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CA-2944720-C - COMPOSITIONS AND METHODS FOR THE TREATMENT OR PREVENTION OF NEURODEGENERATIVE DISORDERS

CA2944720CCA 2944720 CCA2944720 CCA 2944720CCA-2944720-C

Abstract

The present invention provides a method for the prevention or treatment of a neurodegenerative disorder in a subject, comprising administering to the subject a therapeutically effective amount of an agent that increases Nix -mediated mitophagy in a cell. Also provided is a method for identifying a compound useful for the prevention or treatment of a neurodegenerative disorder in a subject.

Inventors

  • Carolyn M. Sue
  • Brianada Koentjoro
  • Jin-Sung Park

Assignees

  • NORTHERN SYDNEY LOCAL HEALTH DISTRICT

Dates

Publication Date
20260505
Application Date
20150407
Priority Date
20140416

Claims (19)

  1. REPLACEMENT SHEET 54 CLAIMS 1. Use of an agent that increases Nix-mediated mitophagy in a cell in the preparation of a medicament for the treatment of a neurodegenerative disorder or reducing the probability of developing a neurodegenerative disorder in a subject with impaired parkin-mediated mitophagy, wherein the agent comprises a Nix polypeptide or analog thereof, and/or a GABARAP-L1 polypeptide or analog thereof, wherein said analog is a polypeptide with the replacement of one or more amino acids of said Nix polypeptide or said GABARAP-L1 polypeptide, respectively, with a D amino acid or an amino acid mimetic, or wherein the agent comprises an expression vector encoding a Nix polypeptide and/or a GABARAP-L1 polypeptide.
  2. 2. The use according to claim 1, wherein the agent comprises an expression vector encoding a Nix polypeptide and/or a GABARAP-L1 polypeptide.
  3. 3.
  4. 4. The use according to claim 2 wherein the expression vector encodes a Nix polypeptide. The use according to claim 1, wherein the agent comprises a Nix polypeptide or analog thereof, and/or a GABARAP-L1 polypeptide or analog thereof, wherein said analog is a polypeptide with the replacement of one or more amino acids of said Nix polypeptide or said GABARAP-L1 polypeptide, respectively, with a D amino acid or an amino acid mimetic.
  5. 5.
  6. 6. The use according to claim 4, wherein the agent comprises a Nix polypeptide. The use according to any one of claims 1 to 5, wherein the cell is a neuron or a neuronal precursor.
  7. 7. The use according to any one of claims 1 to 6, wherein the neurodegenerative disorder is associated with mitochondrial dysfunction.
  8. 8. The use according to any one of the claims 1 to 7 wherein the neurodegenerative disorder is selected from Parkinson's disease, Alzheimer's disease, Lewy body dementia, Creutzfeldt- Jakob disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. REPLACEMENT SHEET 55
  9. 9. The use according to claim 8, wherein the neurodegenerative disorder is Parkinson’s disease.
  10. 10. The use according to any one of the claims 1 to 9, wherein said subject possesses a mutation in parkin and/or PINK1.
  11. 11. An in vitro method for identifying an agent useful for the treatment of a neurodegenerative disorder or reducing the probability of developing a neurodegenerative disorder in a subject with impaired parkin-mediated mitophagy comprising: (a) contacting a cell which displays impaired Parkin-related mitophagy with an agent; and (b) detecting an increase in the biological activity or expression of one or more polypeptides associated with Nix-mediated mitophagy in the cell relative to a control cell not contacted with the agent, or (c) detecting an increase in the expression of one or more polynucleotides encoding a polypeptide associated with Nix-mediated mitophagy in the cell relative to a control cell not contacted with the agent, wherein an agent that increases said activity or said expression is identified as useful for the treatment of said neurodegenerative disorder, wherein said one or more polynucleotides or said one or more polypeptides associated with Nix-mediated mitophagy includes Nix and/or GABARAP-L1.
  12. 12. The in vitro method according to claim 11, wherein the cell comprises a mutation in parkin and/or PINK1.
  13. 13. The in vitro method according to claim 11 or 12, wherein the cell is from a subject that has a neurodegenerative disorder or is at risk of having a neurodegenerative disorder.
  14. 14. The in vitro method according to any one of claims 11 to 13, wherein the cell is a fibroblast, olfactory neurosphere or neuron.
  15. 15. A kit for use to treat a neurodegenerative disorder or to reduce the probability of developing a neurodegenerative disorder in a subject with impaired parkin-mediated mitophagy comprising a pharmaceutical composition comprising a therapeutically effective amount of an agent that increases Nix-mediated mitophagy in a cell, and directions for administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a Nix polypeptide or analog thereof, and/or a GABARAP-L1 REPLACEMENT SHEET 56 polypeptide or analog thereof, wherein said analog is a polypeptide with the replacement of one or more amino acids of said Nix polypeptide or said GABARAP-L1 polypeptide, respectively, with a D amino acid or an amino acid mimetic, or wherein the pharmaceutical composition comprises an expression vector encoding a Nix polypeptide and/or a GABARAP-L1 polypeptide.
  16. 16. The kit for use according to claim 15, wherein the pharmaceutical composition comprises the Nix polypeptide or analog thereof, and/or the GABARAP-L1 polypeptide or analog thereof, wherein said analog is a polypeptide with the replacement of one or more amino acids of said Nix polypeptide or said GABARAP-L1 polypeptide, respectively, with a D amino acid or an amino acid mimetic.
  17. 17. The kit for use according to claim 16, wherein the pharmaceutical composition comprises the Nix polypeptide.
  18. 18. The kit for use according to claim 15 wherein the pharmaceutical composition comprises an expression vector encoding the Nix polypeptide and/or the GABARAP-L1 polypeptide.
  19. 19. The kit for use according to claim 18, wherein the expression vector encodes the Nix polypeptide.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OR PREVENTION a= NEURODEGENERA TIVE DISORDERS Field [0001] This application claims the benefit of and priority to Australian Provisional Application No. 2014901398, filed 16 April 2014. [0002] This invention relates to methods for treating or preventing neurodegenerative disorders by administering an agent that activates Nix-mediated mitophagy. Background [0003] Neurodegenerative diseases are a large group of disabling disorders of the nervous system which are characterised by damage and death of neuronal subtypes. Mitochondrial dysfunction is regarded as a putative causative factor in a variety ofneurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease and mitochondrial disease. [0004] Mitochondria are essential organelles that provide cellular energy through oxidative phosphorylation, regulate calcium homeostasis and cell death. However, mitochondria are also the major source of cellular reactive oxygen species (ROS). Normal levels of ROS can be tolerated because of cellular anti-oxidants, whereas in pathological situations of mitochondrial respiratory defect, increased production of ROS exceeds the capability of antioxidant protection, causing damage to a various cellular components including mitochondria. The accumulation of this damage is considered to render mitochondria dysfunctional. Accordingly, the removal of dysfunctional or damaged mitochondria through autophagy, a process called mitophagy, is critical for maintaining proper cellular functions. [0005] Parkinson's disease (PD) is caused by specific and progressive neuronal loss of mid-brain dopamine neurons. Dopamine is a chemical messenger responsible for transmitting signals between the substantia ni g ra and the corpus striatum. Loss of dopamine causes the nerve cells of the striatum to fire in an uncontrolled manner resulting in the cardinal clinical features of Date Reyue/Date Received 2021-07-28 2 bradykinesia, resting tremor, rigidity and postural instability; features that can be severe and profoundly crippling. l 0006 J Among the several causative genes identified in familial forms of PD, mutations in parkin, a gene that encodes a E3 ubiquitin ligase, represents the most common genetic cause of autosomal recessive early-onset PD. PD patients with parkin mutations exhibit typical parkinsonism with early onset, slow progression, early dystonia and L-dopa responsiveness. Moreover, a wide range of disease expressivity and penetrance is associated with Parkin-related PD. [0007] Parkin has also been implicated in the quality control of mitochondria. Parkin, together with PTEN-induced putative kinase l (PINK I), a mitochondrial kinase, mediates the selective autophagic removal of damaged mitochondria. Accordingly, PD-associated mutations in parkin are associated with impaired mitophagy. [0008] There is no cure for PD. Current therapy relies heavily on replenishing dopamine by giving patients oral doses of a dopaminergic agent like the dopamine precursor levodopa or a dopamine agonist. Such therapy can provide relief but is associated with diminishing therapeutic efficacy requiring increased dosages with continuing treatment which is associated with an increased risk of serious side effects. There is a profound need for additional therapies for PD. Summary of Invention [0009] The present inventors have detennined that activation of mitophagy mediated by Nix can prevent and treat a neurodegenerative disease or disorder. According to one aspect, the present invention provides a method for the prevention or treatment of a neurodegenerative disorder in a subject, comprising administering to the subject a therapeutically effective amount of an agent that increases Nix-mediated mitophagy in a cell. [00010] In one embodiment, the agent increases the expression of a Nix polypeptide or fragment thereof, and/or a GABARAP-Ll polypeptide or fragment thereof in a cell. [0001 I] In one embodiment, the agent comprises a Nix polypeptide or fragment thereof and/or a GABARAP-Ll polypeptide or fragment thereof. 3 [00012] In another embodiment, the agent comprises an expression vector encoding a Nix polypeptide or fragment thereof and/or a GABARAP-Ll polypeptide or fragment thereof. l00013J In one embodiment, the cell is a neuron. [00014] In one embodiment the neurodegenerative disorder comprises deficient mitophagy in neurons of the subject. [00015] In one embodiment the neurodegenerative disorder is selected from the group comprising Parkinson's disease, Alzheimer's disease, Lewy body dementia, Creutzfeldt-Jakob disease, Huntington's disease, mitochondrial disease, multiple sclerosis or amyotrophic lateral sclerosis. [00016] In one embodiment the neurodegenerative disorder is Parkinson's disease. In another embodiment, the Parkinson's diseases is early onset Parkinson's disease (EOPD). [00017] In one embodiment the subject possesses a mutation in parkin and/or PINK/. [00018] Acc