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WO2025008625A1 - Danegaptide destiné à être utilisé dans le traitement de synucléinopathies - Google Patents

Danegaptide destiné à être utilisé dans le traitement de synucléinopathies Download PDF

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WO2025008625A1
WO2025008625A1 PCT/GB2024/051728 GB2024051728W WO2025008625A1 WO 2025008625 A1 WO2025008625 A1 WO 2025008625A1 GB 2024051728 W GB2024051728 W GB 2024051728W WO 2025008625 A1 WO2025008625 A1 WO 2025008625A1
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compound
use according
disease
formula
pharmaceutically acceptable
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Saifur Rahman
Nataly HASTINGS
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Cambridge Enterprise Ltd
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Cambridge Enterprise Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present disclosure relates to therapies for treating a synucleinopathy disease.
  • Parkinson's Disease is an alpha-synucleinopathy and is an incurable neurodegenerative disorder with increasing prevalence. Reportedly, there are up to 10 million people suffering from PD worldwide, including arxound 150,000 people in the UK. Moreover, PD is likely to become more prevalent in ageing populations; PD is more frequently encountered by people over 65 years of age. Contemporarily, approved pharmacological treatments for PD are used to correct for dopamine deficiency in brains of PD sufferers, wherein dopamine is decreased following cell damage and subsequent death of brain cells, in particular dopaminergic neurones in a midbrain region of the human brain.
  • the present disclosure provides a compound for treating or preventing a synucleinopathy disease, according to claim 1.
  • the present disclosure provides a kit for treating or preventing a synucleinopathy disease, according to claim 12.
  • the present disclosure provides a method of treating or preventing a synucleinopathy disease, according to claim 15.
  • the present disclosure provides a use of a compound for treating or preventing a synucleinopathy disease, according to claim 16.
  • FIGs. 1A-1C illustrate the HPLC and electrochemical detection analysis of striatal monoamines (dopamine metabolites: 3,4-Dihydroxyphenylacetic acid, DOPAC; and homovanillic acid, HVA); and tyrosine hydroxylase (TH, marker of dopaminergic neurones) immunostaining in the striatum from the in vivo study conducted in Example 1;
  • striatal monoamines dopamine metabolites: 3,4-Dihydroxyphenylacetic acid, DOPAC; and homovanillic acid, HVA
  • TH marker of dopaminergic neurones
  • FIGs. 2A-2B illustrate the Ibal immunostaining from the in vivo study conducted in Example 1;
  • FIGs. 3A-3B illustrate the cerebrospinal fluid (CSF) cytokine I chemokine profile analysis from the in vivo study conducted in Example 1;
  • CSF cerebrospinal fluid
  • FIGs. 4A-4C illustrate a reduction in a-syn aggregation and phosphorylation of a serine amino acid residue located at position 129 of the a-syn protein sequence, which is associated with pathological a-syn in human PD, in rat and human astrocytes grown in the presence of other cell types such as neurons due to treatment with 30nM DG;
  • FIGs. 5A-D show 3 aspects of therapeutic action of 30nM DG in cell models of synucleinopathy
  • FIGs. 6A-6B illustrate a pharmacodynamic effect of DG in the rat brain, namely a preservation of astrocytic coupling; and a change, namely a decrease, in inflammatory cytokine and chemokine release in the rat CSF due to treatment with lOmg/kg DG under inflammatory challenge induced by LPS injection intraperitoneally;
  • FIGs. 7A-D and 8A-B illustrate changes, namely the downregulation, in Cx43 puncta or Cx43 fluorescence intensity per astrocyte, or per cell, in cell culture models upon various challenges relevant to the pathogenesis of PD over a period ranging from two days to 2.5 weeks, in rat and human cells;
  • FIGs. 9A-9E and 10A-10C illustrate changes, namely the downregulation, in 0x43 puncta or 0x43 fluorescence intensity per cell, in two rat models of a-syn aggregation relevant to human PD pathogenesis, in several brain regions relevant to the motor symptom development in PD, over a period of 12-18 months and 9 months, respectively;
  • FIGs. 11A-11C illustrate functional changes in cortical rat astrocytes in cell culture showing decreased gap junctional (GJ) coupling in astrocytic networks upon inflammatory and a-syn challenges relevant to human PD pathogenesis; and
  • FIGs. 12A-12D illustrate changes, namely the downregulation, in 0x43 puncta per cell or 0x43 protein levels, in human PD from several brain regions relevant to motor and nonmotor symptom development.
  • the present disclosure provides a compound of formula I for treating or preventing a synucleinopathy disease, wherein the compound of formula I is:
  • treatment or “treating” as used herein, we refer to therapeutic (curative) treatment, which includes stopping or slowing the disease from progressing.
  • prevention or “preventing” as used herein, we refer to "prophylactic” treatment, which includes administering the compound of the invention to a patient in a prodromal or early disease phase of Parkinson's Disease.
  • the subject is a human.
  • the compound of formula I is for administration via a non-invasive route.
  • the non-invasive route is oral, intranasal, sublingual, inhalation, rectal or transdermal.
  • the synucleinopathy disease is selected from Parkinson's Disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
  • the disease is Parkinson's Disease.
  • the compound of formula I is for use in mitigating and/or reducing the progression of one or more symptoms associated with a synucleinopathy disease, particularly associated with Parkinson's Disease.
  • the one or more symptoms are selected from motor symptoms (such as tremors, stiffness and slowness of movement), memory disorders, depression, psychotic symptoms (such as hallucinations and delusions), sleep disturbance, and dementia.
  • the patient is exhibiting one or more symptoms selected from motor symptoms (such as tremors, stiffness and slowness of movement), memory disorders, depression, psychotic symptoms (such as hallucinations and delusions), sleep disturbance, dementia.
  • motor symptoms such as tremors, stiffness and slowness of movement
  • memory disorders such as tremors, stiffness and slowness of movement
  • depression such as depression
  • psychotic symptoms such as hallucinations and delusions
  • sleep disturbance dementia
  • kits for treating or preventing a synucleinopathy disease comprising: a compound of formula I: or a pharmaceutically acceptable salt or hydrate thereof.
  • the disclosed kit is configured to provide effective delivery of the therapeutically effective amount ofthe drug, for example danegaptide (DG), to the subject.
  • DG danegaptide
  • delivery is via a non-invasive route, such as by using a delivery system whereby DG is encapsulated within a phospholipid-based delivery vehicle, namely liposomes.
  • a delivery method is expected to enhance drug delivery across the blood-brain barrier of the subject.
  • the system is configured to provide mitigation when the synucleinopathy disease is characterised by an increase in at least one of: inflammatory cytokines/chemokines, accumulation of misfolded a -syn.
  • inflammatory cytokines and chemokines are small signalling proteins that play a crucial role in immune response and regulation of inflammation.
  • the inflammatory cytokines include, but are not limited to, tumour necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-ip), interleukin-6 (IL-6), tumour necrosis factor receptor superfamily member 21 / death receptor 6 (TNR21 1 TNFRSF21 1 DR6), and interferon gamma induced protein 10 (IP-10 I CXCL10).
  • TNF-a tumour necrosis factor-alpha
  • IL-ip interleukin-1 beta
  • IL-6 interleukin-6
  • TNR21 1 TNFRSF21 1 DR6 tumour necrosis factor receptor superfamily member 21 / death receptor 6
  • IP-10 I CXCL10 interferon gamma induced protein 10
  • neuroinflammation is a complex process involving activation of immune cells, including microglia (the resident immune cells of the CNS), and reactive or atrophic changes in astrocytes, that are involved in the pathogenesis and progression of various neurological disorders.
  • microglia the resident immune cells of the CNS
  • reactive or atrophic changes in astrocytes that are involved in the pathogenesis and progression of various neurological disorders.
  • the accumulation of the misfolded a-syn protein which is abundant in the brain, particularly in presynaptic terminals (where it can be involved in the regulation of synaptic function), leads to the formation of protein deposits called Lewy bodies (LB), resulting in LB disease.
  • LB Lewy bodies
  • the inflammatory environment can contribute to a-syn misfolding and aggregation.
  • the misfolded a-syn may disrupt cellular processes, impair neuronal function, increase intracellular calcium, and contribute to neurodegeneration. Moreover, the misfolded a-syn aggregates may further promote an inflammatory response, triggering the release of pro-inflammatory cytokines and activating immune cells in the CNS.
  • misfolded a-syn the interaction between misfolded a-syn and inflammation is complex and may create a self-perpetuating cycle of symptoms that need to be mitigated.
  • Inflammatory processes may promote an accumulation and increased distribution of misfolded a-syn, and, in turn, misfolded a-syn may induce an inflammatory response.
  • Such an interplay between inflammation and a-syn pathology is thought to contribute to a progressive neurodegeneration of dopaminergic neurons and associated motor and non-motor symptoms of synucleinopathies, for example as observed in PD.
  • a method of treating or preventing a synucleinopathy disease the method comprises administering, to a subject, a therapeutically effective amount of a compound of formula I: or a pharmaceutically acceptable salt or hydrate thereof.
  • the term "compound” as used throughout the present disclosure refers to a therapeutically active ingredient or an active pharmaceutical ingredient (API) or pharmaceutically acceptable salts or hydrates (or esters and prodrugs) thereof, that may be administered in the form of suitable pharmaceutical compositions, alone or in combination with any other ingredients (such as with one or more pharmaceutically acceptable carriers, diluents, buffer, preservative, stabiliser or excipients) known in the art, to the subject for their effective and sustained release at the target site.
  • the term “effective and sustained release” refers to a mechanism of delivery of the compound to the target area, such as the brain parenchyma, over many hours or days after administration of the compound via a suitable route of administration thereof. It will be appreciated that the effective and sustained release at the target site may be followed by subsequent administration (after the first administration) of the aforementioned compound.
  • AAP10 peptide which consists of the sequence, Ac-DTyr-DPro-DHyp-Gly-DAIa-Gly-NH2, and/or the drug called Rotigaptide, for use in treating or preventing a synucleinopathy disease as described herein; or a pharmaceutically acceptable salt or hydrate thereof.
  • the pharmaceutically acceptable salts of danegaptide include danegaptide (DG) hydrochloride.
  • the present invention is directed to a composition comprising the compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment or prevention of a synucleinopathy disease, wherein the compound of formula I is the only active agent in the composition.
  • active agent it is meant that the composition does not contain other components which may be used in the treatment or prevention of a synucleinopathy disease, preferably Parkinson's Disease.
  • compositions of the invention comprising the compound of formula I may further contain a pharmaceutically acceptable carrier forming a pharmaceutical composition.
  • pharmaceutically acceptable carrier any diluent or excipient, such as fillers or binders, that is compatible with the other ingredients of the composition, and which is not deleterious to the recipient.
  • the pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.
  • GJIC gap junctional intercellular communication
  • these compounds may provide better coupling between cells, enable cells to share available energy (in the form of ATP), and enable intercellular signaling, including calcium signaling.
  • DG would act to change the 0x43 conformation in such a way as to prevent hemichannel (HC) opening as well as enhance gap junction (GJ) opening, thus restricting inflammasome activation and inflammatory mediator release from the cells such as astrocytes.
  • the compound is encapsulated in the liposome.
  • Liposomes are vesicles composed of lipid bilayers, which are able to encapsulate the compound within their aqueous core or lipid membrane. When used as a sustained release formulation, liposomes allow the compound to cross the blood brain barrier and engage its target that is located within the brain parenchyma.
  • liposomes A technical benefit of liposomes is that liposomal encapsulation of the compound (namely danegaptide, preferably danegaptide hydrochloride) results in controlled release of the compound namely, danegaptide, preferably danegaptide hydrochloride, over an extended period of time, providing sustained and controlled drug delivery to maintain a consistent therapeutic concentration of the compound at the target site that is located within the brain parenchyma.
  • liposomal membranes act as a barrier, shielding the compound from external factors and enzymatic degradation or inactivation, improving its stability, prolonging its shelf life and effectiveness.
  • liposomes may be designed to exhibit specific targeting properties.
  • liposomal surface with ligands or antibodies may result in targeted delivery of the encapsulated compound to specific cells or tissues, enhancing its therapeutic efficacy and reducing potential side effects on non-targeted cells.
  • liposomes may help mitigate the toxicity of the compound by reducing its exposure to non-targeted tissues or organs and improve the therapeutic index of the compound.
  • the term "pharmaceutically acceptable salts” refers to compounds having an acidic moiety formed using organic or inorganic bases or a basic moiety formed using organic or inorganic acids.
  • the pharmaceutically acceptable salts having an acidic moiety include: metal salts, for example, alkali metal or alkaline earth metal salts, for example, sodium, potassium or magnesium salts; ammonia salts and organic amine salts formed with morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-or tri-basic lower alkylamines such as ethyl tert-butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine or dimethylpropylamine, or mono-, di-or tri-basic hydroxy lower alkylamines such as mono-, di- or triethanolamine; internal salts.
  • metal salts for example, alkali metal or alkaline earth metal salts, for example, sodium, potassium
  • the pharmaceutically acceptable salts having a basic moiety include: 1- (2-aminoacetyl) -4- benzoylamino- pyrrolidine-2-carboxylic acid and its enumerated diastereomers.
  • Such pharmaceutically acceptable salts having a basic moiety may be formed from the following acids: acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic acid, etc.
  • therapeutically effective amount refers to an amount of a free unbound compound that is capable of alleviating a symptom of a given synucleinopathy disease (or pathology) and, preferably, is capable of partially or completely normalising the physiological response, such as astrocytic network coupling, of a subject suffering from the given synucleinopathy disease (or pathology).
  • the therapeutically effective amount is determined based on various factors including, but not limited to, the potency of the compound, the age and constitution of the subject, the body weight of the subject, pharmacokinetic characteristics of the compound, and the route of administration, by a person skilled in the art.
  • the dosage of the compound administered to the patient is (e.g., such as the pharmaceutical composition comprises) of from 10 to 350 mg, preferably of from 20 to 300 mg, more preferably of from 30 to 250 mg, even more preferably of from 40 to 225 mg, yet more preferably of from 50 to 200 mg, yet more preferably of from 60 to 175 mg, such as of from 75 to 150 mg, for example of from 100 to 130 mg of the compound of formula (I).
  • the dosage of the compound administered to the patient is of from 0.05 to 5 mg/kg, preferably of from 0.1 to 4.5 mg/kg, more preferably of from 0.3 to 4 mg/kg, even more preferably of from 0.5 to 3.5 mg/kg, yet even more preferably of from 0.7 to 3.5 mg/kg, still more preferably of from 0.9 to 3 mg/kg, such as of from 1 to 2.5 mg/kg, for example of from 1.1 to 2 mg/kg of the compound of formula (I).
  • the dosage of the free compound in the brain or cerebrospinal fluid (CSF) that is predicted to be "therapeutically effective” is in a range of 10 to 100 nM, optionally substantially 30 nM.
  • the dosage of the compound is 10, 20, 30, 40, 50, 60, 70,
  • the compounds are administered in the range of about 10 to 100 nM.
  • a technical effect of the aforementioned dosage of the compound into the brain in the range of 10 to 100 nM, optionally substantially 30 nM, is that, at this specified dosage range, the compound may effectively engage with its target molecule or receptor, and exhibit the desired therapeutic outcome.
  • the dose will be adjusted according to the body weight of the patient.
  • the compound is formulated in a form of liquid phospholipid formulations, by processes that may be known to a person skilled in the art.
  • the non-invasive route is intranasal. Healthcare professionals may consider these factors to determine the most appropriate and effective route of administration for a particular drug and patient.
  • the intranasal route of administration typically involves delivering the compound (namely, drug or medication) through the nasal cavity into the olfactory epithelium region.
  • the compound is usually formulated as a spray, solution, or powder, which is administered using a suitable device and implemented as a nasal spray device.
  • the compound (or drug or medication) may penetrate into the brain parenchyma through the olfactory epithelium and/or may be absorbed through the nasal mucosa and enter the systemic circulation, from where the compound can cross the blood brain barrier directly.
  • a technical effect of the intranasal route includes efficient absorption of the compound into the brain and rapid onset of action. Moreover, via the intranasal route of administration, the compound bypasses the gastrointestinal (GI) tract and liver, to avoid the first-pass metabolism that occurs with oral administration. Additionally, the intranasal administration is relatively simple and non-invasive, making it more convenient for patients.
  • GI gastrointestinal
  • administration of the compounds or pharmaceutically acceptable salts or hydrates thereof may be carried out as a continuous therapy with multiple doses over time, as determined by a healthcare professional associated with the subject.
  • a continuous dosage system or a slow-release (sustained release) depot may be employed.
  • a technical benefit of the non-invasive route implemented as the intranasal administration of the compound is that it is patient-friendly, it does not require assistance from a trained professional, it provides better quality of life to the patient, and it is well-suited for chronic dosing. Additionally, the aforementioned route of administration ensures the effective therapeutic amount of the compound to be delivered at the target site, namely, the brain parenchyma and across the blood-brain barrier, to result in a desired therapeutic effect, in addition to the potency of the compound.
  • the compound is configured to decrease the release of such signalling molecules from astrocytes into the extracellular environment, to help mitigate neuroinflammation and maintain a more balanced signalling environment.
  • inflammatory activation of astrocytes for which excessive nuclear phosphorylated STAT3 at amino acid tyrosine at position 705 serves as a marker can provoke the release of pro-inflammatory cytokines and chemokines, in response to certain stimuli, which contribute to neuroinflammation.
  • the compound is designed to attenuate the inflammatory activation of astrocytes to help modulate the immune response in the central nervous system and promote a more balanced and regulated homeostatic state.
  • LPS lipopolysaccharide I endotoxin
  • IP intraperitoneally
  • DG Danegaptide
  • IN intranasally
  • N 12-15 per group.
  • TH is an enzyme involved in dopamine production; its downregulation has been associated with Parkinsonian motor symptoms. This corroborates the inflammation-induced PD- relevant nigrostriatal pathway damage in the model. TH staining was performed using the DAB agent and analysed with light microscopy.
  • Ibal is a marker protein of a cell type called microglia, which are associated with an inflammatory response and immunoregulation in the brain.
  • Microglial "reactivity" i.e. a pro-inflammatory phenotype
  • morphological features two of which were measured in this study:
  • Form Factor - also called “circularity”, ranges from 0 to 1, relates area to perimeter with the formula 4n x area I perimeter 2 with the value of 1 representing more circular (presumed to be more reactive) cells. Higher values more pro-inflammatory phenotype.
  • Solidity also called “density” ranges from 0 to 1, relates the area of the cell with its convex hull (the “territory” covered). When higher Solidity correlates with a higher Form Factor, this indicates hypertrophic cells associated with tissue damage. However if not correlated with a higher Form Factor, it could also indicate a quiescent highly-ramified cell.
  • CSF cytokines / chemokines of inflammation are translationally-valuable biomarkers of inflammatory changes in the CNS, which have been described in PD and other neurodegenerative and psychiatric conditions.
  • CSF screening is available in human trials as a surrogate marker of mechanism engagement of / pharmacodynamic response to a drug.
  • TNR.21 and prion protein were upregulated in the "PD” group compared to the control and treated groups (Fig.3B), this indicated a pro-inflammatory cytokine environment in the CSF relevant to the human Parkinson's Disease.
  • Example 1 shows that DG reversed phenotypes associated with Parkinson's Disease in an in vivo model. As such, it has been demonstrated that DG may be effective for treating and preventing Parkinson's Disease.
  • FIGs. 4A-4C due to treatment with 30nM DG, there is shown a reduction in a- syn aggregation and of phosphorylated serine residues located at position 129 of the a-syn protein, which is associated with pathological a-syn in human PD, in rat and human astrocytes grown in the presence of other cell types such as neurons.
  • FIGS 5A-D there are shown 3 aspects of therapeutic action of 30nM DG in cell models of synucleinopathy.
  • A IP-10 cytokine released in the medium by rat cortical astrocyte- iNeurone co-cultures lesioned with a-syn PFF over 3 weeks;
  • B-C calcium oscillations in rat cortical astrocytes lesioned with a-syn PFF for 3 days; baseline calcium levels in human cortical astrocytes lesioned with a-syn PFF for 3 days;
  • D nuclear STAT3 in rat cortical astrocyte cultures lesioned with a-syn PFF for 3 days.
  • FIG. 6A-6B there is shown an increase in GJ communication measured by the Lucifer Yellow (LY) dye spread in the brain after a stereotactic injection into the striatum, and a decrease in inflammatory cytokine and chemokine release in the rat CSF under inflammatory challenge (relevant to the pathogenicity of PD) induced by LPS injection intraperitoneally at Img/kg, 1.5 days total lesion duration, upon treatment with DG at 10 mg/kg DG delivered intranasally twice a day when encapsulated in liposomes.
  • Statistics ANOVA with Tukey's multiple comparisons test or t- tests with FDR control; error bars: SEM.
  • FIGs. 7, and 8 there is shown downregulation, in 0x43 puncta or 0x43 fluorescence intensity per astrocyte, or per cell, in cell culture models upon various challenges relevant to the pathogenesis of PD over a period ranging from two days to 2.5 weeks, in rat and human cells thus demonstrating translational conservation of the mechanism.
  • FIGs. 7A-7D there are shown changes in 0x43 puncta per astrocyte upon various challenges over two days up to two weeks.
  • 0x43 protein levels using 0x43 fluorescence intensity and the number of 0x43 puncta per cell (analysed via fluorescent microscopy) are studied.
  • the various challenges are LPS 100 ng/ml and mechanical injury for 48 hours (7A, Left Panel), and a-syn pre-formed fibrils (PFFs) and amyloid-p (Am- b) PFFs at O.lng per 10,000 cells in 72 hours (namely, over 3 days), i.e., misfolded protein challenges (7B, Right Panel).
  • FIGs. 8A-8B there are shown changes in 0x43 puncta per astrocyte upon a-syn challenge in rat cortical astrocyte-iNeurone co-cultures over 2.5 weeks.
  • FIGs. 9A-9E and 10A-10C there are shown changes, namely the downregulation, in 0x43 puncta or 0x43 fluorescence intensity per cell, in two rat models of a-syn aggregation relevant to human PD pathogenesis, in several brain regions relevant to the motor symptom development in PD, over a period of 12-18 months and 9 months, respectively.
  • the first model is generated via peripheral injection of a-syn PFF alongside a carrier protein RVG9R into the tail vein; the rats subsequently develop progressive dopaminergic and cholinergic cell loss, several NMS such as olfactory loss and digestive slow-down, as well as mild motor symptoms, over 6-18 months post-injection.
  • 0x43 puncta and fluorescence intensity per cell is measured in two brain regions relevant to PD pathology: midbrain substantia nigra (SN, A9 group of dopaminergic neurones identified with tyrosine hydroxylase staining) as shown FIG. 9A-9C, and striatum as shown in FIG. 9D-9E.
  • FIGs. 10A-10C there are shown changes in 0x43 protein expression in a rat model of PD generated via a-syn PFF injection into the Nucleus Basalis of Meynert. Brain samples are analysed 9 months post-injection, by which point these animals start developing motor dysfunction and dopaminergic loss. It is observed that there is a significant reduction in 0x43 fluorescence intensity per cell, and a trend towards the downregulation of 0x43 puncta per cell, in the striata of the PFF-lesioned animals compared to the sham-lesioned controls (as shown in FIG. 10B and IOC).
  • FIG. 11A-11C there are shown functional changes in cortical rat astrocytes in cell culture showing decreased GJ coupling in astrocytic networks upon inflammatory and a-syn challenges relevant to human PD pathogenesis.
  • FIG. 12A-12D there are shown changes, namely downregulation, in 0x43 puncta per cell or 0x43 protein levels, in human PD from several brain regions relevant to motor and non-motor symptom development.
  • FIGs. 12B shows representative changes in TritonX-soluble 0x43 protein levels in a human post-mortem brain in PD as compared to controls.
  • FIG. 12B shows the total protein stain of the same membrane as the blot.
  • FIG. 12D is the quantification of the 0x43 protein level analysis. Western blot analysis of the TritonX- soluble fraction is used to complement the microscopic study (FIGs. 12A, C); grey matter of the parietal cortex, striatum, and midbrain SN are included for analysis.
  • the TritonX- soluble fraction of 0x43 is proposed to represent 0x43 en route to the membrane in the Golgi and the endoplasmic reticulum, thus serving as a marker of the cell's ability to produce Cx43 protein, although Cx43 in HC may also be captured. Due to the high number of samples, western blot gels are split into four batches with a parietal cortex sample serving as a loading control among all batches for semi-quantitative analysis of combined protein levels. This protein analysis revealed a similar pattern of significant Cx43 reduction in the parietal cortex, while striatum and midbrain samples showed a non-significant trend towards Cx43 downregulation in PD. Referring to FIGs. 12C, there are shown regional 0x43 protein expression in a human postmortem brain in control and PD, respectively. Midbrain samples present with 0x43 protein distribution that differed in appearance to the punctate staining indicative of GJ plaques.
  • Quantitative microscopic examination in photon-counting mode reveals a significant reduction in 0x43 puncta per cell (i.e., per nucleus) in PD compared to controls in the frontal, parietal, and insular cortical grey matter samples as well as in the globus pallidus. Significant regional differences were also detected with cortical regions exhibiting markedly higher 0x43 puncta levels; this pattern was altered in PD as significant differences between cortex and midbrain disappeared.

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Abstract

L'invention concerne un composé de formule I destiné à être utilisé dans une méthode de traitement ou de prévention d'une maladie synucléinopathique, la méthode comprenant l'administration à un sujet d'une dose thérapeutiquement efficace dudit composé (I) : ou d'un sel ou d'un hydrate pharmaceutiquement acceptable de celui-ci.
PCT/GB2024/051728 2023-07-03 2024-07-03 Danegaptide destiné à être utilisé dans le traitement de synucléinopathies Pending WO2025008625A1 (fr)

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GBGB2310195.9A GB202310195D0 (en) 2023-07-03 2023-07-03 Method for mitigating symptoms of neurological condition and a system therefor
GB2310195.9 2023-07-03

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WO2025008625A1 true WO2025008625A1 (fr) 2025-01-09

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