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WO2023122185A2 - Régulation de la dyshoméostasie lipidique pour la prophylaxie ou l'atténuation de la neurodégénérescence - Google Patents

Régulation de la dyshoméostasie lipidique pour la prophylaxie ou l'atténuation de la neurodégénérescence Download PDF

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Publication number
WO2023122185A2
WO2023122185A2 PCT/US2022/053672 US2022053672W WO2023122185A2 WO 2023122185 A2 WO2023122185 A2 WO 2023122185A2 US 2022053672 W US2022053672 W US 2022053672W WO 2023122185 A2 WO2023122185 A2 WO 2023122185A2
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disease
composition
nucleic acid
lcat
phospholipase
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WO2023122185A3 (fr
Inventor
Laura Beth JOHNSON-MCINTIRE
Ana Paula COSTA
Artur LAZARIAN
Kirsten Alison Rinderspacher
Donald William LANDRY
Shi-Xian Deng
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Columbia University in the City of New York
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Columbia University in the City of New York
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin

Definitions

  • the present disclosure relates to compositions and method for regulation of lipid dyshomeostasis and compositions of lecithin cholesterol acyltransferase (LCAT) activators for prophylaxis or amelioration of neurodegeneration, such as Alzheimer’s disease (AD) and Niemann-Pick type C (NPC).
  • LCAT lecithin cholesterol acyltransferase
  • DHA Docosahexaenoic acid
  • Lipid changes such as enlarged endosomes, have been observed before the accumulation of amyloid 0 (A0) in AD patients (Nixon et al., Neurobio of Aging, 2005 and Cataldo et al., American J. Pathology, 2000).
  • Membrane trafficking and membrane constituents alter cleavage of amyloid precursor protein (APP) can also affect accumulation of A0 (Di Paolo and Kim, Neuroscience Reviews, 2011).
  • Altered lipid metabolism can also be associated with tau accumulation and abnormal clearance (Dall’Armi et al., Nature Comm, 2010 and Dyment et al., Neurobiol Aging, 2015).
  • LCAT lecithi cholesterol acyltransferase
  • lipid composition and metabolism in the brain can play a role in AD.
  • compositions for regulation of lipid dyshomeostasis and LCAT activators for prophylaxis or amelioration of neurodegeneration are provided.
  • the present disclosure provides a method for treating and/or preventing a neurodegenerative disorder in a subject in need thereof.
  • the disorder is selected from the group consisting of Alzheimer’s Disease, Niemann-Pick type C (NPC), familial LCAT deficiency (FLD) and fish eye disease (FED), and cholesteryl ester storage disease (CESD).
  • the method comprising administering a therapeutically effective amount of an agent that regulates lipid dyshomeostasis.
  • the agent is administered via intracerbroventricular injection.
  • the agent prevents the accumulation of amyloid 0 (A0) and/or tau in subject. In certain embodiments, the agent disrupts the expression of a phospholipid modifying enzyme.
  • the agent comprises a functional nucleic acid molecule that targets a transcript encoding a phospholipid modifying enzyme.
  • the agent comprises a functional nucleic acid molecule or a plasmid comprising a segment that encodes a functional nucleic acid molecule.
  • the functional nucleic acid molecule comprises an inhibitory RNA molecule.
  • the phospholipid modifying enzyme is selected from the group consisting of synaptojaninl (Synj l), phospholipase A2 (PLA2), phospholipase DI (PLD1), phospholipase D2 (PLD2), phospholipase C (PLC), phosphoinositide 3 kinase-C2a (P12K), and Myc box-dependent-interacting protein 1 (BINI) and combinations thereof.
  • the agent comprises a small molecule inhibitor.
  • the small molecule inhibitor comprises an inhibitor of phospholipase D 1 and phosphlipase D2.
  • the small molecule inhibitor comprises MI. 299.
  • the method comprising administering a therapeutically effective amount of a lecithin cholesterol acyltransferase (LCAT) activator.
  • LCAT activator comprises the general formula as set forth in Figure 13.
  • the method further comprising administering a polyunsaturated fatty acid (PUFA).
  • PUFA polyunsaturated fatty acid
  • the PUFA is a phosphatidylcholine (PC) or lysoPC (LPC) containing 22:6 at the sn-2 position.
  • the present disclosure also provides a composition comprising a therapeutically effective amount of an agent that regulates lipid dyshomeostasis for use in treating and/or preventing a neurodegenerative disorder in a subject in need thereof.
  • the agent comprises a functional nucleic acid molecule that targets a transcript encoding a phospholipid modifying enzyme.
  • the disorder is selected from the group consisting of Alzheimer’s Disease, Niemann-Pick type C (NPC), familial LCAT deficiency (FLD) and fish eye disease (FED), and cholesteryl ester storage disease (CESD).
  • NPC Niemann-Pick type C
  • FLD familial LCAT deficiency
  • FED fish eye disease
  • CESD cholesteryl ester storage disease
  • the agent comprises a functional nucleic acid molecule or a plasmid comprising a segment that encodes a functional nucleic acid molecule.
  • the functional nucleic acid molecule targets a transcript encoding a phospholipid modifying enzyme that contributes to lipid dyshomeostasis.
  • the functional nucleic acid molecule comprises an inhibitory RNA molecule.
  • the phospholipid modifying enzyme is selected from the group consisting of synaptojaninl (Synj l), phospholipase A2 (PLA2), phospholipase DI (PLD1), phospholipase D2 (PLD2), phospholipase C (PLC), phosphoinositide 3 kinase-C2a (P12K), and Myc box-dependent-interacting protein 1 (BINI) and combinations thereof.
  • the agent comprises a small molecule inhibitor.
  • the small molecule inhibitor comprises an inhibitor of phospholipase D 1 and phosphlipase D2.
  • the small molecule inhibitor comprises ML 299.
  • the composition comprising a therapeutically effective amount of a lecithin cholesterol acyltransferase (LCAT) activator.
  • LCAT activator comprises the general formula as set forth in Figure 13.
  • the method further comprising administering a polyunsaturated fatty acid (PUFA).
  • PUFA is a phosphatidylcholine (PC) or lysoPC (LPC) containing 22:6 at the sn-2 position.
  • kits for use in treating and/or preventing a neurodegenerative disorder in a subject in need thereof comprises an agent that regulates lipid dyshomeostasis.
  • the kit comprises a therapeutically effective amount of a lecithin cholesterol acyltransferase (LCAT) activator.
  • LCAT lecithin cholesterol acyltransferase
  • Figure 1 is a schematic diagram of the genetic disruption-based screening method used to identify enzymes active in brain lipid metabolism in a mouse AD model.
  • Figure 2 which includes (A)-(F), presents results from the optimization of 384-well plate platform for detection of synapses in mESN.
  • Figure 3 which includes (A) and (B), presents results of a pilot screen of multiple phospholipid modifying enzymes.
  • Figure 4 is a diagram of a novel metabolic pathway identified in the cell model of AD.
  • Figure 5 which includes (A)-(D), presents results of the investigation of effects on pathologically enriched lipids in AD.
  • Figure 6 is a diagram showing experimental setup for single intracerebro ventricular injection (ICV) injection for proof of concept for LCAT activation with Compound 2 ( Manthei et al., eLife, 2018) and subsequent behavioral testing.
  • ICV intracerebro ventricular injection
  • FIGS 7A and 7B demonstrate the LCAT activator Compound 2 ameliorates memory in contextual fear conditioning (FC), fear conditioning (FC).
  • FC contextual fear conditioning
  • FC fear conditioning
  • the cued FC a hippocampusindependent task, was used as a control. Briefly, mice were exposed for 2 minutes to the context before the onset of a tone (a 30 second, 85 dV sound at 2800 Hz, serving as a condition stimulus (CS). In the last 2 seconds of the CS, mice received a 2 second, 0.80 mA foot shock unconditional stimulus (US) though the bars of the floor. Freezing, which is defined as a species-specific defensive reaction characterized by the lack of movement, associated with crouching posture was measured right after the end of the CS/US for 30 seconds.
  • the contextual memory test was performed 24 h later, by reexposure of the mice to the same context and by measuring the proportion of freezing time during 5 minutes.
  • Figure 7A shows plot of average percent of time spent freezing (+/- SEM) during initial exposure to the training context (baseline) and 24 hours after footshock for the indicated groups after 3 days of the single intracerebro ventricular injection (ICV) injection of the Compound 2 (50 pg/Kg) ( Manthei et al., eLife, 2018).
  • Figure 8 demonstrates the LCAT activator Compound 2 ( Manthei et al., eLife, 2018) ameliorates memory in the Novel Object Recognition test.
  • the plot shows the average object preference ratio for the indicated groups after 3 days of single ICV injection of the Compound 2 (50 ug/Kg).
  • Figure 9 demonstrates ICV injection of the LCAT activator Compound 2 (Manthei et al., eLife, 2018) did not affect motor behavior in the Open Field Test as indicated by no difference found in (A) Distance traveled (B) Center Crossings (C) Time spent in the center of the open field (Time center), and (D) Speed.
  • Figure 10 demonstrates ICV injection of the LCAT activator Compound 2 ( Manthei et al., eLife, 2018) did not affect amyloid 0-peptide 42 or amyloid 0-peptide 40 levels in the hippocampus (A) or cortex (B).
  • Figure 11 demonstrates ICV injection of the LCAT activator Compound 2 (Manthei et al., eLife, 2018) resulted in a significant decrease in interleukin 4 (IL -4) levels from mouse brain.
  • IL -4 interleukin 4
  • Figures 12A-12D demonstrate the results of assay optimization and LCAT activator synthesis and activity.
  • Figure 12A shows the chemical structured for synthesized LCAT Activators Compound A (Freeman et al., J. Pharmacol and Exp. Therap. 2017) and Compound 2 ( Manthei et al., eLife, 2018).
  • Figure 12B shows rLCAT incubated with increasing amount of substrate MUP and fluorescence read over 45 minutes. The miniaturization MUP assay was performed in a 1536-well platform.
  • Figure 12C shows the detection of LCAT activity using a MUP assay 384-well platform.
  • Figure 12D shows the effect of Compound A on LCAT activity.
  • Recombinant LCAT was incubated in presence or absence of synthesized LCAT activator Compound A. Fluorescence increased over time in reactions containing LCAT and increasing concentrations of Compound A. The increased fluorescence was due to LCAT activity compared to the no enzyme control (no ENZ).
  • Figure 13 provides a generic structure of LCAT activators.
  • Figure 14 provides specific examples of LCAT activators disclosed herein (a) and a blood-brain barrier permeable prodrug.
  • Figure 15 provides a general scheme for synthesis of LCAT activators according to the present disclosure.
  • the present disclosure provides compositions and methods for regulation of lipid dyshomeostasis and compositions of lecithin cholesterol acyltransferase (LCAT) activators for prophylaxis or amelioration of neurodegeneration.
  • LCAT lecithin cholesterol acyltransferase
  • Non-limiting embodiments of the present disclosure are described by the present specification and Examples.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, e.g., up to 10%, up to 5%, or up to 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, e.g. , within 5 -fold, or within 2-fold, of a value.
  • mammals include, but are not limited to, humans, non-human primates, farm animals, sport animals, rodents, and pets.
  • Non-limiting examples of non-human animal subjects include rodents such as mice, rats, hamsters, and guinea pigs; rabbits; dogs; cats; sheep; pigs; goats; cattle; horses; and non-human primates such as apes and monkeys.
  • disease refers to any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • an “effective amount” or “therapeutically effective amount” is an amount effective, at dosages and for periods of time necessary, that produces a desired effect, e.g., the desired therapeutic or prophylactic result.
  • an effective amount can be formulated and/or administered in a single dose.
  • an effective amount can be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen.
  • the term “treating” or “treatment” refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing cancer, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • a treatment can prevent deterioration due to a disorder (e.g., a cancer) in an affected or diagnosed subject or a subject suspected of having the disorder, but also a treatment can prevent the onset of the disorder or a symptom of the disorder in a subject at risk for the disorder or suspected of having the disorder.
  • the decrease can be a 10- 99% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%) decrease in severity of complications, impairments, or symptoms. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • a positive alteration can be an increase of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, about 100% or more.
  • a negative alteration is meant to alter negatively by at least about 5%.
  • a negative alteration can be a decrease of about 5%, about 10%, about 25%, about 30%, about 50%, about 75% or more, even by about 100%.
  • the term “dosage” is intended to encompass a formulation expressed in terms of total amounts for a given timeframe, for example, as pg/kg/hr, pg/kg/day, mg/kg/day, or mg/kg/hr.
  • the dosage is the amount of an ingredient administered in accordance with a particular dosage regimen.
  • a “dose” is an amount of an agent administered to a mammal in a unit volume or mass, e.g., an absolute unit dose expressed in mg of the agent. The dose depends on the concentration of the agent in the formulation, e.g., in moles per liter (M), mass per volume (m/v), or mass per mass (m/m).
  • M moles per liter
  • m/v mass per volume
  • m/m mass per mass
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9.
  • Ranges disclosed herein, for example, “between about X and about Y” are, unless specified otherwise, inclusive of range limits about X and about Y as well as X and Y.
  • “nested sub-ranges” that extend from either endpoint of the range are specifically contemplated.
  • a nested sub-range of an exemplary range of 1 to 50 can include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
  • in vitro refers to an artificial environment and to processes or reactions that occur within an artificial environment.
  • in vitro environments exemplified, but are not limited to, test tubes and cell cultures.
  • behavioral impairment or “behavioral deficit” refers to an acquired deficit in one or more of memory function, problem solving, orientation, attention, visual conceptualization, spatial conceptualization, executive and/or abstraction that impinges on an individual's ability to function independently.
  • nucleic acid refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in either single- or double-stranded form, composed of monomers (nucleotides) containing a sugar, phosphate and a base that is either a purine or pyrimidine. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • nucleic acid sequence also encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated.
  • degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues.
  • a “nucleic acid fragment” is a portion of a given nucleic acid molecule.
  • nucleotide sequence is a polymer of DNA or RNA that can be single- or doublestranded, optionally containing synthetic, non-natural or altered nucleotide bases capable of incorporation into DNA or RNA polymers.
  • nucleic acid refers to any organic compound that can be used interchangeably and can also be used interchangeably with gene, cDNA, DNA and RNA encoded by a gene.
  • genes include coding sequences and/or the regulatory sequences required for their expression.
  • gene refers to a nucleic acid fragment that expresses mRNA, functional RNA, or specific protein, including regulatory sequences.
  • Genes also include nonexpressed DNA segments that, for example, form recognition sequences for other proteins.
  • Genes can be obtained from a variety of sources, including cloning from a source of interest or synthesizing from known or predicted sequence information, and can include sequences designed to have desired parameters.
  • An “allele” is one of several alternative forms of a gene occupying a given locus on a chromosome.
  • Naturally occurring is used to describe an object that can be found in nature as distinct from being artificially produced.
  • a protein or nucleotide sequence present in an organism which can be isolated from a source in nature and that has not been intentionally modified by a person in the laboratory, is naturally occurring.
  • inhibitory RNA is meant to include a functional nucleic acid molecule that contains a sequence that is complementary to a target nucleic acid that mediates a decrease in the level or activity of the target nucleic acid.
  • inhibitory RNAs include interfering RNA, small hairpin RNA (shRNA), small interfering RNA (siRNA), ribozymes, antagomirs, and antisense oligonucleotides. Methods of making inhibitory RNAs are known in the art.
  • RNA interference refers to the selective degradation of a sequence-compatible messenger RNA transcript.
  • an shRNA small hairpin RNA refers to an RNA molecule comprising an antisense region, a loop portion and a sense region, wherein the sense region has complementary nucleotides that base pair with the antisense region to form a duplex stem.
  • the small hairpin RNA is converted into a small interfering RNA by a cleavage event mediated by the enzyme Dicer, which is a member of the RNase III family.
  • Dicer is a member of the RNase III family.
  • post-transcriptional processing refers to mRNA processing that occurs after transcription and is mediated, for example, by the enzymes Dicer and/or Drosha.
  • a “short hairpin RNA” or “short interfering RNA” or “shRNA” or “small interfering RNA” or “siRNA” or “antisense nucleic acid” is a RNA duplex of nucleotides that is targeted to a nucleic acid sequence of interest, for example, synaptojaninl (Synj 1), phospholipase A2 (PLA2), and phospholipase D2 (PLD2).
  • Synj 1 synaptojaninl
  • PDA2 phospholipase A2
  • PLD2 phospholipase D2
  • shRNA duplex refers to the structure formed by the complementary pairing between two regions of a RNA molecule.
  • shRNA is “targeted” to a gene in that the nucleotide sequence of the duplex portion of the shRNA is complementary to a nucleotide sequence of the targeted gene.
  • compositions for regulation of lipid dyshomeostasis corresponds to the observations contained herein regarding the role of lipid dyshomeostatis in AD.
  • Prevention, reduction, or reversal of lipid dyshomeostasis can provide prophylactic or ameliorative effects for AD or other similar neurodegenerative diseases.
  • Compositions and methods according to the present disclosure can disrupt the function of synaptojaninl (Synjl), phospholipase A2 (PLA2), phospholipase D2 (PLD2), or any combinations thereof.
  • Compositions and methods according to the present disclosure can disrupt acyl chain remodeling in the brain of patients with AD or at risk of developing AD.
  • the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models. Lipid species can be altered in mouse brain in a regionally specific manner determined by imaging mass spectrometry.
  • the present disclosure provides for high content screening for Ap-induced synapse loss in mature embryonic stem cell derived neurons (ESN) identified components of lipid metabolism responsible for resistance to A -triggered synapse loss using knock-down in mice. It also provides that acyl chain remodeling/Land’s cycle in lipid metabolism is an important component of AD disease pathology and a target for the development of biomarkers and therapeutics.
  • ESN embryonic stem cell derived neurons
  • the present disclosure provides for additional proteins for preventive and therapeutic targeting, including but not limited to lecithin-cholesterol acyltransferase (LCAT; discussed below), cholesterol ester transfer protein (CETP), ATP- binding cassette sub-family A member 1 (ABCA1), ATP-binding cassette sub-family A member 7 (ABCA7), clusterin (apolipoprotein J) (CLU (ApoJ)), apolipoprotein E (ApoE), acyl-CoA synthetase long chain family member 6 (ACSL6), major facilitator superfamily domain containing 2A (MFSD2a), and combinations thereof.
  • LCAT lecithin-cholesterol acyltransferase
  • CETP cholesterol ester transfer protein
  • ABCA1 ATP- binding cassette sub-family A member 1
  • ABCA7 ATP-binding cassette sub-family A member 7
  • clusterin apolipoprotein J
  • CLU apolipoprotein E
  • ApoE acyl-
  • compositions including a combination of LCAT activator moieties and phosphatidylcholine (PC) or lysoPC (LPC) containing 22:6 at the sn-2 position, as well as compositions comprising PC or LPC 22:6 as a carrier of polyunsaturated fatty acids (PUFA) for incorporation into phospholipid and cholesterol metabolism in the brain.
  • PC phosphatidylcholine
  • LPC lysoPC
  • Alzheimer’s disease and Niemann-Pick type C are terminal, neurodegenerative diseases.
  • Certain research on AD therapeutics has been focused on decreasing biogenesis or clearance of amyloid plaques and tau, two hallmarks of the disease based on protein aggregates, and have failed to prevent cognitive decline in multiple Phase III clinical trials.
  • Certain therapeutics target AD symptoms but have limited long term efficacy often losing effectiveness after several years. Further, many late stage clinical trials for new AD therapeutic strategies targeting clearance or biogenesis of amyloid have failed efficacy trials. Therefore, there is an unmet need for therapeutic intervention in Alzheimer’s disease and NPC.
  • Apolipoprotein E (ApoE) variants are a strong risk factor for developing Alzheimer’s disease, after age.
  • LCAT Cholesterol Acyltransferase
  • LCAT has been shown to be inhibited by certain phosphatidylcholine hydroperoxides which can accumulate during aging (Davit- Spraul et al., 1999, FEBS Letters) and physiologically relevant aldehydes (acetaldehyde, acrolein, hexanal, 4-hydroxynonenal, and malondialdehyde) (McCall et al, 1995, Arterioscler Thromb Vase Biol.). Certain sulfhydryl-reactive beta-lactams were developed as class of LCAT activators for use with familial LCAT deficiency (FLD) and cardiovascular disease (Freeman, et al., 2017, J. Pharmacology and Exp. Therapeutics).
  • Therapeutics and Davit-Spraul can allow use of PC or LPC 22:6 as a carrier of PUFA for incorporation into phospholipid and cholesterol metabolism in the brain.
  • the present disclosure furthermore relates to compositions including small molecules that are capable of activating LCAT activity.
  • the small molecule compositions can lead to cholesteryl ester formation and can be capable of mobilizing cholesterol for amelioration of NPC and AD associated behavioral phenotypes in mouse models.
  • acyl-coenzyme A:cholesterol acyltranserase (ACAT) inhibitor has been shown to reduce amyloid pathology in a mouse model of AD (Hutter-Pai er et al., 2004).
  • LCAT can be more effective due to direct regulation, functional and genetic interaction with ApoE. This can corroborate the ApoE associated HDL pathological changes found in AD patient CSF (Yang et al., 2015, J Neuropath Exp. Neurol).
  • the present disclosure provides that a small molecule can be capable of activating activity of LCAT.
  • the treatment strategy can be both a prophylactic supplement which can delay or prevent onset of Alzheimer’s disease as well as an interventional therapeutic strategy in AD and NPC. Therefore, the therapeutic strategy can impact on Alzheimer’s disease prevention, the standard of care for disease management, and modify disease progression in AD and NPC.
  • NPC Neimann Pick-type C disease
  • AD Alzheimer’s disease
  • NPC mutations in NPC gene lead to aberrant cholesterol accumulation in the endosomal compartment of neurons.
  • the gene product of NPC Niemann Pick type-C proteins type-1 and -2 (NPC1/NPC2) are responsible for transport of free cholesterol to intracellular membranes within neurons.
  • NPC1/NPC2 The gene product of NPC Niemann Pick type-C proteins type-1 and -2 (NPC1/NPC2) are responsible for transport of free cholesterol to intracellular membranes within neurons.
  • AD variants of ApoE4, an apolipoprotein involved in cholesterol transport between astrocytes and neurons, is an important risk factor for late onset sporadic AD (Chen et al., 2014).
  • AD Alzheimer's disease
  • APP Amyloid Precursor Protein
  • A pathological amyloid -peptide
  • tau neurofibrillary tangles
  • CSF cerebrospinal fluid
  • a LCAT activator comprises a piperidinylprazolopyridinge or piperidinylimidazopyridine LCAT activator, or derivatives thereof. In certain embodiments, the LCAT activator binds exclusively to the membrane-binding domain of LCAT. In a further embodiments, a LCAT activator comprises a compound having the general formula as set forth in Figure 13 (Compound 2), or a structurally related compound. In a further embodiments, a LCAT activator comprises, but is not limited to, the compound 3-[5-(ethylthio)-l ,3,4- thiadiazol-2-ylthio]pyrazine-2 -carbonitrile (Compound A; Fig. 12A), and other sulfhydrylreactive compounds based on monocyclic -lactams.
  • compositions for use in the methods disclosed herein.
  • a composition can include a molecule, e.g., therapeutic agent, that modulates or regulates lipid metabolism or lipid dyshomeostasis.
  • a composition disclosed herein can be used for prophylaxis or amelioration of neurodegeneration.
  • the therapeutic agent is a functional nucleic acid molecule. In certain embodiments, the therapeutic agent is an inhibitory RNA. In certain embodiments, the shRNAs are targeted to the sequence encoding Synjl, PLA2, and PLD2.
  • the length of the duplex of shRNAs is less than 30 base pairs.
  • the duplex can be 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10 base pairs in length.
  • the length of the duplex is 19 to 25 base pairs in length.
  • the length of the duplex is 19 or 21 base pairs in length.
  • the RNA duplex portion of the shRNA can be part of a hairpin structure.
  • the hairpin structure can contain a loop portion positioned between the two sequences that form the duplex. The loop can vary in length. In some embodiments the loop is 5, 6, 7, 8, 9, 10, 11, 12 or 13 nucleotides in length.
  • the loop is 9 nucleotides in length.
  • the hairpin structure can also contain 3' or 5' overhang portions.
  • the overhang is a 3' or a 5' overhang 0, 1, 2, 3, 4 or 5 nucleotides in length.
  • the therapeutic agent targets a phospholipid modifying enzyme, including but not limited to synaptojaninl (Synjl), phospholipase A2 (PLA2), phospholipase DI (PLD1), phospholipase D2 (PLD2), phospholipase C (PLC), phosphoinositide 3 kinase-C2a (P12K), and Myc box-dependent-interacting protein 1 (BINI), and combinations thereof.
  • a phospholipid modifying enzyme including but not limited to synaptojaninl (Synjl), phospholipase A2 (PLA2), phospholipase DI (PLD1), phospholipase D2 (PLD2), phospholipase C (PLC), phosphoinositide 3 kinase-C2a (P12K), and Myc box-dependent-interacting protein 1 (BINI), and combinations thereof.
  • the antisense nucleic acid, a shRNA, or a siRNA is homologous to at least a portion of an Synj 1, PLA2, and PLD2 nucleic acid sequence, wherein the homology of the portion relative to the Synj 1, PLA2, and PLD2 sequence is at least about 75 or at least about 80 or at least about 85 or at least about 90 or at least about 95 or at least about 98 percent, where percent homology can be determined by, for example, BLAST or FASTA software.
  • the antisense nucleic acid, shRNA, or siRNA homologous portion constitutes at least 10 nucleotides, at least 15 nucleotides, at least 20 nucleotides, at least 25 nucleotides, at least 30 nucleotides. In certain embodiments, the antisense nucleic acid, shRNA, or siRNA molecules have up to 15, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 75, or up to 100 nucleotides in length. In certain embodiments, the antisense nucleic acid, shRNA, or siRNA molecules include DNA or atypical or non- naturally occurring residues, for example, but not limited to, phosphorothioate residues.
  • the antisense nucleic acid, shRNA, or siRNA molecules disclosed herein can be expressed from a vector or produced chemically or synthetically. Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art.
  • the therapeutic agent is a small molecule activator.
  • the therapeutic agent is a lecithin cholesterol acyltransferase (LCAT) activator.
  • LCAT activator has a chemical structure set forth in Figures 13- 15.
  • compositions disclosed herein can comprising a combination of LCAT activator moieties and phosphatidylcholine (PC) or lysoPC (LPC) containing 22:6 at the sn-2 position, as well as compositions comprising PC or LPC 22:6 as a carrier of polyunsaturated fatty acids (PUFA) for incorporation into phospholipid and cholesterol metabolism in the brain.
  • PC phosphatidylcholine
  • LPC lysoPC
  • PUFA polyunsaturated fatty acids
  • the present disclosure provides methods for the treatment of a subject having a neurodegenerative disease or disorder.
  • the neurodegenerative disease or disorder is associated with altered lipid metabolism or lipid dyshomeostasis.
  • the neurodegenerative disease or disorder is associated with increased protein aggregates, for example, A or tau accumulation and abnormal clearance.
  • the neurodegenerative disease or disorder is associated with lysosomal storage defects.
  • the neurodegenerative disorder or disease that can be treated according to the disclosed subject matter includes, but is not limited to, alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxiatelangiectasia, zeroidea neuronal lipofuscinosis, Batten's disease, bovine spongiform encephalopathy ( BSE), Canavan disease, childhood cerebral palsy, cholesteryl ester storage disease (CESD), Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Familial LCAT deficiency (FLD), fish eye disease (FED), frontotemporal lobular degeneration, Huntington's disease, HIV-associated dementia, Kennedy disease, Lewy body dementia, neuroborreliosis, disease of Machado-Joseph, multisystemic atrophy, multiple sclerosis, multiple sulfatase deficiency, mucolipidosis,
  • lipid storage disorder is Niemann-Pick type C (defect NPC1 and / or NPC2), Smith-Lemli-Opitz syndrome (SLOS), a congenital error of cholesterol synthesis, Tangier disease, Pelizaeus-Merzbacher disease, a zeroide neuronal lipofuscinosis, a primary glycosphingolipidosis, Farber's disease or multiple sulfatase deficiency.
  • primary glycosphingolipidosis is Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease or metachromatic leukodystrophy (LDM).
  • LSD is NPC, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, disease of Fabry, a neurodegenerative mucopolysaccharidosis, MPS I, MPS IH, MPS IS, MPS II, MPS III, MPS IIIA, MPS IIIB, MPS IIIC, MPS HID, MPS, IV, MPS IV A, MPS IV B, MPS VI, MPS VII, MPS IX, a disease with secondary lysosomal involvement, SLOS or Tangier disease.
  • the neurodegenerative disease is cerebellar ataxia, Niemann Pick's disease, parkinsonism, Gaucher's neuropathic disease, Sandhoffs disease, Louis-Barr syndrome, Alzheimer's disease, Parkinson's disease, atrophy multisystemic, frontotemporal dementia or Parkinson's syndrome of the lower limbs.
  • the neurodegenerative disease is Niemann Pick disease, Niemann Pick type C, Niemann Pick type A, Tay-Sachs disease, Sandhoff disease, amyotrophic lateral sclerosis (ALS), cerebellar-type multisystemic atrophy (AMS-C), frontotemporal dementia with parkinsonism, corticobasal degeneration syndrome, progressive supranuclear paralysis or cerebellar downward nystagmus.
  • LSD is Niemann Pick disease, Niemann Pick type C, Niemann Pick type A, Tay-Sachs disease, Sandhoff disease or type II mucolipidosis.
  • signs or symptoms that can be reduced or otherwise ameliorated according to the disclosed subject matter include impairment of short-term memory, impairment of abstract thinking, impairment of judgment, impairment of language skills, and mood changes.
  • the therapeutic agent or LCAT activator disclosed herein can be administered to the subject by any suitable route known in the art, including, but not limited to, oral, parenteral, topical, intravenous, subcutaneous, intraperitoneal, intrapulmonary, intranasal, and/or intralesional, intra-arterial, intrathecal, or intracerbroventricular.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • kits for use in the disclosed methods.
  • a kit can include a container that includes a therapeutic agent or a pharmaceutical formulation thereof.
  • the container can include a single dose of the therapeutic agent or a pharmaceutical formulation thereof or multiple doses of the therapeutic agent or a pharmaceutical formulation thereof.
  • a container can be any receptacle and closure suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • the kit can further include a second container that includes a solvent, carrier, and/or solution for diluting and/or resuspending the therapeutic agent or a pharmaceutical formulation thereof.
  • the second container can include sterile water.
  • kits include a sterile container that contains the therapeutic agent or a pharmaceutical formulation thereof; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • the kit can further include instructions for administering the therapeutic agent or a pharmaceutical formulation thereof.
  • the instructions can include information about the use of the therapeutic agent or a pharmaceutical formulation thereof for treating a subject having neurodegenerative disorder.
  • the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treating a neurodegenerative disorder; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references.
  • the instructions can be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • the instructions can describe the method for administration and the dosage amount.
  • the kit can further include a device for administering the therapeutic agent or a pharmaceutical formulation thereof.
  • the device can include a syringe, catheter, e.g., implantable catheter, and/or pump.
  • Example 1 Candidate based screen for resistance to A f- triggered synapse loss
  • Figure 2D shows representative images for nuclei (detected by Hoechst stain, Sigma); PSD-95 (detected with Alexa 488, Molecular Probes) and S-physin (detected with Alexa 568, Molecular Probes).
  • Figure 3B shows resulting hits from the pilot screen of candidate phosphoinositide metabolizing enzymes and effectors using shRNA Lenti-viral particles (Sigma Mission Particles). ESN were challenged with A [342 containing media or control media (DMSO) for 24 hours. The ratio of PSD-95/S-physin was determined in 3 fields of duplicate well shRNA. Synj 1 was able to prevent synapse loss in presence of A 42 (McIntire et al., 2012) and was the positive control (+). Hits were defined by maintenance of PSD-95/S-physin ratio 4 standard deviations (shown by dashed blue line) greater than the mean of the negative control (A [342 treated neurons).
  • Lipid phosphatases including Synj 1 (positive control) were identified as well as phospholipase C, phospholipase D, phosphoinositide 3 kinase-C2a, and a novel interacting protein Synjl, BINI. Candidates able to completely prevent A(342 induced synapse loss (redline in A) are indicated in bold red.
  • Figure 4 presents the results of lipidomic analysis of metabolic pathways affected by phospholipase D (PLD) inhibition.
  • Figure 4 includes a diagram of a method for PLD activity detection.
  • Human embryonic kidney cells (HEK293T) overexpressing APP with the Swedish mutation were treated with the PLD inhibitor ML-299 (Caymen Chemicals and O’Reily et al., J. Med Chem, 2013) for 24 hours.
  • Phosphatidylethanol (PEtOH) a unique lipid formed by PLD in the presence of alcohol, was detected.
  • Lipidomic analysis indicated only cholesteryl esters (CE) were affected and further analysis showed that CE species are up-regulated after PLD inhibition.
  • Example 5 Lipidomics identified pathological lipid dyshomeostasis in AD cell and mouse models
  • Figure 5 A shows a scheme for immunoisolation of Ap-containing particles.
  • Figure 5B shows that immunoisolation of A particles IP/Westem was detected by the 6el0 antibody.
  • Figure 5C shows the specific mass/charge ratio determined by liquid chromatography mass spectrometry (LC-MS/MS) lipidomics and independently by Desorption Electrospray Ionization (DESI) with SYNAPT G2-Si Mass Spectrometry.
  • Figure 5D shows fold enrichment of CE in immuno-isolated Ap-containing particles from HEK293 APP cell line (using 6el0) compared to control media. Lipidomic analyses were done with an Agilent 6490 Triple Quadrupole LC/MS system.
  • Example 6 Small molecule therapeutic for amelioration of behavioral impairment in mouse model
  • a prominent strategy for amelioration of NPC phenotype has been to accelerate cholesterol clearance using cholesterol lowering drugs including cyclodextrin or derivatives (Aqul et al., 2011, Malnar et al., 2012; Yao et a., 2012; Maulik et al, 2012).
  • these strategies can be limited by ability to effectively alter brain cholesterol which is metabolically distinct from cholesterol metabolism in the periphery (Quan et a., 2003; Madra et al., 2010).
  • effectiveness of this strategy can be impaired by low brain penetrance of cyclodextrin when given systemically (Aqul et al., 2011).
  • the metabolically active cholesterol pool in systemic tissues such as liver, spleen has been well documented by increased levels of cholesterol esters (CE) and reduced sterol synthesis and suppression of SREBP target genes (Liu et a., 2009, 2010).
  • the sequestration of cholesterol in NPC mouse models can be overcome by expansion of metabolically active cholesterol pool shown by increased level of cholesterol esters (CE) when cyclodextrin derivative is administered directly to the brain (Aqul et al., 2011).
  • cholesterol esters metabolically active cholesterol pool
  • AD brain Montine et al., 1997
  • activating the metabolically active pool of cholesterol through cholesterol ester formation in brain can overcome the block in cholesterol trafficking in both NPC and AD allowing normal trafficking through the endo/lysosomal compartment and plasma membrane.
  • mobilization of cholesterol through cholesterol ester formation can be stimulated by fatty acids as has been shown in liver (Daumerie et al., 1992).
  • the disclosed subject matter bypassed the blood brain barrier (BBB) with intracerbroventricular injection of a known LCAT activator Compound 2 (Manthei et al., eLIFE 2018). Injection was accomplished with a Hamilton syringe, 1 ul 3.4mM Compound 2 in ACSF diluted from a 50mM stock, 50ug/kg final. Vehicle alone was used as a control (6.4% DMSO in ACSF). Single intracerebroventricual injection was administered to the ventrical 0.5mm posterior and 1mm lateral to the Bregma at a depth of 2.4mm. Location of injection was confirmed with 3% methylene blue injection at the site and sectioning the brain (Fig- 6).
  • BBB blood brain barrier
  • Compound 2 treatment was accomplished by intracerebroventricular injection (ICV).
  • Aliquots of Compound 2 (50 pg/Kg) or vehicle (0.64% DMSO) were diluted in aCSF (124 mM NaCl, 4.4 mM KC1, 1 mM Na 2 HPO 4 , 25 mM NaHCO 3 , 2 mM CaCh, 2 mM MgCh, and 10 mM glucose).
  • aCSF 124 mM NaCl, 4.4 mM KC1, 1 mM Na 2 HPO 4 , 25 mM NaHCO 3 , 2 mM CaCh, 2 mM MgCh, and 10 mM glucose.
  • volume of 1 pL of Compound 2 was infused ICV at a concentration of 50 pg/Kg over a period of 1 min through cannulas connected to a microsyringe by a polyethylene tubing (Hamilton Company, 10 pL, 26-gauge, #84853). After infusion, the needle was kept in place for an additional minute to allow diffusion of Compound 2 or vehicle into the tissue. Mice were allowed to recover for 2 days and on the third day, behavioral assessment using contextual fear conditioning commenced (Puzzo et al., 2009).
  • FC Contextual fear conditioning
  • Footshocks were administered through a removable metal grid floor, and the entire apparatus was cleaned and deodorized between animals with distilled water and 70% ethanol.
  • Animals were placed in the conditioning chamber once on each of 3 consecutive days. On the first day of exposure, mice were placed in the conditioning chamber for 2 min before the onset of a discrete 30 s, 2800Hz, 85dB tone, the last 2 s of which coincided with a 0.8 mA. After the tone and shock exposure, the mice were left in the conditioning chamber for another 30 s before returning to their home cages. At 24 h after their first exposure, animals were returned to the conditioning chamber for 5min without footshock or tone presentation.
  • Figure 8 demonstrated the LCAT activator Compound 2 ameliorated memory in the Novel Object Recognition test.
  • the plot shows the average object preference ratio for the indicated groups after 3 days of single ICV injection of the Compound 2 (50 ug/Kg).
  • Figure 9 demonstrated ICV injection of the LCAT activator Compound 2 did not affect motor behavior in the Open Field Test as indicated by no difference found in (A) Distance traveled (B) Center Crossings (C) Time spent in the center of the open field (Time center), and (D) Speed.
  • Figure 10 demonstrated ICV injection of the LCAT activator Compound 2 did not affect amyloid P-peptide 42 or amyloid P-peptide 40 levels in the hippocampus (A) or cortex (B).
  • Figure 11 demonstrated ICV injection of the LCAT activator Compound 2 resulted in a significant decrease in interleukin 4 (IL -4) levels from mouse brain.
  • IL -4 interleukin 4
  • the present disclosure demonstrated the activation of LCAT by a small molecule activator result in behavioral rescue in a mouse model of Alzheimer’s disease in both Contextual Fear Conditioning (Fig. 7) and Novel Object Recognition (Fig. 8) without significant changes in motor behavior (Fig. 9).
  • This effect is independent of amyloid accumulation in the mouse model brain since amyloid-P peptide 40 (Ap40) and amyloid-P peptide 42 (Ap42) did not change after treatment with Compound 2 (Fig. 10).
  • Compound 2 activation of LCAT results in anti-inflammatory effects based on the significant reduction in Interleukin 4 (IL-4) (Fig.l 1).
  • IL-4 Interleukin 4
  • LCAT stimulation can result in anti-inflammatory effects leading to behavioral rescue in spite of accumulation of amyloid.
  • LCAT activation also has potential to target orphan indications including Niemann-pick Type C, Familial LCAT deficiency (FLD) and fish eye disease (FED) and Cholesteryl ester storage disease (CESD).
  • FLD Familial LCAT deficiency
  • FED fish eye disease
  • CED Cholesteryl ester storage disease
  • the disclosed subject matter can provide a brain permeable small molecule activator of LCAT to engage physiologically relevant pathways such as HDL maturation in the case of AD or cholesterol trafficking and efflux in the case of NPC.
  • a brain penetrant small molecule activator of LCAT can lead to increase in CE formation in the brain to facilitate clearance of pathologically accumulated cholesterol from intracellular stores in NPC. Further, facilitating HDL maturation and cholesterol trafficking in the brain can lead to prophylactic and therapeutic benefit in AD as well.
  • the disclosed subject matter can serve as both a prophylactic target which can safely delay onset of AD as well as therapeutic intervention for NPC and AD where none currently exist.
  • An improved in vitro assay for LCAT activity can be used together with certain published LCAT activators (Manthei et al., 2018; Freeman et al., 2017, assay Fig. 12).

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Abstract

La présente divulgation concerne l'utilisation d'agents thérapeutiques pour prévenir et/ou traiter des troubles neurodégénératifs. Les méthodes consistent à prévenir et/ou à traiter des troubles neurodégénératifs par l'administration à un sujet des agents thérapeutiques divulgués. La présente divulgation concerne en outre des compositions et des kits pour mettre en œuvre de telles méthodes.
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