Compositions and methods for treatment and prevention of neurodegenerative diseases and disorders

HK40137831APending Publication Date: 2026-09-18THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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Patent Information

Application Number
HK62026126465
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-05-23
Filing Date
2026-07-21
Publication Date
2026-09-18
Estimated Expiration
2044-05-22

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Abstract

The present invention relates to compositions and methods for promoting the removal of misfolded proteins and protein aggregates. The compositions and methods may be used to treat or prevent a neurodegenerative disease or disorder associated with misfolded proteins or protein aggregates. In various embodiments, the compositions and methods relate to activators of one or more TRIM proteins.
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Description

Abstract This invention relates to compositions and methods for promoting the clearance of misfolded proteins and protein aggregates. These compositions and methods can be used to treat or prevent neurodegenerative diseases or conditions associated with misfolded proteins or protein aggregates. In several embodiments, the compositions and methods relate to activators of one or more TRIM proteins.

Claims

CLAIMS What is claimed is:

1. A composition for treating or preventing a disease or disorder associated with aggregation of one or more selected from the group consisting of tau, α- Synuclein (α-Syn), superoxide dismutase 1 (SOD1), TAR DNA binding protein 43 (TDP- 43), FUsed in Sarcoma / Translocated in LipoSarcoma (FUS / TLS), ataxin 1, huntingtin (Htt), Aβ42, and heterogeneous ribonucleoprotein A1 (hnRNPA1), the composition comprising an activator of the level or activity of one or more tripartite motif (TRIM) proteins wherein the one or more TRIM proteins are one or more selected from the group consisting of human TRIM10, TRIM2, TRIM3, TRIM4, TRIM5, TRIM9, TRIM11, TRIM17, TRIM18, TRIM19, TRIM21, TRIM24, TRIM26, TRIM29, TRIM30, TRIM31, TRIM34, TRIM36, TRIM37, TRIM39, TRIM40, TRIM41, TRIM42, TRIM43, TRIM46, TRIM47, TRIM48, TRIM49, TRIM52, TRIM54, TRIM55, TRIM56, TRIM58, TRIM63, TRIM64, TRIM65, TRIM68, TRIM69, TRIM70, TRIM71, TRIM73, and TRIM77.

2. The composition of claim 1, wherein the activator is one or more selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomimetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, an antisense nucleic acid, siRNA, shRNA, and a guide RNA.

3. The composition of claim 1, wherein the disease or disorder is associated with aggregation of tau; and wherein the one or more TRIM proteins are selected from the group consisting of TRIM10, TRIM2, TRIM3, TRIM4, TRIM5, TRIM9, TRIM11, TRIM12, TRIM17, TRIM18, TRIM19, TRIM21, TRIM26, TRIM29, TRIM30, TRIM31, TRIM34, TRIM36, TRIM39, TRIM40, TRIM42, TRIM43, TRIM46, TRIM47, TRIM48, TRIM49, TRIM52, TRIM54, TRIM55, TRIM58, TRIM63, TRIM64, TRIM65, TRIM68, TRIM69 and TRIM70.

4. The composition of claim 1, wherein the disease or disorder is associated with aggregation of α-Syn; and wherein the one or more TRIM proteins are selected from the group consisting of TRIM10, TRIM2, TRIM3, TRIM17, TRIM18, TRIM19, TRIM26, TRIM29, TRIM30, TRIM31, TRIM36, TRIM41, TRIM42, TRIM43, TRIM46, TRIM49, TRIM55, TRIM56, TRIM63, TRIM64, TRIM68, TRIM69, TRIM70, TRIM71, and TRIM73.

5. The composition of claim 1, wherein the disease or disorder is associated with aggregation of SOD1; and wherein the one or more TRIM proteins are selected from the group consisting of TRIM10, TRIM11, TRIM24, TRIM36, and TRIM58.

6. The composition of claim 1, wherein the disease or disorder is associated with aggregation of TDP-43; and wherein the one or more TRIM proteins are selected from the group consisting of TRIM10, TRIM11, TRIM17, TRIM36, TRIM 37, TRIM 40, TRIM49, and TRIM55.

7. The composition of claim 1, wherein the disease or disorder is associated with aggregation of FUS / TLS, ataxin 1, Htt, Aβ42, and hnRNPA1; and wherein the one or more TRIM protein is TRIM10.

8. The composition of any one of claims 3-7, wherein the activator of the TRIM protein is a peptide comprising the amino acid sequence of the TRIM protein or a functional variant thereof.

9. The composition of any one of claims 3-7, wherein the activator of the TRIM protein is a nucleic acid encoding the TRIM protein or a functional variant thereof.

10. The composition of any one of claims 3-7, wherein the activator of the TRIM protein is a vector comprising a nucleic acid encoding the TRIM protein or a functional variant thereof.

11. The composition of claim 10, wherein the vector is a virus.

12. The composition of claim 11, wherein the virus is an adeno-associated virus.

13. A method of treating or preventing a neurodegenerative disease or disorder associated with aggregation of one or more proteins selected from the group consisting of tau, α-Syn, SOD1, TDP-43, FUS / TLS, ataxin 1, Htt, Aβ42, and hnRNPA1 comprising administering to the subject a composition according to any one of claims 1- 12.

14. The method of claim 13, wherein the neurodegenerative disease or disorder associated with tau is selected from the group consisting of Alzheimer’s disease, frontotemporal lobar degeneration (FTLD-tau), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), vacuolar tauopathy, Lytico-bodig disease, globular glial tauopathy (GGT), ageing-related tau astrogliopathy (ARTAG), Pick’s disease, and amyotrophic lateral sclerosis (ALS), primary age-related tauopathy (PART), tangle only dementia (TOD), chronic traumatic encephalopathy (CTE), anti-IgLON5-related tauopathy, Guadeloupean parkinsonism, multisystem proteinopathy (MSP) Nodding Syndrome (NS), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase- associated neurodegeneration, and lipofuscinosis; and wherein the activator of the one or more TRIM proteins is an activator of one or more selected from the group consisting of TRIM10, TRIM11, and TRIM55.

15. The method of claim 14, wherein administering the composition is effective in one or more selected from the group consisting of: a) reducing tau aggregates by at least about 60%; b) reducing the ratio of insoluble tau to soluble tau by at least about 50%; and c) reducing tau aggregates by about 90% six to eight days after administration of the composition.

16. The method of claim 13, wherein the neurodegenerative disease or disorder associated with α-Syn is selected from the group consisting of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Shy- Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, Hallervorden- Spatz syndrome, REM sleep behavior disorder (RPD), and Alzheimer’s disease with amygdala restricted Lewy bodies (AD / ALB); and wherein the activator of one or more TRIM proteins is an activator of one or more selected from the group consisting of TRIM10, TRIM36, TRIM55, and TRIM68.

17. The method of claim 13, wherein the neurodegenerative disease or disorder associated with SOD1 is selected from the group consisting of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD); and wherein the activator of one or more TRIM proteins is an activator of one or more selected from the group consisting of TRIM10, TRIM11, TRIM24, TRIM36, and TRIM58.

18. The method of claim 13, wherein the neurodegenerative disease or disorder associated with TDP-43 is selected from the group consisting of frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD-TDP), multiple system proteinopathy (MSP), Perry disease, facial onset sensory and motor neuronopathy (FOSMN), Alzheimer’s disease (AD), cerebral age-related TDP-43 with sclerosis (CARTS), limbic-predominant age-related TDP-43 encephalopathy (LATE), sporadic inclusion body myositis (sIBM), chronic traumatic encephalopathy (CTE), primarylateral sclerosis (PLS), progressive muscular atrophy (PMA), Guam Parkinson-dementia complex (G-PDC), Guam amyotrophic lateral sclerosis (G-ALS); Parkinson’s disease (PD), and Huntington’s disease (HD); and wherein the activator of one or more TRIM proteins is an activator of one or more selected from the group consisting of TRIM10, TRIM11, TRIM17, TRIM36, TRIM37, TRIM40, TRIM49, and TRIM55.

19. The method of any one of claim 13-18, wherein the composition is administered to the subject in their cerebrospinal fluid (CSF).

20. The method of claim 19, wherein the composition is administered by intracerebroventricular (ICV) injection.

21. The method of any one of claims 13-20, wherein the composition is administered to the subject before onset of symptoms of the disease or disorder.

22. The method of any one of claims 13-20, wherein the composition is administered to the subject after onset of symptoms of the disease or disorder.

23. The method of any one of claims 13-22, wherein the method further comprises administering one or more additional therapeutic agents.