of this application. In specific aspects, an inhibitor according to the invention leads to a knockout via gene editing, e.g. via the CRISPR/Cas9 system. In specific aspects, an inhibitor according to the invention is an enzyme. Again, in all cases, and irrespective of the nature of the inhibitor and the manner in which it binds to PLA2G15 and/or influences PLA2G15 activity or expression, the inhibitor used in the invention is preferably such that it is capable of reducing at least one activity of PLA2G15, and preferably at least one enzymatic activity of PLA2G15. Compositions In a further aspect, the invention provides a composition for use in the treatment of a lysosomal storage disease comprising an inhibitor according to the invention and a pharmaceutically acceptable excipient. Such compositions are referred to in the current application as compositions according to or of the invention. This term implies the use of the composition in the treatment of a lysosomal storage disease. All specific aspects disclosed above for an inhibitor according to the invention may be applied accordingly for an inhibitor according to the invention comprised in a composition according to the invention. A composition according to the invention may be presented or formulated as capsules, tablets, powders, granules, solutions, suspensions in aqueous or non-aqueous liquids, edible, oil-in-water liquid emulsions, water- in-oil liquid emulsions, solution, syrups and elixirs, in microencapsulated form, liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles, transdermal patches, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, drops, sprays, aerosols, oils, lozenges, pastilles, mouth washes, suppositories, enemas, aqueous and non-aqueous sterile injection solutions, and so on. It will be appreciated that the compositions may include other agents conventional in the art having regard to the type of formulation. Non-limiting examples of a pharmaceutically acceptable carrier comprised in a composition are saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds, besides an inhibitor according to the invention, can also be incorporated into the compositions. A composition according to the invention formulated as solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. A composition according to the invention formulated as compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, a composition for parenteral administration must be sterile and should be fluid to the extent that easy syringeability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. In a composition according to the invention prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. A composition according to the invention formulated as oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the inhibitor according to the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. A composition according to the invention may be formulated for administration by inhalation, the inhibitor according to the invention can be delivered in the form of an aerosol spray from a pressurized container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. A composition according to the invention may be formulated for transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. In one aspect, transdermal administration may be performed my iontophoresis. A composition according to the invention may comprise a carrier system such as a colloidal system. The colloidal system can be a liposome, a phospholipid bilayer vehicle. In one aspect, the inhibitor according to the invention is encapsulated in a liposome. An inhibitor according to the invention can also be loaded into a particle prepared from pharmaceutically acceptable ingredients including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems. Therapeutic uses Wherever an inhibitor according to the invention for use in the treatment of a disease as specified above, or a composition according to the invention for use in the treatment of a said disease are disclosed in this application, a corresponding method for the manufacture or the production of a medicament comprising such an inhibitor or such a composition, a corresponding method of treatment of a lysosomal storage disease comprising the administration of the inhibitor or composition to a subject in need thereof, and a corresponding use of such an inhibitor or such a composition as a medicament are also disclosed. In all these contexts, the inhibitor according to the invention and the composition according to the invention may be referred to as a medicament according to the invention. A medicament according to the invention may be administered orally, nasally, buccally, sublingually, vaginally, parenterally, topically, systemically, intravenously, subcutaneously, intraperitoneally, intramuscularly, intrathecally, by inhalation or epidurally. A medicament according to the invention, preferably for use in the treatment and/or prevention of a lysosomal storage disease, may be administered separately, sequentially or simultaneously in combination with another medicament for the treatment of a disease as specified herein, a lysosomal storage disease, or any of its associated symptoms and/or diseases. A medicament according to the invention, preferably for use in the treatment and/or prevention of a disease as specified herein , may be administered separately, sequentially or simultaneously in combination with (i.e. co- administered with) arimoclomol, a cyclodextrin, preferably hydroxypropyl-beta-cyclodextrin (HPbCD), N-acetyl- L-leucine, miglustat, lucerastat, sinbaglustat, and/or nizubaglustat. As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time. The term "separate" therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes. The term "sequential" therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case. In the context of this application, the terms treating" or "treatment" refer to therapeutic treatment, wherein the object is to prevent, reduce, alleviate or slow down (lessen), respectively and as applicable, the targeted pathologic disorder or disease and/or its progression in a subject. In particular, said terms relate to a treatment which has the object of improving one or more symptoms and/or physiological parameters that are caused by, associated with and/or characteristic of the disease or disorder that is to be treated, and/or the object to preventing that such symptom(s) to arise and/or that such symptom(s) or physiological parameter(s) further deteriorate. Based on his general knowledge and the further disclosure herein, the skilled person (and in particular, the treating physician) will be able to suitably determine and measure said symptom(s) or physiological parameter(s), depending on the specific disease involved. For example, a subject is successfully "treated" for a lysosomal storage disease if, after receiving a therapeutic amount of an inhibitor or a composition according to the invention, the subject shows observable and/or measurable stabilization, reduction or absence of one or more signs and symptoms of a lysosomal storage disease, preferably NP-C such as, e.g., cerebellar ataxia, dysarthria, vertical gaze palsy, dysmetria, dysphagia, psychotic episodes, and dementia. It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean "substantial," which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved. In the context of this application, the terms "prevention" or "preventing" of a disorder or disease refers to a compound that, in a statistical sample, reduces the occurrence of symptoms of a disorder or disease in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. For example, preventing a lysosomal storage disease includes preventing or delaying the initiation of, preventing, delaying, or slowing the progression or advancement of, and/or reversing the progression of a disease as specified herein. As used herein, prevention of a disorder or a disease as specified herein, such as a lysosomal storage disease, also includes preventing a recurrence of one or more signs or symptoms said disorder or disease. A medicament according to the invention is administered to a subject in need thereof in an effective amount (i.e., amount that have desired therapeutic effect). Preferably, an effective amount refers to an amount of an inhibitor according to the invention comprised in said medicament. The dose and dosage regimen will depend upon the degree of the infection in the subject, the characteristics of the particular inhibitor according to the invention, e.g., its therapeutic index, the subject, and the subject's history. Certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the medicaments according to the invention can include a single treatment or a series of treatments. The effective amount may be determined during pre-clinical trials and clinical trials by methods familiar to physicians and clinicians. An effective amount of a peptide useful in the methods may be administered to a subject in need thereof by any of a number of well-known methods for administering pharmaceutical compounds. Dosage, toxicity and therapeutic efficacy of a medicament according to the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Medicaments that exhibit high therapeutic indices are preferred. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any medicament according to the invention, the therapeutically effective dose can be estimated initially from cell culture assays. Double mutants In a further aspect, the invention provides an organelle (preferably an endosome or a lysosome), a cell fraction, a cell, tissue, organ or subject comprising a mutation in an NPC1 or NPC2 gene, preferably an NPC1 gene, and a mutation in an PLA2G15 gene. An organelle, a cell fraction, a cell, tissue, organ or subject according to this aspect may be called a double mutant according to the invention. In specific aspects, a double mutant according to the invention is obtainable by combining an organelle (preferably an endosome or a lysosome), a cell fraction, a cell, tissue, organ or subject comprising a mutation in an NPC1 or NPC2 gene, preferably an NPC1 gene, with an organelle (preferably an endosome or a lysosome), a cell fraction, a cell, tissue, organ or subject comprising a mutation in an PLA2G15 gene. More preferably, said combining is a hybridisation. In specific aspects, said mutations in said NPC1 or NPC2 gene and said PLA2G15 gene result in a decreased expression level of or an expression of a defective NPC1 or NPC2 protein and PLA2G15 protein, respectively. A decreased expression level means an expression level lower than a normal expression level, preferably decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01, wherein a normal expression level is defined as the expression level of in a corresponding organelle (preferably an endosome or a lysosome), cell fraction, cell, tissue, organ or subject not comprising a corresponding mutation. In the context of this application, a defective NPC1 or NPC2 protein is an NPC1 or NPC2 protein whose cellular activity is decreased, preferably decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 relative to an NPC1 or NPC2 protein expressed in a healthy subject, or no longer comprises such cellular activity. In specific aspects, a double mutant according to the invention is a non-human animal, more preferably a non-human vertebrate, most preferably a non-human mammal. Assays In an aspect, the invention provides a method for screening or identifying an inhibitor according to the invention. In specific aspects, the invention provides a method for screening or identifying an inhibitor according to the invention comprising a competitive assay. Preferably, the competitive assay comprises the steps of (a) mixing two types of cells, preferably in a 1:1 ratio, wherein the types of cells differ in the level and/or the type of NPC1 or NPC2 and/or PLA2G15 expressed, and (b) incubating part of the mixed cells in the presence of a compound and incubating another part of the mixed cells in the absence of the compound, (c) monitoring one or more cell viability parameters of each type of cells during both incubations. Suitable examples of cell viability parameters are, without being limiting, the number of cells (e.g. competitive growth assay), the number of cell deaths (e.g. TUNEL assay) or metabolic activity (e.g. XTT assay, Resazurin asay). Suitable types of cells may be selected, without being limiting, from wild type, NPC1 or NPC2 knock-out (NPC1 KO or NPC2 KO), PLA2G15 knockout (PLA2G15 KO) or (NPC1/NPC2+PLA2G15) double knockout (DKO) cells, wherein in each of these cells wild-type or mutant PLA2G15 may be overexpressed, wherein the two types of cells should differ as described above, preferably wherein the cells are HAP1 cells. Preferably, NPC1 or NPC2 is NPC1. In more specific aspects, the invention provides a method for screening or identifying an inhibitor according to the invention comprising a competitive growth assay (i.e. a type of competitive assay as described above). Preferably, the competitive growth assay comprises the steps of (a) mixing two types of cells in a 1:1 ratio, wherein the types of cells differ in the level and/or the type of NPC1 or NPC2 and/or PLA2G15 expressed, and (b) incubating part of the mixed cells in the presence of a compound and incubating another part of the mixed cells in the absence of the compound, (c) monitoring the number of each type of cells during both incubations. Wherever reference is made to a competitive assay in this application, this type of assay is meant, unless explicitly mentioned otherwise. Suitable types of cells may be selected, without being limiting, from wild type, NPC1 or NPC2 knock-out (NPC1 KO or NPC2 KO), PLA2G15 knockout (PLA2G15 KO) or (NPC1/NPC2+ PLA2G15) double knockout (DKO) cells, wherein in each of these cells wild-type or mutant PLA2G15 may be overexpressed, wherein the two types of cells should differ as described above, preferably wherein the cells are HAP1 cells. The number of cells of the types of cells in the incubations may be monitored (i.e. measured) via fluorescence- activated cell sorting (FACS). The difference between the incubation with and the incubation without the compound in the ratio of the number of cells of each type, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days after the start of the incubations, is related to the suitability of the compound as an inhibitor for use as described herein. This difference can easily be interpreted by the skilled person in view of the clinical mechanism described herein. Preferably, NPC1 or NPC2 is NPC1. As a specific example, and without being limiting, the competitive growth assay may comprise the steps of (a) mixing NPC1 knock-out (NPC1 KO) HAP1 cells with PLA2G15-NPC1 double knock-out (DKO) HAP1 cells in a 1:1 ratio; (b) incubating part of the mixed cells in the presence of a compound and incubating another part of the mixed cells in the absence of the compound, (c) monitoring the number of KO and DKO cells during both incubations. The difference between the incubation with and the incubation without the compound in the ratio of the number of DKO cells to the number of KO cells positively correlates with the suitability of the compound as an inhibitor for use as described herein. In another specific embodiment, said for screening or identifying an inhibitor relates to a method to measure cellular target engagement of inhibitors against a specific serine hydrolase enzyme, in a background containing many other serine hydrolases. The method is in principle applicable for all serine hydrolase enzymes, however here it is exemplified for PLA2G15. At present there is no cellular assay for PLA2G15. For many other serine hydrolases there may be functional cellular assays, however cellular assays that directly interrogate their enzymatic activity do not exist for many. Further embodiments of the method for screening or identifying PLA2G15 inhibitors suitable for the treatment of lysosomal storage disorders, metabolic diseases, liver and kidney diseases, HIV, cancers, and neurodegenerative disorders are described herein. The method comprises several essential steps. Initially, a candidate compound is contacted with the PLA2G15 protein in vitro, and its binding affinity is determined. A compound is selected if it demonstrates a binding affinity with a half maximal inhibitory concentration (IC50) of 50 µmol/L or less for the PLA2G15 protein, as determined by an enzymatic activity assay. The enzymatic activity can suitably be assessed using two types of assays, which can be employed separately or in combination to screen and select candidate compounds. Firstly, an enzymatic assay, as described in Example 3, involves measuring the hydrolysis of a substrate such as 4-nitrophenyl butyrate by PLA2G15 in vitro. This assay provides a direct measure of the compound's ability to inhibit PLA2G15 enzymatic activity. Secondly, an enzymatic assay performed in cells, as described in Example 4, involves treating cultured cells expressing PLA2G15 with the candidate compound. This assay evaluates the compound's efficacy in inhibiting PLA2G15 activity within a cellular context, thus providing insights into the compound's performance in a more physiologically relevant environment. To further ensure the suitability of the candidate compounds, the method preferably includes assessing the impact of the candidate compound on phospholipid accumulation. This assessment involves treating cultured cells human derived cells, preferably primary and/or immortalized cells, preferably phagocytic cells, preferably microglial cells, with the candidate compound. The cells are then stained with a lipid-specific dye, such as Nile Red, BODIPY, or Oil Red O, to detect and quantify phospholipid content. Phospholipid levels in the treated cells are measured using fluorescence microscopy or a fluorescence plate reader, or using flow cytometry, ensuring accurate quantification as outlined in Example 6. A compound is selected if it does not cause an increase in phospholipid accumulation compared to suitable control cells. Additionally, the method encompasses a thorough evaluation of the candidate compound’s cytotoxicity to ensure it does not adversely affect cell viability. This step is crucial to confirm the therapeutic potential of the compound without detrimental effects on the cells. Further evaluation can also include testing the selected candidate compounds in animal models of lysosomal storage diseases to validate their efficacy and safety in vivo. In summary, this method involves a comprehensive screening and selection process for PLA2G15 inhibitors, incorporating detailed enzymatic activity assays both in vitro and in cellular contexts as demonstrated in Examples 3 and 4, respectively, and phospholipid accumulation assessments as demonstrated in Example 6. By combining these steps, the method ensures the identification of potent and safe PLA2G15 inhibitors, suitable for therapeutic applications in treating a variety of diseases associated with lysosomal dysfunction. A complication arises measuring enzymatic activity (or conversely inhibition) of a single serine hydrolase such as PLA2G15 due to lack of specific reagents: existing reagents will pick up signal from many other serine hydrolases present in the cell and a specific window is unlikely to exist. This is exemplified by reference [1] which describes the activity-based labelling of serine hydrolases in tissue lysates and shows that for every serine hydrolase of interest, a dozens of additional serine hydrolases will be present in a given sample. A key part of the solution presented below is the use of an activity probe, for instance the TAMRA-FP probe or similar activity based probe. These have been used before to label serine hydrolases in activity-based protein profiling experiments, for example in reference [2]. However, such experiments were exclusively performed in lysates and not in live cells, so technically even when those experiments were performed with inhibitors, no good measure of intracellular target engagement was obtainable. Furthermore, those experiments were performed by gel electrophoresis to distinguish enzyme of interest from other serine hydrolases present in a sample: this will not work (1) for non-abundant serine hydrolases, (2) in cases where electrophoretic separation between the enzyme of interest and another protein is poor. Finally, this experimental setup is laborious and time-consuming making routine compound testing an impractical proposition.

The solution is to employ a cell where overexpression of the serine hydrolase of interest can be induced at will, combined with a suitable control, preferably another cell expressing the enzyme of interest carrying a fully inactivating mutation. Said cell and the control cell are treated with the inhibitor of interest, followed by the activity probe. This probe reacts with and irreversibly labels serine hydrolases provided they are enzymatically active, and a successful inhibitor will diminish this labelling efficiency. Because of the overexpression of the enzyme of interest, a signal is obtained that can be distinguished from the background of all other serine hydrolases. This background can be determined by measuring the signal in the control cell in which only the background, off-target labelling occurs. Quantification of the residual labelling efficiency may suitably be performed in a flow cytometry analyzer and yields a signal inversely proportional to the inhibitor potency. [1] Bachovchin et al. Proc. Natl. Acad. Sci. U.S.A.2010, 107(49), 20941. [2] Zhou et al. ACS Chem Biol.2019, 14, 164. In a specific embodiment, the invention provides a method for determining the inhibition of an enzyme by a putative inhibitor in a cell comprising steps of: • Providing a putative inhibitor to a cell expressing the serine hydrolase of interest and a control cell, • Adding a labelled activity probe containing a reactive group capable of binding to said enzyme, preferably a fluorophosphonate group, • Measuring the signal of the signal of the labelled activity probe in said cell and control cell. • Determine the inhibition of the enzyme activity by the putative inhibitor comparing the labelling efficiency in said cell and control cell. In a preferred embodiment, serial dilutions of said putative compound are provided. Preferably, said cell is a cell with an inducible expression system containing said enzyme. Preferably, said enzyme is a serine hydrolase, more preferably PLA2G15. Preferably, said inducible expression system is a Tet-inducible PLA2G15[WT]-EGFP or a PLA2G15[S198A]-EGFP. Preferably, PLA2G15[S198A] cells to serve as controls. Preferably, an uninduced PLA2G15[WT] cell is used a control. In a preferred embodiment, flow cytometry is used to measure signals of the labelled activity probes. Preferably, said enzyme is expressed as a fluorescent protein, preferably a GFP construct. An advantage thereof is that a fluorescent protein combined with a suitable fluorescently labelled activity probe can display Förster resonance energy transfer (FRET) activity. A skilled person in the art knows which fluorescent dyes can be combined to enable FRET activity. In a preferred embodiment, said activity probe is labelled with TAMRA and said enzyme is a GFP labelled PLA2G15. 4-Nitrophenyl butyrate activity assay In another aspect, the invention provides a PLA2G15 enzyme inhibition assay. The compounds p-nitrophenol A and B are substrates that can be used to detect PLA2G15 enzyme activities. The PLA2G15 enzyme catalyzes the hydrolysis of ester bonds between an acyl moiety and p-nitrophenol: The release of 4-nitrophenolate anion (yellow at pH values above its pKa of 7.08 at 22 °C) is determined as a strong increase in absorbance at 405 nm. Method for Screening and Selecting PLA2G15 Inhibitors The invention provides a comprehensive method for screening and selecting PLA2G15 inhibitors suitable for therapeutic applications in lysosomal storage disorders, metabolic diseases, liver and kidney diseases, HIV, cancers, and neurodegenerative disorders. The method comprises the following sequential steps: a) Contacting Candidate Compounds: Candidate compounds are contacted with isolated, purified, or recombinantly expressed PLA2G15 protein. This step provides a foundational assessment of compound-protein interactions. The PLA2G15 protein may be expressed in bacterial, insect, or mammalian systems and purified using standard techniques such as affinity chromatography, reversed-phase high-performance liquid chromatography (HPLC), flash silica gel chromatography, or preparative thin-layer chromatography (prep-TLC), depending on the specific requirements of the purification process. b) Binding Affinity Measurement: Binding affinity is optionally determined using methods such as surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), or fluorescence polarization assays. These techniques quantitatively measure the interaction strength between the candidate compound and PLA2G15. A preferred embodiment involves measuring the hydrolysis of a specific substrate, such as 4-nitrophenyl butyrate, in vitro. The reaction generates a measurable chromophore or fluorophore, and the reduction in the rate of hydrolysis in the presence of the candidate compound is indicative of inhibition. A compound demonstrating a half-maximal inhibitory concentration (IC50) of 50 µmol/L or less is considered suitable for further evaluation. In a preferred embodiment, binding affinity thresholds may be defined as less than 40 µmol/L, 30 µmol/L, 20 µmol/L, 10 µmol/L, 5 µmol/L, 4 µmol/L, 3 µmol/L, 2 µmol/L, 1 µmol/L, 0.5 µmol/L, 0.1 µmol/L, 0.03 µmol/L, or 0.01 µmol/L. These thresholds ensure specificity and sufficient interaction strength to merit further investigation. c) Enzymatic Activity Assay In a preferred embodiment, cells expressing PLA2G15 are treated with the candidate compound in a cellular context, and the enzymatic activity of PLA2G15 is evaluated within the physiological environment. This assay accounts for cellular factors that may influence the compound's activity, such as cell permeability, intracellular localization, or metabolic stability. Preferably, the enzymatic activity of PLA2G15 in the presence of the candidate compound is assessed using cellular enzymatic activity assays, which allow for evaluation under physiologically relevant conditions. In a preferred embodiment, wildtype cells and disease-model cells are used to evaluate the effect of the candidate compound. Wildtype cells are preferably used to establish baseline enzymatic activity under normal conditions. These cells are preferably genetically unmodified and express functional PLA2G15. Preferably, the enzymatic activity in wildtype cells is quantified by measuring substrate hydrolysis (e.g., using 4-nitrophenyl butyrate as a substrate) in the absence and presence of the candidate compound. Comparison with vehicle-treated controls is preferably used to assess whether the candidate compound inhibits PLA2G15 without disrupting normal cellular processes. Disease-model cells are preferably employed to mimic the pathology of lysosomal storage disorders or other conditions associated with lysosomal dysfunction. For example, NPC1-deficient cells, which lack functional NPC1 protein, are a preferred disease model for Niemann-Pick type C (NPC) disease. These cells are preferably genetically modified, chemically treated, or otherwise altered to replicate key features of the disease state, such as lysosomal lipid accumulation. In a preferred embodiment, disease-model cells are generated using techniques such as CRISPR/Cas9, RNA interference, or homologous recombination to inactivate or alter genes of interest, such as PLA2G15, NPC1, or NPC2. Alternatively, chemical treatments (e.g., lysosomal inhibitors or cholesterol-accumulating agents) may be used to induce disease-like phenotypes. Suitable disease-model cell lines preferably include HAP1, HeLa, ARPE19, or SH-SY5Y cells, but other immortalized or primary cells derived from patient samples or disease-model animals may also be used. In a further preferred embodiment, activity-based probes specific to PLA2G15 are employed to directly measure enzymatic activity in cellular assays. These probes react with enzymatically active PLA2G15, allowing for quantification of activity in the presence and absence of the candidate compound. For example, TAMRA-labeled fluorophosphonate probes are preferred for monitoring the residual enzymatic activity of PLA2G15. However, other probes known in the art may also be used. Assays are preferably conducted over a time period ranging from 24 to 72 hours, allowing sufficient time to capture the compound's effect on enzymatic activity. High-throughput assay formats, such as 96-well or 384- well plates, are preferably used to enable efficient data collection. Enzymatic activity is preferably measured using fluorescence-based detection of substrate hydrolysis, and results are preferably normalized to cell viability using parallel assays, such as DAPI staining, MTT, or ATP-based methods. Other suitable methods for assessing cell viability may also be employed. In a preferred embodiment, primary and/or immortalized cells are used as cellular models for disease or wild type cells. Suitable cell types include phagocytic cells, and preferably microglial cells which are particularly relevant due to their lysosomal activity and role in lysosomal storage disorders. Specific examples of preferred cellular models include: • Human microglial cells (HMC3): These cells are preferred for their relevance in studying lysosomal and neurodegenerative diseases. Both wildtype and genetically modified versions (e.g., PLA2G15 knockout or overexpressing cells) are preferably used to evaluate the activity of candidate compounds. • Human monocytic cells (THP1): These cells are preferably differentiated into macrophage-like cells, providing a model for lysosomal activity in phagocytic contexts. A candidate compound is preferably selected if it significantly inhibits PLA2G15 enzymatic activity in cellular assays while maintaining cell viability. At the end of the screening process, data from step b (binding affinity) and step c (enzymatic activity) are preferably integrated to ensure robust candidate selection. This dual-step approach offers several advantages: • Enhanced Specificity: Compounds that bind to but do not inhibit PLA2G15 are excluded, reducing false positives. • Functional Validation: Cellular enzymatic activity assays confirm that the compound not only interacts with PLA2G15 but also modulates its function, which is critical for therapeutic efficacy. • Comprehensive Evaluation: By combining binding affinity data with enzymatic activity results, the method ensures the identification of compounds with both strong binding specificity and functional inhibition. This approach is exemplified in Examples 3 and 4, where both biochemical and cellular enzymatic assays are performed to validate the inhibitory effects of candidate compounds. Together, these steps provide a reliable framework for selecting PLA2G15 inhibitors with therapeutic potential. d) Phospholipid Accumulation Assay: In a preferred embodiment, the effect of the candidate compound on lysosomal phospholipid accumulation is further assessed using a fluorescence-based assay. In this step, wildtype and disease-model cells are preferably treated with the candidate compound alongside appropriate controls, such as a reference inhibitor or a vehicle control. The treated cells are preferably stained with a lipid accumulation dye or a neutral lipid-specific dye, such as Nile Red, BODIPY, or Oil Red O, and fluorescence intensity is measured to assess intracellular lipid levels. Fluorescence intensity in wildtype cells treated with the candidate compound is preferably compared to vehicle-treated controls to ensure that the compound does not result in accumulation of phospholipids. Disease-model cells, such as NPC1-deficient cells, are preferably employed to mimic the cellular pathology of lysosomal storage disorders. Cultured wildtype and disease-model cells are preferably treated with the candidate compound, reference inhibitor, and vehicle control for a preferred duration of 24 to 72 hours. Fluorescence intensity is preferably measured using fluorescence microscopy, a fluorescence plate reader, or flow cytometry. High-throughput assay formats, such as 96-well or 384-well plates, are preferred for efficient data collection. Fluorescence intensity is preferably normalized to viable cell counts using parallel viability assays, such as DAPI staining, MTT, or ATP-based methods, ensuring accurate quantification. A candidate compound is preferably selected if it does not induce lysosomal phospholipid accumulation exceeding a predefined threshold in wildtype or disease model cells compared to vehicle-treated controls. This threshold is preferably set at ≤10%, 15%, or 20% above baseline fluorescence intensity. Cholesterol Accumulation Assay In a preferred embodiment, the effect of the candidate compound on lysosomal cholesterol accumulation is assessed using a fluorescence-based assay as described in Example 8. This is particularly relevant for testing compounds for treatment of a disease characterized by cholesterol accumulation, such as NP-C. Disease model cells are treated with the candidate compound for 24–72 hours, stained with a lysosomal marker and a cholesterol-specific probe (e.g., Alexa-647-labeled recombinant PFO), and analyzed to quantify lysosomal cholesterol levels. In a preferred embodiment, the compound is selected if it reduces cholesterol accumulation in disease-model cells without significantly altering cholesterol levels in wildtype cells. In another embodiment, a compound is selected if it significantly reduces lysosomal cholesterol accumulation in disease model cells compared to untreated controls or cells treated with the vehicle. In a further preferred embodiment, therapeutic efficacy is assessed through disease-specific assays, such as the cholesterol accumulation assay described in Example 8. In this assay, disease model cells, such as NPC1- deficient cells are treated with the candidate compound, and lysosomal cholesterol levels are quantified using a cholesterol-specific probe, such as Alexa-647-labeled perfringolysin O (PFO), in conjunction with a lysosomal marker. Wildtype cells treated under identical conditions serve as controls. In a further preferred embodiment, the ratio of fluorescence intensities between wildtype and disease-model cells treated with the candidate compound may also be evaluated. A compound is selected if this ratio is similar to or better than the ratio observed with the reference inhibitor, indicating both safety in wildtype cells and efficacy in disease-model cells. By applying these specific testing and comparison criteria, the assay provides a clear and reproducible framework for selecting or rejecting candidate compounds based on their safety and therapeutic potential, ensuring that only suitable PLA2G15 inhibitors are advanced for further development. In a specific embodiment, the method includes all three optional steps (binding affinity, enzymatic activity, and phospholipid accumulation assessments). The selection criteria are as follows: • If binding affinity is determined, the candidate compound demonstrates an IC50 of 50 µmol/L or less for PLA2G15 protein. • If enzymatic activity is measured, the candidate compound shows significant inhibition of PLA2G15 enzymatic activity. • If phospholipid accumulation is assessed, the candidate compound does not cause an increase in intracellular lipid content compared to suitable controls. In a preferred embodiment, the method integrates these assessments in a tiered approach: 1. Initial screening for binding affinity using in vitro assays. 2. Functional evaluation of enzymatic inhibition in biochemical and/or cellular contexts. 3. Assessment of cellular lipid metabolism to ensure the candidate compound does not induce phospholipid accumulation. The method provides flexibility in its implementation, allowing one or more of the optional steps to be performed. At least one of the steps involving binding affinity (step b) or enzymatic activity (step c) must be included to ensure the candidate compound directly interacts with and inhibits PLA2G15. This method is exemplified by Examples 3, 4, and 6, which demonstrate the enzymatic activity assays, cellular assays, and phospholipid accumulation tests, respectively. Together, these steps provide a comprehensive approach for identifying PLA2G15 inhibitors that meet the therapeutic requirements for treating diseases associated with lysosomal dysfunction. The method of the invention is applicable to various types of candidate compounds, including small molecules, antibodies, antibody fragments, aptamers, and nucleic acids. Small molecules are particularly preferred due to their ability to penetrate cells and inhibit enzymatic activity directly. Antibodies and antibody fragments provide specificity in extracellular or membrane-associated PLA2G15 inhibition, while aptamers and nucleic acids offer emerging modalities with high binding specificity and stability. The method preferably involves determining the IC50 value of the candidate compound using dose-response curves. Candidate compounds are tested at a range of concentrations, typically spanning several orders of magnitude, to generate a sigmoidal dose-response curve. The IC50 value, representing the concentration at which enzymatic activity or binding affinity is reduced by half, is calculated using curve-fitting algorithms. This approach provides a quantitative assessment of compound potency. The method of the invention preferably further includes evaluating the cytotoxicity of candidate compounds. Cytotoxicity assays, such as MTT, resazurin-based assays, or ATP-based viability measurements, may be performed in parallel with functional assays to ensure that selected compounds do not adversely affect cell viability. This step may confirm the therapeutic potential of the compound while minimizing off-target effects. The method preferably involves further testing of selected candidate compounds in animal models of lysosomal storage diseases. Suitable models include NPC1-knockout mice for Niemann-Pick disease type C or CLN3-knockout mice for Batten disease. These in vivo studies assess the compound’s pharmacokinetics, biodistribution, efficacy in restoring lysosomal function, and overall safety profile. Definitions All documents cited in the present specification are hereby incorporated by reference in their entirety. Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention. Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is made to the standard handbooks, to the general background art referred to above and to the further references cited therein. As used herein, the singular forms 'a', 'an', and 'the' include both singular and plural referents unless the context clearly dictates otherwise. The terms 'comprising', 'comprises' and 'comprised of' as used herein are synonymous with 'including', 'includes' or 'containing', 'contains', and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. Physiological conditions are defined in the context of this application as typical environmental conditions in a vertebrate, mammalian or human cell or tissue that is in homeostasis and is not subject to extraordinary external stress. Preferably, physiological conditions mean a temperature from 25°C up to 45°C, more preferably from 30°C up to 40°C. A concentration is preferably a molar concentration, preferably a molar concentration per weight or per volume, most preferably measured under physiological conditions. A subject is defined in the context of this application as a (living) organism, unless explicitly stated otherwise. A subject may be any organism, including invertebrates and vertebrates. Preferably, a subject is a vertebrate. More preferably, a vertebrate is a starfish or a mammal. Even more preferably, a mammal is a rat, a mouse, dog, monkey, a rabbit or a human. Most preferably, a mammal is a human. In an alternative specific aspect, a subject is a non-human animal, more preferably a non-human vertebrate, most preferably a non- human mammal. An organelle is preferably a lysosome or an endosome, more preferably a lysosome. An endosome is preferably a late endosome. An increase of a parameter by a factor equal to or higher than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or higher than A*X. An increase of a parameter by a factor equal to or lower than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or lower than A*X. A decrease of a parameter by a factor equal to or lower than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or lower than A*X. A decrease of a parameter by a factor equal to or higher than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or higher than A*X. A parameter that is essentially the same as in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or as in a corresponding healthy subject, preferably means that the value of said parameter cannot be distinguished by a skilled person from the value of a corresponding parameter in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or in a corresponding healthy subject, and/or that the value of said parameter would be interpreted by a skilled person as measured in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or in a corresponding healthy subject. An alteration of a parameter which is significantly smaller after introduction of an inhibitor in a composition, organelle, cell fraction, cell, membrane, tissue, organ or subject preferably means that the absolute difference between the value of said parameter and the value of a corresponding parameter in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or in a corresponding healthy subject is decreased by a factor equal to or lower than 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 after said introduction. Any parameter referred to herein is preferably determined using the specific method, assay or methodology described herein. Where the present specification does not mention or describe a specific method, assay or methodology for determining said parameter, said parameter can be measured in a manner suitable per se, as will be clear to the skilled person based upon reading the present disclosure. A small molecule is defined in the context of this application as a term commonly used in molecular biology and pharmacology for referring to an organic compound having a low molecular weight (< 900 daltons) with a size on the order of 1 nm. Because of their upper molecular-weight limit of 900 daltons, small molecules can rapidly diffuse across cell membranes to reach intracellular sites of action (e.g. Golgi). Preferably, a small molecule has a molecular weight lower than 500 daltons. Each amino acid sequence described herein by virtue of its identity or similarity percentage (at least 60%) with a given amino acid sequence respectively has in a further specific aspect an identity or a similarity of at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identity or similarity with the given amino acid sequence respectively. In a specific aspect, sequence identity or similarity is determined by comparing the whole length of the sequences as identified herein. Unless otherwise indicated herein, identity or similarity with a given SEQ ID NO means identity or similarity based on the full length of said sequence (i.e. over its whole length or as a whole). Sequence identity is defined in the context of this application as a relationship between two or more amino acid (polypeptide or protein) sequences or two or more nucleic acid (polynucleotide) sequences, as determined by comparing the sequences. The identity between two amino acid sequences is preferably defined by assessing their identity within a whole SEQ ID NO as identified herein or part thereof. Part thereof may mean at least 50% of the length of the SEQ ID NO, or at least 60%, or at least 70%, or at least 80%, or at least 90%. In the art, sequence identity also means the degree of sequence relatedness between amino acid sequences, as the case may be, as determined by the match between strings of such sequences. Sequence similarity between two amino acid sequences is determined by comparing the amino acid sequence and its conserved amino acid substitutes of one polypeptide to the sequence of a second polypeptide. Sequence identity and similarity can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heine, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48:1073 (1988). Preferred methods to determine sequence identity are designed to give the largest match between the sequences tested. Methods to determine sequence identity and similarity are codified in publicly available computer programs. Preferred computer program methods to determine sequence identity and similarity between two sequences include e.g. the GCG program package (Devereux, J., et al., Nucleic Acids Research 12 (1): 387 (1984)), BestFit, FASTA, BLASTN, and BLASTP (Altschul, S. F. et al., J. Mol. Biol. 215:403-410 (1990)), EMBOSS Needle (Madeira, F., et al., Nucleic Acids Research 47(W1): W636-W641 (2019)). The BLAST program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, MD 20894; Altschul, S., et al., J. Mol. Biol.215:403-410 (1990)). The EMOSS program is publicly available from EMBL- EBI. The well-known Smith Waterman algorithm may also be used to determine identity. The EMBOSS Needle program is the preferred program used. Preferred parameters for polypeptide sequence comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol. 48 (3):443-453 (1970); Comparison matrix: BLOSUM62 from Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA.89:10915-10919 (1992); Gap Open Penalty: 10; and Gap Extend Penalty: 0.5. A program useful with these parameters is publicly available as the EMBOSS Needle program from EMBL-EBI. The aforementioned parameters are the default parameters for a Global Pairwise Sequence alignment of proteins (along with no penalty for end gaps). Preferred parameters for nucleic acid comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol.48:443-453 (1970); Comparison matrix: DNAfull; Gap Open Penalty: 10; Gap Extend Penalty: 0.5. A program useful with these parameters is publicly available as the EMBOSS Needle program from EMBL- EBI. The aforementioned parameters are the default parameters for a Global Pairwise Sequence alignment of nucleotide sequences (along with no penalty for end gaps). Optionally, in determining the degree of amino acid (sequence) similarity, the skilled person may also take into account so-called "conservative" amino acid substitutions, as will be clear to the skilled person. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; a group of amino acids having acidic side chains is aspartate and glutamate; and a group of amino acids having sulphur-containing side chains is cysteine and methionine. Preferred conservative substitutions for each of the naturally occurring amino acids are as follows: Ala to Ser; Arg to Lys or Gln; Asn to Asp, His or Ser; Asp to Glu or Asn; Gln to Glu, Lys or Arg; Glu to Lys, Asp, Gln; His to Tyr or Asn; Ile to Leu, Val, or Met; Leu to Ile, Met or Val; Lys to Arg, Gln or Glu; Met to Val, Leu or Ile; Phe to Trp or Tyr; Ser to Thr, Ala or Asn; Thr to Ser; Trp to Tyr or Phe; Tyr to His, Trp or Phe; and Val to Ile, Leu or Met. Substitutional variants of the amino acid sequence disclosed herein are those in which at least one residue in the disclosed sequences has been removed and a different residue inserted in its place. Preferably, the amino acid change is conservative. Examples The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Example 1: In vivo validation of PLA2G15 as a target for NP-C disease: generation and characterization of Npc1:Pla2g15 double knockout mice PLA2G15 was identified by our Cell-Seq platform as a genetic modifier of NP-C as described in WO2016190743A1. Here we report on the validation of this potential target in a mouse model of NPC1 disease. To this end, exon 3 of Pla2g15 was removed in BALB/c mouse embryo’s using CRISPR/Cas9, to obtain Pla2g15 heterozygous (HET) and knockout (KO) mice. The resulting mouse line was crossed with Npc1 m1N/J, a commonly used mouse model for NP-C that recapitulates most features of the human disease, including shortened lifespan, cerebellar ataxia, accumulation of glycosphingolipids and neurodegeneration. Pla2g15 KO in the Npc1 m1N/J mouse model appeared to slow down disease progression as evident by an increased lifespan (~60%), reduced ataxia and delayed neurodegeneration. Methods The Pla2g15 knockout (KO) mouse model was created at Taconic Biosciences using CRISPR/Cas9. It was crossed with Npc1 m1N/J, the most commonly used NP-C mouse model (14), and Npc1 m1N/J homozygous (HOM) mice are considered a good model for human NP-C. Crossbreeding was used to obtain the following phenotypes (gene order: Npc1/Pla2g15): WT/WT, HOM/WT, HOM/HET, HOM/KO and WT/KO. For survival analysis, 12 mice (6 male / 6 female) of each genotype were generated, and monitored for clinical signs. Mice that showed signs of moribundity, chronic pain or distress or any of the following clinical symptoms were euthanized: high grade of weight loss (a chronic body weight loss of more than 20 % combined with a decreased general behavior or a persistent weight loss), severe cachexia, severe lethargy, high grade of immobility, high grade of dehydration, dyspnea, severe diarrhea, high grade of enlarged abdomen, severe icterus or anemia, uncontrolled bleeding from body orifice, persistent self-mutilation, severe large and/or deep skin lesions that are resistant to therapy (e.g. dermatitis, wounds), any condition interfering with food or water uptake (e.g. injuries, difficulty with ambulation), excessive or prolonged hyperthermia or hypothermia, discolored urine or inability to urinate, severe central nervous system symptoms (e.g. severe persistent tremor), paralysis, tumor (e.g. single tumor greater than 1.2 cm diameter in mice, up to 2.5 cm diameter in rats or greater than 10 % body weight). The rotarod assay was used to assess motor coordination by placing the mice on a rotating rod (four-lane- Rota Rod; Ugo Basile) that ran at a constant or an accelerating speed. If a mouse lost its balance and fell onto an underlying platform, the rod was automatically stopped to record a measure of the latency to fall as well as the speed at fall. Prior to the first test session, mice were habituated to the testing system, until they were able to stay on the rod at a constant speed of 2 rpm for approximately one minute. During testing, a single mouse was exposed to the apparatus three times for a 180 sec trial. The initial speed increased from 2 to 20 rpm over an accelerating time of 180 sec. If the mice fell, the session was over and the Ugo Basile Program stopped the timer. To measure neurofilament light chain (NF-l) levels, mice were sacrificed using intraperitoneal injection of Pentobarbital (600 mg/kg) at post-natal day 56, and blood plasma and cerebrospinal fluid (CSF) samples were obtained. After confirmation of deep anesthesia, CSF was obtained by dissection of the muscles and exposure of the foramen magnum. Upon exposure, a Pasteur pipette was inserted in an approximate depth of 0.3 - 1 mm into the cisterna magna. CSF was collected by suction and capillary action until flow fully ceased in 0.2 ml polypropylene PCR tubes. The tubes were spun briefly and immediately frozen in an upright position on dry ice. The tubes were stored at -80°C. The thorax was opened and blood was collected by heart puncture with a 23- gauge needle. Collected blood was then transferred to the sample tube (MiniCollect® K2EDTA (potassium ethylenediaminetetraacetic acid). The tube was inverted thoroughly to facilitate homogeneous distribution of the EDTA and prevent clotting. The blood samples were centrifuged at 3,000 x g for 10 min at room temperature (22°C). Plasma was transferred to a pre-labeled 1.5 ml LoBind Eppendorf tubes [1 x 40 µl (NF-L), 1 x 100 µL and 1 x rest aliquot], frozen on dry ice and stored at -80 °C. The NF-light® (Neurofilament-light) ELISA 10-7001 CE from UmanDiagnostics was used for analysis. For immunohistochemistry, Pla2g15 KO mice were crossed with a Npc1 knockout mouse model (Npc1 KO) where exons 2-9 were removed. All mice were on BALB/c background. The following genotypes were obtained (Npc1/Pla2g15): WT/WT, KO/WT, KO/KO and WT/KO, and animals were sacrificed at post natal day 57-60. Briefly, brain samples were processed, embedded and cryo-sectioned (7 to 10 sections per organ collected). The tissue samples were fixed in paraformaldehyde and then stored in EtOH; Three sections per organ were used for qualitative immunofluorescent labeling for Calbindin (Purkinje cells) and DAPI. Whole slides were scanned on a confocal microscope and the image evaluated for pathology. To generate NPC1 knockout HMC3 cells, wild type cells were infected with lentiviral constructs encoding for Cas9 and gRNAs targeting NPC1. After negative selection with puromycin, successful knockout was confirmed by western blot using an antibody against human NPC1 (Abcam ab134113). Cell lines were maintained as a polyclonal pool. For lipidomics, cells were plated in EMEM medium containing 10% fetal calf serum and 1% penicillin/streptomycin. Cells were subjected to 25 uM PLA2G15 inhibitor (dissolved in DMSO) or DMSO alone, and harvested after 48 hours. Harvesting was performed by trypsinization, and cells were washed with PBS, pelleted and snap frozen on dry ice. Results Pla2g15 KO improves motor coordination and extends lifespan in an NP-C mouse model The effect of Pla2g15 KO on motor coordination in NP-C was assessed using the rotarod assay. This assay measures the time that mice are able to stand on a rotating rod, and is a generally accepted measure of cerebellum-dependent motor coordination. The NP-C model (HOM/WT) has a clear defect in rotarod performance, as evidenced by a reduced time spent on the rotarod compared to WT/WT (Figure 1, data from 12 mice per genotype). Knockout of Pla2g15 in the disease model (HOM/KO) restores rotarod performance to WT/WT levels in post-natal week 6, and the performance remains stable at all time points tested. Knockout of Pla2g15 alone does not affect outcome of the rotarod. Thus, knockout of Pla2g15 improves motor performance in a mouse model of NP-C. In the same set of mice, life span was measured as a widely used readout for disease severity in NP-C (14). HOM/WT mice displayed a shortened lifespan with a median of 71 days (Figure 2, data from 12 mice per genotype). While HOM/HET only moderately affects lifespan (median of 77 days), HOM/KO shows a significantly extended lifespan with a median of 117 days. WT/KO and WT/WT mice survived the entire length of the study, as anticipated. Thus, Pla2g15 knockout extended the lifespan of NP-C mice. Additionally, these data suggest feasibility of PLA2G15 inhibition in vivo without causing major adverse events. Knockout of Pla2g15 reduces neurodegeneration in NP-C NP-C is characterized by profound neurodegeneration in humans and in mouse models, which underlies many of the neurological phenotypes of the disorder. Neurofilament light chain (NF-l) is an axonal cytoskeleton protein that is commonly used as biomarker to measure neurodegeneration. To measure NF-l levels, mice were sacrificed at day 56, which is around the peak of disease progression in Npc1 m1N/J (14), and collected blood plasma and cerebrospinal fluid (CSF) samples. In both fluids, we observed a strong increase in NF-l concentration in HOM/WT, indicating a high degree of neurodegeneration (Figure 3, data from 8 mice per genotype). Importantly, NF-l levels were substantially reduced in HOM/KO mice, indicating that knockout of Pla2g15 in NP-C mice reduces neurodegeneration. Pla2g15 KO ameliorates accumulation of glycosphingolipids in brain and liver NP-C interferes with the lysosomal degradation of glycosphingolipids and sphingomyelin, leading to their accumulation across multiple tissues in mice and men (15). A similar accumulation is observed in a wide range of other lysosomal storage diseases, indicating that lipid accumulation contributes to pathology (15). To test if Pla2g15 KO affects lipid accumulation in NP-C, we harvested brain and liver from post-natal day 56 mice for untargeted lipidomics. In brain, we observed a slight reduction of sphingomyelin and hexosylceramides (which includes glucosylceramide and galactosylceramide) when comparing HOM/WT with HOM/KO. Strong reductions were observed for dihexosylseramides (which includes lactosylceramides), GM2 and GM3, and a small decrease in sulfatide (Figure 4). In liver, similar effects were overall more profound than in brain. Strong reductions were observed for the concentration of lipid class in HOM/KO compared to HOM/WT (Figure 5). Knockout of Pla2g15 in wild-type background (WT/KO) had no obvious effect on glycosphingolipid levels compared to WT/WT. To further address the role of PLA2G15 in glycosphingolipid accumulation, cultured microglial HMC3 NPC1 KO cells were exposed to inhibitors of PLA2G15 (compounds SC3863 and SC4611, 48 h exposure at 25 μM). Both compounds reduced the accumulation of hexosylceramides in NPC1 KO cells (Figure 6), indicating that pharmacological inhibition of PLA2G15 ameliorates glycosphingolipid accumulation. Thus, deletion or inhibition of PLA2G15 lessens sphingomyelin and glycosphingolipid accumulation in disease models of NP-C, and might be beneficial for other lysosomal storage diseases. Pla2g15 KO delays degeneration of cerebellar Purkinje cells NP-C causes progressive degeneration in the cerebellum, in particular of primary Purkinje cells, and this contributes to cerebellar ataxia phenotypes. To test the effect of Pla2g15 KO on cerebellar neurodegeneration, mice were sacrificed at post-natal day 57-60, and stained brain sections for the specific Purkinje cell marker Calbindin D (Data from 1 mouse per genotype). In the NP-C mouse model (KO/WT), a clear loss of Purkinje cells was observed, however, in KO/KO, only a minor loss of Calbindin D staining was observed. WT/KO showed Calbindin D staining patterns comparable to WT/WT. This data indicates that removal of Pla2g15 delays cerebellar neurodegeneration in an NP-C mouse model. Conclusion Based on cellular experiments, it is hypothesized that Pla2g15 is a genetic modifier for NPC, and that knockout of Pla2g15 lessens the disease phenotype. Here, evidence is presented supporting that Pla2g15 knockout delays NP-C progression to propose PLA2G15 as target for the treatment of NP-C. Pla2g15 knockout reduced neurodegeneration in NP-C mice, as evidenced by lower levels of NF-l in CSF and plasma, as well as a reduced loss of Calbindin D-positive Purkinje cells in the cerebellum. Furthermore, the Pla2g15 knockout improved performance in the rotarod test, indicating improvement in cerebellar motor performance. The accumulation of sphingomyelin and glycosphingolipids, hallmarks of multiple lysosomal storage diseases, is reduced after Pla2g15 KO or pharmacological inhibition in cellular models. Finally, Pla2g15 KO led to a significant increase in lifespan in an NP-C mouse model. Thus, deletion of PLA2G15 expression delays the progression of NP-C in mice, and its inhibition is an attractive candidate to treat lysosomal storage diseases. Example 2: Synthesis of PLA2G15 inhibitors Synthesis of SC-003863 Synthetic Scheme 1: Synthesis of Intermediate 5a Synthetic Scheme 2: Synthesis of SC-003863 Experimental Procedure: Synthesis of compound 3a A mixture of compound 1a (500 mg, 4.09 mmol, 1 eq), 4-methylbenzenesulfonyl chloride (936.74 mg, 4.91 mmol, 1.2 eq), DMAP (50.02 mg, 409.46 μmol, 0.1 eq), DIEA (1.59 g, 12.28 mmol, 2.14 mL, 3 eq) in DCM (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 h under N2 atmosphere. EtOAc (20 mL) and water (20 mL) were added and layers were separated. The aqueous phase was extracted with EtOAc (10 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 1: 0 to 3: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.46) to give compound 3 (600 mg, crude) as white solid. ¹H NMR: (400 MHz, CDCl3) δ = 7.80 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.07 (d, J = 6.6 Hz, 2H), 2.70 - 2.58 (m, 2H), 2.47 (s, 3H), 2.36 - 2.23 (m, 2H). Synthesis of compound 4a A mixture of compound 3a (600 mg, 2.17 mmol, 1 eq), potassium; ethanethioate (496.02 mg, 4.34 mmol, 2 eq) in DMF (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 h under N2 atmosphere. The reaction mixture was cooled to room temperature. EtOAc (20 mL) and water (15 mL) were added and layers were separated. The aqueous phase was extracted with EtOAc (5 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 1: 0 to 3: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.43) to give compound 4a (400 mg, crude) as white solid. ¹H NMR: (400 MHz, CDCl3) δ = 3.04 (d, J = 7.4 Hz, 2H), 2.74 - 2.61 (m, 2H), 2.43 - 2.36 (m, 1H), 2.35 (s, 3H), 2.31 - 2.17 (m, 2H). Synthesis of compound 5a To a mixture of NCS (592.77 mg, 4.44 mmol, 4 eq), HCl (2 M, 1.11 mL, 2 eq) in ACN (3 mL) was added compound 4a (200 mg, 1.11 mmol, 1 eq) at 0 °C. Then the mixture stirred at 0 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate = 1: 0 to 3: 1, TLC: Petroleum ether: Ethyl acetate = 5: 1, Rf = 0.47) to give compound 5a (200 mg, crude) as white solid. ¹H NMR: (400 MHz, CDCl3) δ = 3.87 (d, J = 6.9 Hz, 2H), 3.04 - 2.87 (m, 3H), 2.63 - 2.48 (m, 2H). Synthesis of compound 3 To the mixture of compound 1 (25 g, 111.86 mmol, 1 eq, HCl) in AcOH (60 mL) was added compound 2 (14.56 g, 111.86 mmol, 14.16 mL, 1 eq). The mixture was stirred at 100 °C for 1 h. The reaction mixture diluted with EtOAc (60 mL), the resulting mixture was stirred at 25 °C for 2 h. The mixture was filtered, the filter cake was collected and dried under reduced pressure to give compound 3 (22 g, crude) as a white solid, the filtrate was discarded. Synthesis of compound 4 To the mixture of compound 3 (1 g, 3.95 mmol, 1 eq) in ACN (120 mL) was added MeI (3.36 g, 23.71 mmol, 1.48 mL, 6 eq). The mixture was stirred at 120 °C for 4 h under microwave. Twelve batches of the reactions were combined together. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 10 um); mobile phase: [water (FA) -ACN]; gradient: 20%- 50% B over 20 min). Compound 4 (5.45 g, 19.19 mmol, 40.48% yield, 94% purity) was obtained as a yellow NMR: (400 MHz, DMSO-d6) δ = 7.57 - 7.53 (m, 1H), 7.52 - 7.41 (m, 2H), 7.35 - 7.28 (m, 1H), 5.35 (s, 1H), 3.07 (s, 3H), 2.24 (s, 3H). Synthesis of compound 5 To the mixture of compound 4 (5.45 g, 20.40 mmol, 1 eq) in TFA (20 mL) was added dropwise HNO3 (6.91 g, 71.28 mmol, 4.94 mL, 65% purity, 3.49 eq) at - 20 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into ice water (50 mL), and the pH of mixture was neutralized by adding sodium bicarbonate to about 7. The mixture was filtrate. The filter cake was collected and dried by oil pump to give compound 5 (5.3 g, 16.81 mmol, 82.40% yield, 99% purity) as a white solid. Then the filtrate was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 5 (1 g, 2.27 mmol, 11.15% yield, 71% purity) as a yellow oil.¹H NMR: (400 MHz, DMSO-d6) δ = 7.78 - 7.64 (m, 2H), 7.54 (br t, J = 7.8 Hz, 1H), 7.44 (br d, J = 7.4 Hz, 1H), 3.42 (s, 3H), 2.69 (s, 3H). Synthesis of compound 7 To the mixture of compound 5 (100 mg, 320.39 μmol, 1 eq) in dioxane (3 mL) was added compound 6 (48.41 mg, 384.47 μmol, 1.2 eq) and Na2CO3 (67.92 mg, 640.78 μmol, 2 eq) and Pd (dppf)Cl2 (11.72 mg, 16.02 μmol, 0.05 eq) and H2O (0.5 mL). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was diluted with H2O (20 mL) and the resulting mixture was extracted with Ethyl acetate (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Ethyl acetate: MeOH = 20: 1, RF = 0.08). Compound 7 (35 mg, 69.26 μmol, 21.62% yield, 62% purity) was obtained as a brown oil. LCMS: RT =0.379min, m/z =314.1(M+H)⁺. Synthesis of compound 8 To the mixture of compound 7 (35 mg, 111.71 μmol, 1 eq) in EtOH (2 mL) and H₂O (2 mL) was added Fe (24.95 mg, 446.84 μmol, 4 eq) and NH4Cl (29.88 mg, 558.55 μmol, 5 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, the filtrate was concentrated at reduced pressure to give a residue. The residue was triturated with Ethyl acetate (200 mL) and MeOH (20 mL), the resulting mixture was filtered. The filtrate was concentrated at reduced pressure to give compound 8 (40 mg, crude) as a brown oil. Synthesis of SC-003863 To a mixture of compound 8 (60 mg, 148.24 μmol, 1 eq) and pyridine (117.26 mg, 1.48 mmol, 119.65 μL, 10 eq) in DCM (1 mL) was added compound 5a (36.40 mg, 177.89 μmol, 1.2 eq) at 0 °C, then the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 26%- 56% B over 10 min). SC-003863 (19.53 mg, 41.09 μmol, 27.72% yield, 95% purity) was obtained as a white solid. ¹H NMR: (400 MHz, CDCl3) δ = 7.80 (d, J = 10.1 Hz, 2H), 7.54 (s, 1H), 7.49 (br d, J = 4.5 Hz, 2H), 7.21 - 7.15 (m, 1H), 7.06 (br s, 1H), 3.97 (s, 3H), 3.33 (br d, J = 6.4 Hz, 2H), 3.24 (s, 3H), 2.87 - 2.71 (m, 3H), 2.52 - 2.42 (m, 2H), 2.40 (s, 3H); LCMS: RT = 0.450 min, m/z = 452.1 (M+H)⁺. Synthesis of SC-003865 Synthetic Scheme 3: Synthesis of SC-003865 Experimental Procedure: Synthesis of compound 2 A mixture of compound 1 (1 g, 4.14 mmol, 1 eq, HCl), ethyl 3-oxobutanoate (538.91 mg, 4.14 mmol, 524.24 μL, 1 eq) in AcOH (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 h under N₂ atmosphere. The mixture was concentrated under reduced pressure to give compound 2 (1 g, crude) as white solid. LCMS: RT = 0.495 min, m/z = 271.0 (M+H)⁺. Synthesis of compound 3 A mixture of compound 2 (1 g, 3.69 mmol, 1 eq), MeI (1.57 g, 11.07 mmol, 688.94 μL, 3 eq) in ACN (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 3 h under microwave reactor. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH3·H2O condition), the eluent was concentrated and then freeze dried to give compound 3 (1 g, crude) as white solid. LCMS: RT = 0.436 min, m/z = 287.0 (M+H)⁺. Synthesis of compound 4 To a mixture of compound 3 (2 g, 7.01 mmol, 1 eq) in TFA (5 mL) was added HNO3 (1.5 g, 23.80 mmol, 1.07 mL, 3.39 eq) at 0 °C. Then the mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was poured into ice cold water (50 mL), and the pH of mixture was neutralized by adding sodium bicarbonate to about 7. Then the resulting mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by reversed-phase HPLC (0.1% NH3·H2O condition), the eluent was concentrated and then freeze dried to give a compound 4 (2.2 g, 6.46 mmol, 92.16% yield, 97% purity) as white solid. LCMS: RT = 0.416 min, m/z = 332.0 (M+H)⁺. Synthesis of compound 5 A mixture of compound 1 (300 mg, 908.79 μmol, 1 eq), Fe (253.76 mg, 4.54 mmol, 5 eq), NH4Cl (486.12 mg, 9.09 mmol, 10 eq) in MeOH (8 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 2 (20 mg, crude) as white solid. LCMS: RT = 0.386 min, m/z = 302.1 (M+H)⁺. Synthesis of compound 4 A mixture of compound 2 (120 mg, 399.83 μmol, 1 eq), compound 3 (98.18 mg, 479.80 μmol, 1.2 eq), pyridine (94.88 mg, 1.20 mmol, 96.82 μL, 3 eq) in DCM (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 h under N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH3·H2O condition), the eluent was concentrated and then freeze dried to give compound 4 (50 mg, crude) as white solid. LCMS: RT = 0.498 min, m/z = 468.1 (M+H)⁺. Synthesis of SC-003865 A mixture of compound 4 (45 mg, 96.09 μmol, 1 eq), compound 5 (18.15 mg, 144.14 μmol, 1.5 eq), CsF (29.19 mg, 192.19 μmol, 7.09 μL, 2 eq), Pd(dppf)Cl2 (7.03 mg, 9.61 μmol, 0.1 eq) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18150*30 mm*7um; mobile phase: [water (FA) - ACN]; gradient: 30%- 660% B over 10 min) to give SC-003865 (10.24 mg, 21.16 μmol, 22.02% yield, 97% purity) as white solid.¹H NMR: (400 MHz, CDCl3) δ = 7.95 - 7.81 (m, 2H), 7.63 - 7.47 (m, 1H), 7.26 - 7.09 (m, 2H), 6.56 - 6.18 (m, 1H), 4.01 - 3.95 (m, 3H), 3.37 (br s, 2H), 3.24 (br s, 3H), 2.91 - 2.71 (m, 3H), 2.55 - 2.43 (m, 2H), 2.40 (br s, 3H); LCMS: RT = 0.464 min, m/z = 470.2 (M+H)⁺. Synthesis of SC-003512_peak2 Synthetic Scheme 4: Synthesis of intermediate 11a Synthetic Scheme 5: Synthesis of SC-003512_peak2 Experimental Procedure: Synthesis of compound 8a To a solution of compound 7a (300 mg, 2.91 mmol, 1 eq) in MeOH (4 mL) was added SOCl2 (1.04 g, 8.73 mmol, 633.91 μL, 3 eq) dropwise under 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum to give compound 8a (300 mg, crude, HCl) as yellow solid. ¹H NMR: ¹H NMR (400 MHz, DMSO-d6) δ = 8.19 (br s, 3H), 3.64 (s, 3H), 3.03 (br s, 1H), 2.85 (br s, 2H), 1.16 (br d, J = 5.5 Hz, 3H) Synthesis of compound 10a To a mixture of compound 8a (300 mg, 1.95 mmol, 1 eq, HCl), HOBt (316.68 mg, 2.34 mmol, 1.2 eq), EDCI (449.28 mg, 2.34 mmol, 1.2 eq), DIEA (757.25mg, 5.86 mmol, 1.02 mL, 3 eq) in DMF (5 mL) was added compound 9a (265.80 mg, 1.95 mmol, 1 eq). The mixture was stirred at 20 °C for 16 h. The mixture was diluted with water (20 mL), then the resulting mixture was extracted with ethyl acetate (2x30 mL). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 10a (500 mg, crude) as brown gum. LCMS: RT = 0.414 min, m/z = 236.1 (M+H)⁺. Synthesis of compound 11a To a solution of compound 10a (500 mg, 2.13 mmol, 1 eq) in THF (3 mL), H2O (1 mL) and MeOH (1 mL) was added LiOH (101.81 mg, 4.25 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. The pH of the reaction mixture was adjusted to 7 with 1 M HCl aqueous solution, then the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (2x30 mL). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 11 (400 mg, crude) as yellow solid. LCMS: RT = 0.363 min, m/z = 222.1 (M+H)⁺. Synthesis of compound 4 To a solution of compound 1 (380 mg, 3.16 mmol, 1 eq) in THF (4 mL) was added compound 2 (358.76 mg, 3.80 mmol, 293.35 μL, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 30 min. The iminium salt solution was cooled to 0 °C, and the solution of compound 3 (1 M, 6.33 mL, 2 eq) was added. The reaction mixture was allowed to warm to 20 °C and stirred for 14 h. The reaction mixture was poured into saturated NH4Cl aqueous solution (10 mL) and the resulting mixture was extracted with EtOAc (15 mL*3). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated at reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 50 mL/min). Compound 4 (450 mg, 1.66 mmol, 52.62% yield) was obtained as a yellow oil. Synthesis of compound 5 To a solution of compound 4 (450 mg, 1.66 mmol, 1 eq) in EtOH (15 mL) was added Pd/C (200 mg, 187.93 μmol, 166.49 μL, 10% purity, 1.13e- 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (30 psi) at 30 °C for 3 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: MeOH = 3: 1). Compound 5 (310 mg, 1.10 mmol, 66.33% yield, 97% purity) was obtained as a yellow oil. LCMS: RT =0.507 min, m/z =273.1 (M+H)⁺. Synthesis of compound 6 To a solution of compound 5 (310 mg, 1.14 mmol, 1 eq) in EtOH (15 mL) and H2O (3 mL) was added KOH (638.79 mg, 11.38 mmol, 10 eq) at 25 °C. The mixture was stirred at 90 °C for 14 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 60~100% Ethyl acetate/Petroleum ether gradient @ 35 mL/min). Compound 6 (80 mg, 291.23 μmol, 25.58% yield, 78% purity) was obtained as a yellow oil. 4. Synthesis of compound SC-003512_peak1& SC-003512_peak2 To a solution compound 11a (20.13 mg, 91.01 μmol, 1.3 eq) in Py (1 mL) was added EDCI (20.13 mg, 105.01 μmol, 1.5 eq) and compound 6 (15 mg, 70.01 μmol, 1 eq). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with H2O (20 mL) and the resulting mixture was extracted with Ethyl acetate (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue (Batch 1). To the mixture of compound 11a (82.59 mg, 373.37 μmol, 2 eq) in Py (1 mL) was added EDCI (53.68 mg, 280.03 μmol, 1.5 eq) and compound 6 (40 mg, 186.69 μmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with H2O (20 mL) and the resulting mixture was extracted with Ethyl acetate (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue (Batch 2). Two batches were combined and purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 32%- 62% B over 9 min) to give SC-003512 (30 mg, purity 92%) as a white solid, which was further separated by SFC ( (RT = 1.041 min and 1.284 min, column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10um); mobile phase: [CO2 -i-PrOH (0.1%NH3H2O)]; B%: 25%, isocratic elution mode). Compound SC-003512_peak1 (9.48 mg, 22.26 μmol, 9.54% yield, 98% purity) was obtained as a yellow solid. Compound SC-003512_peak2 (10.56 mg, 24.03 μmol, 10.30% yield, 95% purity) was obtained as a yellow solid. SC-003512_peak2: NMR: (400 MHz, CDCl3) δ = 7.86 (s, 1H), 7.26 - 7.18 (m, 1H), 7.15 - 7.04 (m, 3H), 6.81 - 6.06 (m, 2H), 5.07 - 4.09 (m, 1H), 3.61 - 3.46 (m, 1H), 3.46 - 3.30 (m, 2H), 3.28 - 3.11 (m, 1H), 2.97 - 2.44 (m, 7H), 2.40 - 2.24 (m, 3H), 1.24 - 1.06 (m, 3H); LCMS: RT = 0.566 min, m/z = 418.2 (M+H)⁺; SFC: RT = 1.280 min.

Synthesis of SC-004395 Synthetic Scheme 6: Synthesis of intermediate 7 Synthetic Scheme 7: Synthesis of SC-004395 Experimental Procedure Synthesis of compound 3b A mixture of compound 1b (500 mg, 2.62 mmol, 1 eq), compound 2b (475.04 mg, 3.93 mmol, 314.60 μL, 1.5 eq) and Cs2CO3 (1.71 g, 5.24 mmol, 2 eq) in NMP (10 mL) was atirred at 140 °C for 16 h. The reaction mixture was diluted with water (50 mL) and the resulting mixture was extracted with ethyl acetate (20 mL * 4), the combined organic phase was washed with saturated brine (50 mL * 3), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/0, TLC (SiO2, Ethyl acetate: Petroleum ether = 1: 5, Rf = 0.71). Compound 3b (150 mg, 649.18 μmol, 12.40% yield) was obtained as a colorless oil. Synthesis of compound 7 To a mixture of compound 3b (150 mg, 649.18 μmol, 1 eq), compound 4b (197.82 mg, 779.01 μmol, 1.2 eq) and AcOK (127.42 mg, 1.30 mmol, 2 eq) in dioxane (4 mL) was added Pd(dppf)Cl2 (23.75 mg, 32.46 μmol, 0.05 eq) under N2 atmosphere, then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The the reaction mixture was diluted with water (6 mL), the resulting mixture was extracted with ethyl acetate (3 mL * 4), and the combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. Compound 7 (300 mg, crude) was obtained as a brown oil Synthesis of compound 3 A mixture of compound 1 (9 g, 68.95 mmol, 1 eq), compound 2 (23.42 g, 82.74 mmol, 1.2 eq) and Cs2CO3 (44.93 g, 137.90 mmol, 2 eq) in DMF (120 mL) was stirred at 80 °C for 16 h. The reaction mixture was diluted with H2O (400 mL) and the resulting mixture was extracted with EtOAc (100 mL * 4). The combined organic layers were washed with brine (150 mL * 4), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1), TLC (SiO2, Ethyl acetate: Petroleum ether = 1: 1, Rf = 0.29). Compound 3 (17 g, 58.31 mmol, 84.57% yield, 98% purity) was obtained as an orange oil. Synthesis of compound 2 A mixture of compound 1 (2 g, 7.00 mmol, 1 eq) and TFA (15.35 g, 134.62 mmol, 10 mL, 19.23 eq) in DCM (20 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was neutralized to pH = 9 with Na2CO3 aqueous solution and NH3•H2O. To the mixture was added water (60 mL), the resulting mixture was extracted with ethyl acetate (20 mL * 4), and the combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. Compound 2 (1.9 g, crude) was obtained as a yellow oil. Synthesis of compound 5 A mixture of compound 3 (150 mg, 738.40 μmol, 1 eq), compound 2 (137.05 mg, 738.40 μmol, 1 eq), EDCI (283.10 mg, 1.48 mmol, 2 eq) in pyridine (3 mL) was stirred at 25 °C for 1 h. To the reaction mixture was added water (30 mL), the resulting mixture was extracted with ethyl acetate (10 mL * 4), and the combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/0, TLC (SiO2, Ethyl acetate: Petroleum ether = 1: 0, Rf = 0.14). Compound 4 (60 mg, 161.84 μmol, 21.92% yield) was obtained as a colorless oil. Synthesis of SC-004395

To a mixture of compound 4 (25 mg, 67.43 μmol, 1 eq), compound 7 (28.13 mg, 101.15 μmol, 1.5 eq) and KF (11.75 mg, 202.30 μmol, 4.74 μL, 3 eq) in dioxane (1 mL) was added Pd(dppf)Cl2 (9.87 mg, 13.49 μmol, 0.2 eq) under N₂ atmosphere, then the mixture was degassed and purged with N₂ for 3 times, and then the mixture was stirred at was stirred at 80 °C for 16 h. To the reaction mixture was added water (5 mL), the resulting mixture was extracted with ethyl acetate (2 mL * 4), and the combined organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to Ethyl acetate: MeOH = 3: 1, TLC (SiO2, Ethyl acetate: Petroleum ether = 1: 0, Rf = 0.10) to give a crude product. The crude product was purified by prep-HPLC (column: YMC-Actus Triart C18150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 38%- 68% B over 10 min). SC-004395 (3.26 mg, 6.70 μmol, 9.94% yield, 100% purity) was obtained as a brown oil. ¹H NMR: (400 MHz, CDCl3) δ = 8.31 (t, J = 2.8 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.35 (d, J = 2.7 Hz, 2H), 7.12 (dd, J = 2.3, 10.5 Hz, 1H), 6.89 (d, J = 9.8 Hz, 1H), 6.81 (dt, J = 2.5, 8.3 Hz, 1H), 6.22 - 5.89 (m, 1H), 5.86 - 5.77 (m, 1H), 4.75 - 4.60 (m, 2H), 4.60 - 4.48 (m, 2H), 4.25 (dt, J = 4.2, 13.0 Hz, 2H), 3.79 (qd, J = 2.8, 5.8 Hz, 1H), 0.92 - 0.77 (m, 4H); LCMS: RT =0.504 min, m/z =487.2 (M+H)⁺. PLA2G15 inhibitors were synthesized represented by formula (I), or a salt or solvate thereof: wherein ^ is a single or a double bond; wherein W is C or N; wherein X and Y are independently N, CR^XY or C(R^XY)2, wherein each R^XY is independently H, a halogen, a pseudohalogen, or a C1-4 alkyl which may be substituted with one or more halogens or pseudohalogens, preferably wherein each R^XY is independently H, F, CH3 or CF3, more preferably wherein R^XY is H; wherein Z is CO, CH or N; wherein L is a non-aromatic group comprising 2 to 6 carbon atoms and at most 1 nitrogen atom, wherein any nitrogen atom is attached to J; wherein J is a single bond, or CO, CO-NH or CO-CH2 attached to L via CO; wherein R^J and R^W are independently ring systems attached to J or W via a ring atom comprised in R^J or R^W, respectively, wherein R^W comprises an aromatic ring. In a second aspect, the invention provides a PLA2G15 inhibitor represented by formula (II), or a salt or solvate thereof: wherein ^ is a single or a double bond; wherein L is a non-aromatic group comprising 2 to 6 carbon atoms and at most 1 nitrogen atom, wherein any nitrogen atom is attached to J; wherein J is a single bond, or CO, CO-NH or CO-CH2 attached to L via CO; wherein R^J and R^W are independently ring systems attached to J or W via a ring atom comprised in R^J or R^W, respectively, wherein R^W comprises an aromatic ring. It is clear that an inhibitor according to this second aspect is a preferred inhibitor according to the first aspect. A halogen is F, Cl, Br, I, or At. Preferably, a halogen is F, Cl, Br, or I. More preferably, a halogen is F, Cl, or Br. Even more preferably, a halogen is F or Cl. Most preferably, a halogen is F. A pseudohalogen is -CN, -CP, -NC, -OH, -SH, -SeH,-TeH, -OCN, -SCN, -NCS, -SeCN, -TeCN, -N3, -NO, or -NO2. Preferably, a pseudohalogen is -CN, -NC, -OH, -SH, -OCN, -SCN, -NCS, -N3, -NO, or - NO2. SC-004611 is an example of such inhibitor. Synthetic Scheme SC-004611:

Synthetic scheme 8. Synthesis of intermediate 6 Synthetic Scheme 9. Synthesis of SC-004611 Synthesis of compound 3 To the mixture of compound 1 (5 g, 38.30 mmol, 1 eq) in dioxane (50 mL) was added compound 2 (8.57 g, 45.97 mmol, 1.2 eq) and Na2CO3 (8.12 g, 76.61 mmol, 2 eq) and Pd (dppf) Cl2 (1.40 g, 1.92 mmol, 0.05 eq) and H2O (5 mL). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The residue was diluted with H2O (50 mL) and the resulting mixture was extracted with Ethyl acetate (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 3 (10 g, crude) was obtained as a brown solid. Synthesis of compound 5 To the mixture of compound 3 (5 g, 21.13 mmol, 1 eq) in DMF (50 mL) was added Cs2CO3 (13.77 g, 42.26 mmol, 2 eq) and compound 4 (5.98 g, 21.13 mmol, 1 eq). The mixture was stirred at 80 °C for 16 h. The mixture was diluted with H2O (50 mL) and the resulting mixture was extracted with Ethyl acetate (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether: Ethyl acetate = 1: 0 to 1: 2, Rf = 0.42) to give crude product. The crude was purified by prep-HPLC (column: Phenomenex luna C18150*40 mm* 15um; mobile phase: [water (FA) -ACN]; gradient: 48%- 78% B over 11 min). Compound 5 (665 mg, crude) was obtained as a yellow NMR: (400 MHz, CDCl3) δ = 7.71 (d, J = 9.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.06 (dd, J = 1.9, 8.3 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.89 (d, J = 9.8 Hz, 1H), 5.74 (t, J = 6.8 Hz, 1H), 4.32 (d, J = 6.9 Hz, 4H), 3.89 (s, 3H), 1.45 (s, 9H). Synthesis of compound 6 To the mixture of compound 5 (665 mg, 1.70 mmol, 1 eq) in DCM (7 mL) was added TFA (6.14 g, 53.85 mmol, 4 mL, 31.73 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with MeOH (300 mL), ion exchange resin (~30 g) was added and the mixture was stirred at 25 °C for 1 h. The resulting mixture was filtered and the filtrate was concentrated at reduced pressure to give compound 6 (830 mg, crude) as a yellow oil. Synthesis of compound 2a A mixture of compound 1a (40 mg, 196.91 μmol, 1 eq) and LiOH•H2O (16.53 mg, 393.81 μmol, 2 eq) in MeOH (1 mL) and H₂O (0.2 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (5 mL) and acidified to pH = 5 - 6 with 1 M HCl aqueous solution, the resulting mixture was extracted with EtOAc (2 mL * 5). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 2a (20 mg, 105.76 μmol, 53.71% yield) was obtained as a light yellow solid. Synthesis of SC-004611 A mixture of compound 2a (20 mg, 105.76 μmol, 1 eq), compound 6 (30.85 mg, 105.76 μmol, 1 eq), HOBt (17.15 mg, 126.91 μmol, 1.2 eq), EDCI (24.33 mg, 126.91 μmol, 1.2 eq) and DIEA (34.17 mg, 264.39 μmol, 46.05 μL, 2.5 eq) in DMF (2 mL) was stirred at 25 °C for 16 h. To the reaction mixture was added water (8 mL), the resulting mixture was extracted with ethyl acetate (3 mL * 4), and the combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 40%- 70% B over 10 min). SC-004611 (10.64 mg, 22.99 μmol, 21.74% yield, 100% purity) was obtained as a white solid. ¹H NMR: (400 MHz, CDCl3) δ = 8.48 (br d, J = 3.9 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.65 (br d, J = 7.8 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.44 - 7.38 (m, 1H), 7.07 (br d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.93 - 6.89 (m, 1H), 6.89 - 6.52 (m, 1H), 5.90 - 5.78 (m, 1H), 4.74 - 4.64 (m, 3H), 4.63 - 4.58 (m, 1H), 3.90 - 3.86 (m, 3H); LCMS: RT =0.506 min, m/z =463.1 (M+H)⁺. PLA2G15 inhibitors were synthesized, represented by formula (2), or a salt or solvate thereof: wherein X is CR⁶R⁷, O, NR⁶ or a single bond; wherein R^A comprises a ring; wherein R^B comprises a ring, preferably an aliphatic ring, more preferably a cyclopropyl; wherein R^S, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are independently H, a C1-4 alkyl, a C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl and C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens; and wherein R¹ and R², and/or R³ and R⁴, and/or R⁵ and R⁶ may alternatively form =O SC-004742

SC-004742 is an inhibitor according to formula (2) above. Scheme 10. Synthesis SC-004742 Experimental Procedure Synthesis of (R)-tert-butyl-2-carbamothioylmorpholine-4-carboxylate CDI (1.599 g, 9.861 mmol, 1.2 eq) was added to a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (2.0 g, 8.216 mmol, 1 eq) in THF (20 mL). The reaction mixture was stirred at r.t. for 2 h. NH4OH (13.3 M, 6.178 mL, 82.46 mmol, 10 eq) was added and the solution was at r.t. for 1 h. It was poured into H2O (40 mL) and it was extracted with EtOAc (4x20 mL). Combined organic layers were washed with citric acid (5% aqueous solution, 40 mL) and brine (40 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give (R)- tert-butyl-2-carbamoylmorpholine-4-carboxylate (1.76 g, 93% yield) as a white solid. It was submitted to next step without NMR (300 MHz, CDCl₃) δ 6.51 (bs, 1H), 5.62 (bs, 1H), 4.32 (d, J = 13.6 Hz, 1H), 4.00- 3.85 (m, 3H), 3.58 (td, J = 11.6, 2.8 Hz, 1H), 3.03-2.61 (m, 2H), 1.47 (s, 9H); MS (ESI) m/z 231 [M + H]⁺. (R)-tert-Butyl-2-carbamoylmorpholine-4-carboxylate (500 mg, 2.171 mmol, 1 eq) was added to a suspension of Lawesson's reagent (555 mg, 1.302 mmol, 0.6 eq) in THF (5 mL). The reaction mixture was stirred at r.t. for 2 h. H2O (10 mL) was added, the mixture was poured into NH4Cl (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (2x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-40% EtOAc/hexanes), to give (R)- tert-butyl-2-carbamothioylmorpholine-4-carboxylate (490 mg, 92% yield) as a white solid. ¹H NMR (300 MHz, CDCl3) δ 7.97 (bs, 1H), 7.53 (bs, 1H), 4.66 (d, J = 13.8 Hz, 1H), 4.20 (dd, J = 10.5, 3.1 Hz, 1H), 4.03-3.90 (m, 2H), 3.61 (td, J = 11.7, 2.8 Hz, 1H), 2.88 (t, J = 12.2 Hz, 1H), 2.68 (t, J = 12.1 Hz, 1H), 1.48 (s, 9H); MS (ESI) m/z 246 [M + H]⁺ 191 (M-tBu); SFC: RT 3.04 min. Synthesis of (R)-(2-(4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholino)(1-methylcyclopropyl)methanone A suspension of 1-(4-fluoro-2-methoxyphenyl)ethanone (760 mg, 4.293 mmol, 1 eq) and copper (II) bromide (2.100 g, 9.402 mmol, 2.08 eq) in a mixture of EtOAc (15 mL) and CHCl3 (15 mL) was refluxed for 90 min. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (100 mL). The organic layer was washed with NH4Cl (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (1.2 g, 113% yield) as a beige-colored solid. It was submitted to next step without purification, considering it was 88% pure (w/w). NMR (300 MHz, CDCl3) δ 7.88 (dd, J = 8.7, 6.8 Hz, 1H), 6.82-6.62 (m, 2H), 4.55 (s, 2H), 3.95 (d, J = 7.0 Hz, 3H). A solution of (R)-tert-butyl-2-carbamothioylmorpholine-4-carboxylate (200 mg, 0.811 mmol, 1 eq) and 2-bromo- 1-(4-fluoro-2-methoxyphenyl)ethan-1-one (290 mg, 88% pure w/w, 1.032 mmol, 1.27 eq) in EtOH (12 mL) was refluxed for 90 min. The mixture was cooled down to r.t., HCl (4 M in dioxane, 2.00 mL, 8 mmol, 9.85 eq) was added and it was reacted for 18 h. The reaction mixture was poured into K2CO3 (saturated aqueous solution, 80 mL) and it was extracted with EtOAc (2x25 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-8% MeOH/CH2Cl2) to give (R)-2-(4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (105 mg, 44% yield) as a brown-coloured solid.¹H NMR (300 MHz, CDCl3) δ 8.18 (t, J = 7.8 Hz, 1H), 7.82 (s, 1H), 6.73 (m, 2H), 4.85 (dd, J = 9.9, 2.8 Hz, 1H), 4.05 (d, J = 11.6 Hz, 1H), 3.93 (s, 3H), 3.88-3.74 (m, 1H), 3.48 (d, J = 12.5 Hz, 1H), 2.96 (m, 3H); MS (ESI) m/z 295 [M + H]⁺; SFC: RT 3.18 min HATU (141 mg, 0.37 mmol, 1.1 eq) and DIPEA (172 mL, 1.004 mmol, 2.99 eq) were added to a solution of 1- methylcyclopropane-1-carboxylic acid (35 mg, 0.332 mmol, 0.99 eq) and (R)-2-(4-(4-fluoro-2- methoxyphenyl)thiazol-2-yl)morpholine (99 mg, 0.336 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 18 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography [Column C18 Gold 50g. Buffer pH7 aq. (NH4HCO3/HCO2H)/CH3CN. 15-60%] to give (R)-(2- (4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholino)(1-methylcyclopropyl)methanone (104 mg, 82% yield) as a beige-colored solid after lyophilization.¹H NMR (300 MHz, CDCl3) δ 8.25 (dd, J = 8.6, 7.1 Hz, 1H), 7.89 (s, 1H), 6.85-6.68 (m, 2H), 4.89-4.75 (m, 2H), 4.36 (d, J = 13.5 Hz, 1H), 4.15 (dd, J = 11.4, 3.5 Hz, 1H), 3.96 (s, 3H), 3.77 (td, J = 11.8, 2.8 Hz, 1H), 3.23-3.15 (m, 3H), 1.39 (s, 3H), 1.01 (m, 2H), 0.67 (m, 2H); MS (ESI) m/z 377 [M + H]⁺; SFC: RT 2.82 min Example 3: Determining the inhibitory activity of PLA2G15 Compounds were prediluted starting from 10mM DMSO stocks to obtain 10-point 3-fold dilution series in neat DMSO. 0.1μL of all resulting samples was diluted 100x to 10μL assay buffer (35mM aq. sodium acetate, pH4.5, 0.01% BSA, 0.01% pluronic F-127) in a clear 384-well flatbottom plate. The dose responses for each compound were performed in duplicate. To both high and low control wells 10μL 1% DMSO in assay buffer was added. Then, 5μL assay buffer was added to the low control wells or 5μL 24.2μM PLA2G15 (recombinantly produced in HEK293T) solution in PBS to all other wells. 3.5μL neat 4-nitrophenyl butyrate (Sigma) was diluted to 400 μL with neat DMSO to obtain a 50mM stock which was stored at -20^oC until use. Directly prior to an experiment, 100μL of this substrate stock was diluted to 10mL with assay buffer, and 15 μL was added to all wells. The plate was spun at 1,000 rpm for 1’, and then incubated at RT for exactly 45 min, followed by another spin at 1,000 rpm for 1’. After adding 30μL stop solution (50 mM aq. Tris, pH9.0) to all wells, the plate was spun at 1,000 rpm for 1 min and the absorbance at 405nm measured in a platereader (SpectraMax). All absorbances were normalized to high control (100%) and low control (0%) and fitted to a 4-parameter dose-response model with free plateaus in an unweighted fit, yielding the reported IC50. Example 4: In vitro and in vivo effects of PLA2G15 inhibitors Cellular BMP levels are distorted in multiple human disorders, underscoring its importance in lysosomal biology (3). Several forms of neuronal ceroid lipofuscinosis (NCL), including CLN3 Batten (11–13), CLN5 Batten (10) and GRN (16,17), as well as frontotemporal dementia (16) show reductions in BMP levels, while in many other LSDs, including NP-C, BMP levels are increased (13,18,19). Increasing BMP levels has beneficial effects on the disease phenotype in NCL GRN, suggesting that the decrease in BMP directly contributes to pathology (17). In cellular models of NP-C, increases in BMP reduces cholesterol accumulation, alleviates autophagy defects and restores sphingomyelin metabolism (20–23). Thus, changes in BMP directly contribute to cellular defects in human disease, and increasing BMP levels is an attractive candidate mechanism to alleviate these defects. Compared to other phospholipids, BMP exhibits an unusual sn-1-glycerophosphate-sn-1’-glycerol stereo- configuration, and the cellular metabolism of BMP is not fully understood (24). Based on structural similarity with phosphatidylglycerol (PG), it is often assumed that its synthesis is based on either PG or lysophosphatidylglycerol (LPG) as precursor (1,5,10,24). Indeed, CLN5 was recently identified as a lysosomal BMP synthase, using LPG as precursor in vitro and in cellular models, and knockout of CLN5 virtually ablates all BMP from lysosomes (10). In addition, the lysosomal phospholipase PLA2G15 (also named LPLA2, LLPL or LYPLA3) has also been implicated in BMP metabolism, but currently available data is conflicting on its exact role in regulating BMP levels (3,5,7,8). A study by Chen et al (5) proposes that PLA2G15 hydrolyses PG to generate LPG and thereby indirectly stimulates BMP synthesis. Indeed, in their hands, an siRNA targeted against PLA2G15 reduces BMP levels in HeLa cells (5). Conversely, Jain et al (7) suggest that PLA2G15 degrades BMP into LPG, and that a PLA2G15 siRNA increases cellular BMP levels. These opposite findings illustrate that the role of PLA2G15 in BMP synthesis and breakdown is unclear. Our data in Example 1 identifies Pla2g15 as a genetic modifier of NP-C, and given the link between BMP and NP-C, we hypothesized that PLA2G15 may control cellular BMP levels. In the present study, we demonstrate that PLA2G15 hydrolyses PG, LPG and BMP, and that PLA2G15 knock out leads to an elevation of BMP in cultured cells and in vivo. Furthermore, we show that pharmacological inhibition of PLA2G15 leads to progressive elevation of BMP in a cellular model. Thus, our studies conclusively demonstrate that PLA2G15 is essential to control cellular BMP levels, and inhibition of PLA2G15 enzymatic activity leads to an elevation of BMP in various biological samples. It is therefore plausible that by inhibiting the enzyme activity of PLA2G15 the reduced levels of BMP in LSDs can return to normal levels and result in improved pathology. In vitro lipid hydrolysis assay Human PLA2G15 WT and PLA2G15 with mutation serine 198 to alanine (S198A) were purified using standard laboratory techniques. 300 ng/mL protein in 25 mM sodium acetate buffer (pH 4.5) was mixed with 20 ug of one of the following lipids: BMP(18:1, 18:1) S,S (Merck cat no# 857135P), PG(18:1(9Z), 18:1(9Z)) (Merck 840475P), or LPG (18:1(9Z)) to reach 100uM substrate concentration. After incubation for 1 hour at 37°C with gentle agitation, formation of free oleic acid was measured using a free fatty acid quantification kit (Abcam AB65341) according to vendor supplied protocol, with a Synergio Neo2 plate reader, measuring the OD at 570 nm. HAP1 cell line generation and lipidomics Targeted mutagenesis on HAP1 cells was performed using CRISPR with standard laboratory techniques. Plasmids encoding for Cas9 and sgRNAs targeting the coding region of PLA2G15 exon 2 and exon 5 were transfected using lipofectamine, and after negative selection with puromycin, monoclonal lines were obtained. Sanger sequencing was performed on the targeted loci to select lines that contain frameshift mutations (presumed knockout). Overexpression of PLA2G15 WT or S198A was carried out from a doxycycline-inducible PinPoint-HR attp site (System Biosciences) integrated in the AAVS1 locus. For lipidomic analysis, cells were sorted by flow cytometry to select haploid cells, and cultured in IMDM medium containing 1% penicillin/streptomycin and 10% fetal calf serum. Cells were harvested by trypsinization, washed with PBS, and 60 * 106 cells were pelleted and snap-frozen on dry ice. Lipidomic analyses were performed as described in reference (25). Generation of PLA2G15 knockout HMC3 cells and lipidomic analysis To generate PLA2G15 knockout HMC3 cells, wild-type cells were infected with lentiviral constructs encoding for Cas9 and gRNAs targeting PLA2G15 (see HAP1 mutagenesis, above). After negative selection with puromycin, successful knockout was confirmed by Western blot using an antibody against human PLA2G15 (Santa Cruz Biotechnology SC-376078). Cell lines were maintained as a polyclonal pool. For lipidomics, cells were plated in EMEM medium containing 10% fetal calf serum and 1% penicillin/streptomycin. Cells were subjected to 25 uM PLA2G15 inhibitor (dissolved in DMSO) or DMSO alone, and harvested after 6, 24 or 48 hours. Harvesting was performed by trypsinization, and cells were washed with PBS, pelleted and snap frozen on dry ice. Subsequently, cells were subjected to targeted lipidomics, measuring BMP concentration. The cell pellets, containing 1,000,000 or 1,500,000 cells (determined by cell counting in a Biorad TC20 cell counter according to manufacturer specifications prior to freezing) were spiked with 20 ng each of deuterated internal standards (C16 lactosylceramide-d3, C18 ceramide-d7, C18 globotriaosylceramide-d3 and sphingosine- d7). A Folch extraction was performed on the spiked pellets, extraction solvents evaporated, and lipid extract reconstituted in absolute ethanol. The resulting clear fractions were analysed using an Agilent 1290 HPLC system equipped with a Poroshell C18, 2.1x50mm, 1.9 uM reversed phase column in a gradient of aqueous acetate to methanol/isopropanol. Flow rate was 0.4 mL/min and injection volume was 1uL. MS/MS detection was performed in line on an Agilent 6495 triplequad mass spectrometer with negative mode electrospray ionisation. Analysis was performed by Multiple Reaction Monitoring with a requirement of 2 transitions/compound. Quantification was achieved through calibration curves of 2,2’-BMP (18:1,18:1) and LPG (18:1) against the internal standards. Generation of Pla2g15 knock out mouse line and lipidomic analysis Targeted mutagenesis using CRISPR was used to obtain Pla2g15 knock out mice on BALB/c background. gRNAs flanking exon 3 of Pla2g15 were used, and successful deletion of exon 3 was determined using Sanger sequencing. Founder mice were crossed with BALB/c wild-type mice, and colony was maintained as Pla2g15 heterozygous mice. For lipidomics, 5 Pla2g15 knock out (KO) and 5 wild-type littermates (mixed sex) of 13 weeks old were sacrificed by intraperitoneal injection of pentobarbital (600 mg/kg). The thorax is opened and blood is collected by heart puncture with a 23-gauge needle. EDTA was added and samples were centrifuged at 3,000 x g for 10 minutes, and obtained plasma was snap frozen on dry ice. Mice were perfused transcardially with 0.9% saline, and organs were harvested. Left hemi brain, left liver lobe, left lung and spleen were snap frozen on dry ice and subjected to lipidomics, as described in the section above (“Generation of PLA2G15 knockout HMC3 cells and lipidomic analysis”). 4-Nitrophenyl butyrate assay to measure enzymatic activity Compounds were prediluted starting from 10 mM DMSO stocks to obtain 10-point 3-fold dilution series in DMSO.0.1 μL of all resulting samples was diluted 100x to 10 μL assay buffer (35 mM aq. sodium acetate, pH4.5, 0.01% BSA, 0.01% pluronic F-127) in a clear 384-well flatbottom plate. The dose responses for each compound were performed in duplicate. To both high and low control wells 10 μL 1% DMSO in assay buffer was added. Then, 5 μL assay buffer was added to the low control wells or 5 μL 24.2 μM human PLA2G15 (recombinantly produced in HEK293T) solution in PBS to all other wells.3.5 μL 4-nitrophenyl butyrate (Sigma) was diluted to 400 μL with DMSO to obtain a 50 mM stock which was stored at -20 °C until use. Directly prior to an experiment, 100 μL of this substrate stock was diluted to 10 mL with assay buffer, and 15 μL was added to all wells. The plate was spun at 1,000 rpm for 1 minute, and then incubated at room temperature for exactly 45 minutes, followed by another spin at 1,000 rpm for 1 minute. After adding 30μL stop solution (50mM aq. Tris, pH9.0) to all wells, the plate was spun at 1,000rpm for 1 minute and the absorbance at 405 nm measured in a plate reader (SpectraMax). All absorbances were normalized to high control (100%) and low control (0%) and fitted to a 4-parameter dose- response model with free plateaus in an unweighted fit, yielding the reported IC50. In vivo assessment of BMP elevation upon inhibition of PLA2G15 Compound SC-003865 was dissolved at 10 mg/mL in 20% PEG400/10%solutol HS15/70%, and applied intraperitoneally in adult BALB/c mice. Mice received 1, 2 or 3 doses at 12 hours interval, and mice were sacrificed 12 hours after the final dose. For tissue collection, mice received an intraperitoneal fentanyl injection and tissues were perfused under terminal isoflurane anaesthesia. For the perfusion, the heart was exposed and major veins leading to the right atrium were severed. Approximately 10 mL of refrigerated saline was infused into the heart via a blunt needle inserted into the left ventricle, allowing all the blood to be removed from the body via the severed veins. Tissues were then immediately collected, frozen in dry ice and stored at -80˚C until sample preparation. Lung was subjected to targeted lipidomics for BMP as described above. 1. RESULTS PLA2G15 hydrolyses PG, LPG and BMP in vitro To test whether PG, LPG and BMP are substrates for PLA2G15, their hydrolysis was measured in vitro. PG, LPG and BMP variants containing oleic acid as acyl chains (PG(18:1; 18:1), LPG(18;1) and BMP(18:1; 18:1), respectively) were mixed with purified human PLA2G15. After 1 hour incubation, the formation of free oleic acid was tested, which would indicate cleavage of acyl chains from their phospholipid headgroup (Figure 7). We indeed observed the formation of free oleic acid from PG, LPG and BMP, indicating hydrolysis of these lipids by PLA2G15. No oleic acid formation was observed using the catalytically inactive S198A mutant of PLA2G15 (26). In conclusion, PG, LPG and BMP are enzymatically cleaved by PLA2G15 in vitro. Knockout of PLA2G15 leads to an elevation of BMP in HAP1 cell culture To test the role of PLA2G15 in controlling cellular BMP levels, we generated PLA2G15 knockout (KO) monoclonal HAP1 cell lines, and quantified BMP levels using lipidomics. In three independent PLA2G15 KO clones, BMP levels were increased compared to WT HAP1 (Figure 8). To further explore the role of PLA2G15, we overexpressed PLA2G15 WT or PLA2G15 S198A in WT HAP1 cells. While PLA2G15 WT had no effect on BMP, PLA2G15 S198A increased BMP levels, indicating a dominant negative effect. Overall, these data indicate that PLA2G15 metabolizes BMP in cultured cells, and that interference with PLA2G15 activity increases BMP levels. Elevation of BMP and LPG in Pla2g15 knockout mice We next generated a Pla2g15 KO mouse line, and harvested tissues from 13 week old mice for lipidomics. In brain, liver, lung and spleen, we observed strong elevation of BMP and LPG in Pla2g15 KO compared to wild-type littermates, (Figure 9). In plasma, BMP and LPG levels were very low, and no difference was observed between wild-type and Pla2g15 KO. Thus, removal of Pla2g15 leads to BMP and LPG elevation in multiple tissues in mouse. Pharmacological inhibition of PLA2G15 results in progressive BMP elevation To test if acute inhibition of PLA2G15 affects BMP metabolism, we generated multiple small molecules that potently reduce catalytic activity of human PLA2G15 in vitro (Figure 10). HMC3 WT cells were subjected to PLA2G15 inhibitors at 25 μM, and cells were harvested for lipidomics after 6, 24 or 48 hours exposure. After 24 hours, we observed strong increase in total BMP concentration, and levels progressively increased after 48 hours exposure, to levels comparable to, or slightly higher than PLA2G15 KO HMC3 cells (Figure 11). Similar effects were observed for all three inhibitors, indicating a specific effect on PLA2G15. To further test the effect of pharmacological inhibition on BMP, we administered compound SC-003865 to wild-type mice. Dosing was performed at 100 mg/kg, 1 to 3 times at 12 hours interval, and lung was harvested 12 hours after the last dose to measure BMP concentration (Figure 12). We observed a progressive increase in lung BMP concentration, with the highest concentration after 36 hours of exposure to SC-003865. In conclusion, inhibition of the catalytic activity of PLA2G15 leads to an elevation of BMP in HMC3 cells and in lung tissue of wild-type mice. EXAMPLE 5 cellular inhibition assay The assay was performed with HAP1 cells expressing either a Tet-inducible PLA2G15[WT]-EGFP or a PLA2G15[S198A]-EGFP. Batches of both these cell types were treated with 2 µg/mL doxycycline for 48 h at 37^oC in DMEM supplemented with 10% FCS and 1% pen/strep. A 2-fold dilution series of compound was prepared in neat DMSO, which is then diluted 50x with unsupplemented DMEM. The cells were washed with PBS, harvested by trypsinization, counted, and resuspended in unsupplemented DMEM in a concentration of 10 M cells/mL. In a U-bottom 96-well plate, 25 µl of cells was added per well. Apart from PLA2G15[WT] cells, several wells were filled with PLA2G15[S198A] cells to serve as controls. A well with uninduced PLA2G15[WT] cells was taken along on each plate as well. Each compound dilution as described above was then added (25 µL/well) to an individual PLA2G15[WT] well. Furthermore, 2% DMSO in unsupplemented medium was added to PLA2G15[WT] and PLA2G15[S198A] wells as control. Finally, 25µL of the highest concentration of all compounds on the plate was added to individual PLA2G15[S198A] wells. After all additions, the sample was well mixed by pipetting 5x. The plate was incubated for 1 hour at 37^oC, after which 10 µL of 6µM TAMRA-FP in unsupplemented medium was added to all wells, except for the DMSO-treated non-induced well and the one well of DMSO-control PLA2G15[WT]. To these last two wells, a vehicle control was added comparable to the TAMRA-FP treatment. The cells were resuspended and incubated for 8 minutes at 37^oC, after which the plate was spun for 2 minutes at 1,500 rpm. The medium was aspirated and the cells stained for 5 minutes with 100uL 1:1,000 DAPI in 10% FCS in PBS, except for the two special wells mentioned above. The plate was spun for 4 minutes at 1,500 rpm and the cells washed 2x with 150µL 10% FCS in PBS. After resuspension in 10% FCS in PBS (120uL), the DAPI, EGFP and TAMRA signals were measured for all wells on a FACS Celesta analyzer. Gating was performed for single, DAPI negative and EFGP positive cells, after which the median of the TAMRA signal within this population was quantified as median. Normalization was performed on DMSO-treated PLA2G15[WT] samples and DMSO-treated PLA2G15[S198A] samples. Example data from this assay is shown in Figure 13, demonstrating cellular inhibition of PLA2G15. Cellular IC50 values that were obtained are: Compound IC50 (μM) SC-003512p2 0.1 SC-004395 0.6 SC-003863 0.6 SC-003865 2.5 SC-004611 0.2 Fosinopril >12.5 (0% inhibition at 12.5uM) Example 6 A clear 96-well high content imaging plate was coated with 0.1% gelatin for 1h at 37oC. HMC3 cells or HMC3 cells with constitutive PLA2G15 knockout (EMEM supplemented with 10% FCS and 1% penstrep was used as medium throughout) were washed with PBS, trypsinized with 0.25% trypsin/EDTA for 5’, resuspended in medium and spun at 1500rpm for 4’. After resuspending in 3mL medium, cells were counted in a BioRad TC20 counter according to vendor protocol, and the cells diluted with medium to 75,000 cells/mL. Of this cell stock, 100uL was plated onto the 96-well plate after aspiration of the gelatin. An 8-point 2-fold serial dilution of the compounds SC-001713, SC-003512, SC-003863 and other compounds according to formula (1) and formula (2) in DMSO prepared from 10mM stocks so that after adding to the well as below, a final top concentration of 10mM was obtained. For amiodarone a similar serial dilution series was added however starting at 4mM top concentration in well.12uL LipidTox Green was added to 12mL medium. And pass through a 2um filter. After removing the medium on the plate, to individual wells were added 199.5uL medium with LipidTox Green and 0.5uL compound dilution. A well with medium without LipidTox Green was added as negative control. The plates were then incubated for 48h at 37oC. Lysotracker was diluted 1:333 in medium, and 50uL was added to each well, followed by further incubation of 1h at 37oC. Cells were washed with PBS and fixed for 10’ at 37oC in 4% PFA, followed by another wash. A mixture of 1:10,000 CellMask Far Red (ThermoFisher, C10046) and 1:1000 Dapi (1mg/mL stock) in 12mL PBS was prepared, of which 100uL was added to each well, followed by incubation for 1h at 37oC and 2 PBS washes. Images were taken on a Revvity Operetta confocal microscope employing 4 fluorescence channels (Dapi 350nm ex, 430-500 filter; LipidTox Green 495nm ex, 500-550 filter; Lysotracker 577nm ex, 570-650nm filter; CellMask 650nm ex, 655-760nm filter). Quantification was by spot intensity as mean per well. Conclusions: The LipidTox assay effectively distinguishes between compounds that induce phospholipid accumulation and those that do not. Amiodarone, used as a control, clearly causes phospholipid accumulation, validating the assay. In contrast, the specific PLA2G15 inhibitors tested did not show a phospholipidosis phenotype in this assay, making them suitable candidates for further development without the associated risk of inducing this condition. Example 7 Lysosomal storage diseases, in particular Niemann Pick disease type C (NPC) are hallmarked by liver malfunction and progressive neurodegeneration in human. The liver phenotype includes enlargement of the liver (hepatomegaly), macrophage infiltration, foam cell formation and storage of glycosphingolipids, contributing to apoptosis of hepatic cells. The loss of neurons in the central nervous system leads to a multitude of neurological symptoms, and most commonly a loss of motor function is observed. Patients regularly experience ataxia, difficulty walking, swallowing problems, loss of muscle tone and tremors. Both the liver and neurological phenotypes are well recapitulated in animal models. We identified PLA2G15 as genetic modifier of NPC in cellular models, and we hypothesized that Pla2g15 knockout would alleviate the liver and neurological phenotype in Npc1 KO mice. In the experiments below, we tested the effect of Pla2g15 knockout on liver damage using established biomarkers aspartate transaminase (AST) and alanine transaminase (ALT). Both enzymes are highly expressed in liver, and during liver injury, damaged cells will release both enzymes into the bloodstream. Thus, elevated levels of AST and ALT are commonly used as biomarkers to monitor liver damage. Furthermore, we quantified neurological function using a neurological composite score, where an observer scores mouse performance on six neurological-driven behavioral phenotypes. We observed significant improvements in both the liver damage and neurological composite scoring tests, indicating that knockout of Pla2g15 lessens liver and neurological phenotypes in NPC. Neurological composite score Pla2g15^-/- Balb/C animals were crossed with Npc1^m1N/J heterozygous (HET) animals, and from the resulting offspring, double heterozygous mice were used to obtain the following genotypes (gene order: Npc1^m1N/J/Pla2g15): WT/WT, HOM/WT, HOM/HET, HOM/KO and WT/KO. Neurological composite phenotype score (consisting of ledge test, hindlimb clasping, gait, kyphosis, tremor, and grooming scores) was performed on a weekly basis starting at 6 weeks of age. These tests were performed following an established protocol (Davidson et al 2022, PMID 34407999). Higher composite score means worse neurological performance. In the Npc1 disease model (HOM/WT), we observed a progressive worsening in the neurological composite score compared to WT/WT starting from week 7, across all domains tested (Figure 15). In mice that lack both Npc1 and Pla2g15 expression (HOM/KO), the neurological phenotype was significantly improved at week 7 compared to HOM/WT. And although slow worsening of the phenotype was observed after week 7, the neurological composite score remained significantly lower compared to HOM/WT at all time points tested. Improvement was found across all domains tested, and was strongest in the gait, tremor and ledge tests. Heterozygous deletion of Pla2g15 (HOM/HET) did not affect performance in the neurological composite score compared to HOM/WT. In conclusion, these results show that deletion of PLA2G15 expression in a NPC1 disease model slows neurological disease progression. AST and ALT plasma concentration At 8 weeks of age (P56 ± 2 days) animals were terminally anesthetized by intraperitoneal injection of Pentobarbital (600 mg/kg) and blood plasma was obtained. AST and ALT levels were determined with a Kit (AST: Cat# 04467493190, Roche; ALT: Cat No 04467388190, Roche) according to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) with pyridoxal phosphate activation (Roche). Therefore, a kinetic measurement of the enzyme activity with a redox reaction of NADH was performed, using L-Aspartate and 2- Oxoglutarat as substrate for the AST measurement and L-Alanine and 2-Oxoglutarat as substrate for the ALT determination. The two enzyme levels were measured on a Roche Cobas 6000/c501 analyzer. To measure the effect of Pla2g15 KO on liver damage in the NPC1 mouse disease model, we measured the levels of biomarkers aspartate transaminase (AST) and alanine transaminase (ALT). We observed a profound increase in both AST and ALT in the disease model (Npc1 KO). Removal of Pla2g15 in the disease model (double knockout, DKO) strongly reduced AST and ALT levels, indicating reduced liver damage (Figure 14A and B, respectively). Knock out of Pla2g15 alone did not influence the levels of either biomarker. Thus, Pla2g15 KO lessens liver damage in Npc1 KO mice. Example 8 HMC3 PFO cholesterol accumulation assay HMC3 cells were used to assess the effects of PLA2G15 inhibitors on lysosomal cholesterol accumulation. A total of 200,000 HMC3 cells/well were plated into 6-well cell culture plates and treated with DMSO or compound SC-003863 for 7 days at 37°C in a CO₂ incubator. The medium (MDEM supplemented with 10% FCS and 1% PenStrep) was refreshed after 4 days. The experiment utilized wildtype (WT), NPC1-deficient (NPC1- ko), and NPC1/PLA2G15 double-knockout (NPC1/PLA2G15-dko) cells, all derived from the HMC3-WT parent line as polyclonal pools generated by CRISPR/Cas9 modification. After 7 days of incubation, the cells reached confluence and were reseeded into individual wells of a Phenoplate-96 plate at 15,000 cells/well. The cells were allowed to attach for at least 6 hours, preferably overnight, in 100 µL medium. Subsequently, 1:1000 v/v Lysotracker Red reagent was added to each well and incubated for 1 hour at 37°C. After incubation, the medium was aspirated, and the cells were washed with PBS. Fixation was performed using 4% PFA in PBS for 10 minutes at 37°C, followed by washing twice with PBS. The cells were permeabilized with 0.1% saponin in PBS for 10 minutes at room temperature. After washing, the cells were stained with Alexa-647 labelled recombinant perfringolysin O (PFO) to detect cholesterol-rich lysosomal membranes. Staining was performed using 60 µL/well of PFO diluted in PBS (1:1000 from a 0.3 mg/mL stock). After staining, the cells were washed with PBS and counterstained with CellMask Green and DAPI according to the vendor protocol. Following a final wash with PBS, the plates were imaged using an Operetta CLS Imager, employing appropriate channels for Alexa-647 (PFO), DAPI, CellMask Green, and Lysotracker Red. Viability was assessed by counting DAPI-positive nuclei, and individual cells were segmented based on CellMask Green staining. PFO fluorescence was quantified exclusively in Lysotracker Red-positive puncta. Baseline cholesterol accumulation was assessed in WT, NPC1-ko, and NPC1/PLA2G15-dko cells using the PFO staining assay. As shown in Figure 16, NPC1-ko cells exhibited significant lysosomal cholesterol accumulation compared to WT cells, consistent with the pathological impact of NPC1 deficiency. In NPC1/PLA2G15-dko cells, cholesterol accumulation was reduced compared to NPC1-ko cells but remained elevated relative to WT levels, indicating a partial rescue of cholesterol storage in the absence of PLA2G15. Further analysis demonstrated the effect of a PLA2G15 inhibitor on lysosomal cholesterol levels in NPC1-ko and NPC1/PLA2G15-dko cells. As shown in Figure 17, the PLA2G15 inhibitor significantly reduced cholesterol accumulation in NPC1-ko cells while having no effect in NPC1/PLA2G15-dko cells. This indicates that the observed rescue of lysosomal cholesterol accumulation is specifically dependent on PLA2G15 activity. These findings highlight the dual role of PLA2G15 inhibition in restoring lysosomal homeostasis and reducing pathological cholesterol accumulation in NPC1-deficient cells. Furthermore, they underscore the therapeutic potential of targeting PLA2G15 in NPC, providing robust support for the claims and aligning with the proposed mechanisms of BMP regulation and lysosomal function in NPC pathology. Example 9 Evaluation of PLA2G15 Inhibitors in Restoring BMP Levels in Models of Batten Disease and GRN-Mediated Conditions This study evaluated the potential of PLA2G15 inhibitors to restore BMP levels in cellular models of Batten disease and GRN-mediated conditions. Cellular models included CLN3- and CLN5-deficient ARPE19 cells generated using CRISPR-Cas9 technology and GRN-deficient bone marrow-derived macrophages (GRN-KO BMDMs) derived from GRN knockout mice. The models were selected to represent lysosomal storage disorders characterized by BMP deficiency, a hallmark of these conditions. Cells were grown to confluency for 4 days and treated with 10 µM of PLA2G15 inhibitors SC4395 or SC3863 for an 11-day experimental duration. During the first 2 hours of this period, cells were exposed to the cell cycle inhibitor mitomycin C to synchronize cell division. DMSO-treated cells served as controls. After treatment, BMP levels were quantified using a validated UPLC-MS/MS-based method. Cell pellets containing 2 million cells were resuspended in 100 µL water and lysed by sonication. The lysates were transferred to a 96-well plate and spiked with the internal standard d5-36:2-BMP. In-plate protein precipitation was performed by adding 300 µL acetonitrile supplemented with 1% formic acid. Samples were processed using positive pressure SPE filtration, employing methanol as the eluent (5 min loading followed by 5 min elution). The filtrate was evaporated completely over 2 hours, and the resulting lipid pellet was reconstituted in 100 µL of 10 mM ammonium formate in methanol. A 10 µL aliquot was injected into an ACE3 C18 reversed- phase column mounted on a Vanquish UPLC system and eluted using a gradient of 10 mM ammonium formate in water to 10 mM ammonium formate in methanol. The eluate was analyzed on an inline TSQ Quantiva MS/MS detector in positive mode electron spray ionization, focusing on a predefined library of BMP species with acyl chain profiles of 36:2, 38:5, 40:7, and 44:12. Results are shown in Figure 18: herein the levels of multiple species of Bis(monoacylglycerol)phosphate (BMP) are shown in the ARPE19 retinal pigment epithelial cell line with wildtype, CLN3ko, or CLN5ko genotype. The BMP levels were significantly reduced in untreated CLN3ko and CLN5ko cells compared to wildtype cells. Treatment with SC4395 or SC3863 restored BMP levels in CLN3ko cells, with SC4395 also partly restoring BMP levels in CLN5ko cells. 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Claims

Claims 1. An inhibitor of a PLA2G15 protein for use in the treatment of Niemann-Pick disease type C, wherein the inhibitor does not induce lysosomal phospholipid accumulation exceeding levels observed in wildtype cells, as determined by a fluorescence-based assay measuring intracellular lipid accumulation.

2. An inhibitor of a PLA2G15 protein for use in the treatment of a Neuronal ceroid lipofuscinosis selected from CLN3 and CLN 5.

3. An inhibitor of a PLA2G15 protein for use in the treatment of a lysosomal storage disease selected from Niemann-Pick disease, preferably of type C, a Neuronal ceroid lipofuscinosis preferably selected from CLN3, CLN 5 and CLN11, and a condition caused by mutations in the GRN gene, Alzheimer’s disease, HIV, or Parkinson’s disease.

4. The inhibitor for use according to claim 3, wherein the inhibitor does not induce lysosomal phospholipid accumulation exceeding levels observed in wildtype cells, as determined by a fluorescence-based assay measuring intracellular lipid accumulation.

5. The inhibitor for use according to claim 3 or 4, wherein the lysosomal storage disease is Niemann-Pick disease type C caused by a mutation in an NPC1 gene or an NPC2 gene, preferably in an NPC1 gene.

6. The inhibitor for use according to any one of claims 3 to 5, wherein the administration of the inhibitor or composition restores or partially restores lysosomal bis(monoacylglycero)phosphate (BMP) levels.

7. The inhibitor for use according to any one of claims 3 to 6, wherein the administration of the inhibitor results in the alleviation of at least one of the following symptoms: cerebellar ataxia, dysarthria, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and dementia.

8. The inhibitor of a PLA2G15 protein for use according to any of claims 3 to 7, wherein said condition is susceptible to being improved or prevented by an increase in levels of bis(monoacylglycero)phosphate.

9. The inhibitor of a PLA2G15 protein for use according to any of claims 3 to 8, wherein said PLA2G15 inhibitor reduces levels of glycolipids, preferably sphingolipids.

10. The inhibitor for use according to any of claims 3 to 9, wherein the PLA2G15 protein is represented by an amino acid sequence having 90% sequence identity with SEQ ID NO: 1 or 2.

11. The inhibitor for use according to any of claims 3 to 10, wherein the inhibitor does not specifically inhibit other phospholipases than the PLA2G15 protein.

12. The inhibitor for use according to any one of claims 3 to 11, wherein the inhibitor has a half maximal inhibitory concentration (IC50) of 50 µM or less for the PLA2G15 protein.

13. The inhibitor for use according to any one of claims 3 to 12, wherein the inhibitor is a small molecule, an antibody, an antibody fragment, an aptamer, or a nucleic acid.

14. A composition for use in the treatment of a lysosomal storage disease, HIV, Alzheimer’s disease, or Parkinson’s disease comprising the inhibitor as defined in any one of claims 3 to 13, and a pharmaceutically acceptable excipient.

15. A method for screening and selecting PLA2G15 inhibitors suitable for the treatment of lysosomal storage disorders, metabolic diseases, liver and kidney diseases, HIV, cancers, and neurodegenerative disorders, comprising the steps of: a. Contacting a candidate compound with PLA2G15 protein in vitro; b. Optionally determining the binding affinity of the candidate compound to the PLA2G15 protein, wherein a compound is selected if it demonstrates a binding affinity with a half maximal inhibitory concentration (IC50) of 50 µmol/L or less for the PLA2G15 protein, as determined by an enzymatic activity assay; c. Optionally testing the candidate compound for enzymatic activity by measuring the ability of the compound to inhibit PLA2G15 enzymatic activity in an assay where the hydrolysis of a substrate by PLA2G15 is quantified; d. Optionally assessing the effect of the candidate compound on phospholipid accumulation by: i. Treating cultured cells with the candidate compound; ii. Staining the treated cells with a dye to detect phospholipid content; iii. Quantifying the phospholipid levels in the treated cells using fluorescence microscopy, flow cytometry or a fluorescence plate reader; e. Selecting the candidate compound based on the results of steps b, c, and d, wherein the candidate compound: i. If step b is performed, demonstrates a binding affinity with an IC50 of 50 µmol/L or less for the PLA2G15 protein, and ii. If step c is performed, shows inhibition of PLA2G15 enzymatic activity, and iii. If step d is performed, does not cause an increase in phospholipid accumulation in treated cells compared to control cells, wherein at least one of steps b or c is performed.

16. The method of claim 15, wherein both steps b and c are performed.

17. The method of claim 15, wherein all of steps b, c, and d are performed.

18. The method of claim 15-17, wherein the effect of the candidate compound on cholesterol accumulation is assessed using a fluorescence-based cholesterol accumulation assay, comprising the steps of: a. Treating cultured cells, with the candidate compound for a period of 24 to 72 hours; b. Staining the treated cells with a lysosomal marker and a cholesterol-specific probe, such as Alexa- 647 labeled recombinant perfringolysin O (PFO); c. Quantifying the cholesterol accumulation in lysosomal compartments by measuring fluorescence intensity in lysosomal puncta preferably using high-resolution imaging, flow cytometry or a fluorescence plate reader; and d. Selecting the candidate compound if it reduces lysosomal cholesterol accumulation in a disease model cell, such as a NPC1-deficient cell, compared to an untreated control.

19. The method of claim 15, 16, 17 or 18, wherein the substrate is 4-nitrophenyl butyrate.

20. The method of any of claims 15 to 19, wherein the dye to detect phospholipid content is selected from the group consisting of Nile Red, BODIPY, and Oil Red O.

21. The method of any of claims 15 to 20, wherein the cultured cells are human microglial or phagocytic cells.

22. The method of any of claims 15 to 21, wherein the phospholipid levels are quantified using fluorescence detection, including fluorescent microscopy and a fluorescence plate reader.

23. The method of any of claims 15 to 22, wherein the candidate compound is a small molecule, an antibody, an antibody fragment, an aptamer, or a nucleic acid.

24. The method of any of claims 15 to 23, wherein the IC50 value is determined using a dose-response curve.

25. The method of any of claims 15 to 24, wherein the cultured cells are treated with the candidate compound for a period ranging from 24 to 72 hours.

26. The method of any of claims 15 to 25, wherein the candidate compound is further evaluated for cytotoxicity in the cultured cells.

27. The method of any of claims 15 to 26, wherein the selected candidate compound is further tested in an animal model of lysosomal storage disease.

28. The compound selected by the method according to any of claims 15-27.