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WO-2026095932-A1 - COMPOSITIONS AND METHODS TO TREAT NEURODEGENERATION AND COGNITIVE DECLINE

WO2026095932A1WO 2026095932 A1WO2026095932 A1WO 2026095932A1WO-2026095932-A1

Abstract

The present disclosure provides methods for treating neurodegeneration or cognitive decline in a subject comprising administering an effective amount of catestatin (CST) or its equivalent to a subject afflicted with a neurodegenerative disease, thereby, reducing neurodegeneration or cognitive decline.

Inventors

  • MAHATA, SUSHIL K.
  • JATI, Suborno

Assignees

  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date
20260507
Application Date
20241030

Claims (18)

  1. 1. A method for treating neurodegeneration in a subject in need thereof comprising administering an effective amount of catestatin (CST) or an equivalent thereof to the subject.
  2. 2. The method of claim 1, wherein the effective amount of CST is an amount that results in (i) at least 50% decrease in phosphorylation of Tau in the subject or (ii) an improvement in memory function of the subject.
  3. 3. The method of claim 1 or claim 2, wherein the effective amount is between about 20 mg to about 200 mg.
  4. 4. The method of any one of claims 1-3, wherein the subject has low levels of naturally occurring CST in the subject’s plasma cortex or hippocampus.
  5. 5. The method of any one of claims 1-3, wherein the subject is suffering from a tauopathy.
  6. 6. The method of any one of claims 1-5, wherein the CST or the equivalent thereof comprises a peptide selected from SEQ ID NOs: 1-28.
  7. 7. The method of claim 6, wherein the CST or the equivalent thereof further comprises a non-natural amino acid at position R8 of SEQ ID NO: 1, or an equivalent thereof.
  8. 8. The method of claim 6, wherein the CST or the equivalent thereof further comprises a fatty acid and/or an acyl group, wherein the fatty acid has 10, 12, 14, 16, or 18 carbons.
  9. 9. The method of claim 6, wherein the CST or the equivalent thereof further comprises at least one polyethylene glycol (PEG) moiety.
  10. 10. The method of any one of claims 1-5, wherein the equivalent of CST comprises a retro-inverso peptide of any of the sequences selected from SEQ ID NOs: 1-28.
  11. 11. The method of any one of claims 1-10, wherein the CST or an equivalent thereof is administered every 12 hours, once every day, once every three days, once every week, once in two weeks or once every month.
  12. 12. The method of any one of claims 1-11, wherein the subject is a mammal, optionally a human patient.
  13. 13. The method of any one of claims 1-12, wherein the CST or an equivalent thereof is administered by an enteral route, buccal route, intraperitoneal route, inhalation route, intravenous route, subcutaneous route or intramuscular route. 29 4867-5418-2384.2 Aty. Dkt. No.: 114198-3450
  14. 14. A composition comprising a CST or an equivalent thereof that comprises a peptide selected from SEQ ID NOs: 1-28, wherein the CST or the equivalent thereof further comprises a non-natural amino acid at position R8.
  15. 15. The composition of claim 14, wherein the non-natural amino acid is D-Arginine, a methyl amino acid or a P-amino acid.
  16. 16. A composition comprising a CST or an equivalent thereof that comprises a peptide selected from SEQ ID NOs: 1-28, wherein the CST or the equivalent thereof further comprises a fatty acid and/or an acyl group, wherein the fatty acid has 10, 12, 14, 16, or 18 carbons.
  17. 17. The composition of claim 16, wherein the fatty acid is attached to the CST or the equivalent thereof comprises 16 carbons.
  18. 18. A composition comprising a CST or an equivalent thereof that comprises a peptide selected from SEQ ID NOs: 1-28, wherein the CST or the equivalent thereof further comprises at least one polyethylene glycol (PEG) moiety. 30 4867-5418-2384.2

Description

Atty. Dkt. No.: 114198-3450 COMPOSITIONS AND METHODS TO TREAT NEURODEGENERATION AND COGNITIVE DECLINE STATEMENT OF GOVERNMENT SUPPORT [0001] This invention was made with government support under AG080246 and AG078635 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0002] Neurodegeneration refers to the progressive loss of structure or function of neurons, including their death. This process is a hallmark of various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. These conditions gradually damage and destroy parts of the nervous system, particularly the brain, leading to a decline in cognitive functioning. [0003] Cognitive decline is a common symptom of neurodegenerative diseases and can manifest in various ways, including memory loss, difficulty with problem-solving, and impaired judgment. Better treatments for slowing down or reversing neurodegeneration and cognitive decline are needed. [0004] Tauopathies are a broad class of neurodegenerative diseases characterized by the accumulation of tau aggregates in the brain. Primary tauopathies such as Pick’s disease (PiD: 3R, where R represents microtubule binding domain), corticobasal degeneration (CBD: 4R), progressive supranuclear palsy (PSP: 4R), globular glial tauopathy (GGT: 4R), argyrophilic grain disease (AGD: 4R) and exhibit only tau inclusions, whereas AD, a secondary tauopathy, is characterized by the presence of extracellular beta-amyloid (AP) plaques and intracellular neurofibrillary tau tangles. Six major isoforms were detected in the brains of AD patients: 2N4R (441 aa), 1N4R (412 aa), 0N4R (383 aa), 2N3R (410 aa), 1N3R (381 aa) and 0N34 (352aa), where N represents the amino-terminal region. Hyperphosphorylation of tau weakens tau’s microtubule-binding affinity, leading to its neurotoxic aggregation, forming tangles of different substructures. Tauopathies are closely associated with metabolic dysfunctions, including insulin resistance, hyperglycemia, and hypertension, as well as neuroinflammation. However, the pathophysiology underlying tauopathy development during aging remains elusive. 1 4867-5418-2384.2 Atty. Dkt. No.: 114198-3450 SUMMARY OF THE DISCLOSURE [0005] In one aspect, provided herein is a method for treating neurodegeneration in a subject in need thereof comprising, or alternatively consisting essentially of, or consisting of, or yet further consisting of administering an effective amount of chromogranin A (CgA)-derived peptide catestatin (CST: human CgA352-372) or an equivalent thereof to the subject. [0006] In some embodiments, the effective amount of CST is an amount that results in (i) at least 50% decrease in phosphorylation of Tau in the subject or (ii) an improvement in memory function of the subject. [0007] In some embodiments, the effective amount is between about 20mg and about 200mg. [0008] In some embodiments, the subject in need thereof has low levels of naturally occurring CST in the subject’s plasma, cortex or hippocampus. [0009] In some embodiments, the subject is suffering from a tauopathy. [0010] In some embodiments, the CST or the equivalent thereof comprises, or alternatively consists essentially of, or consists of, or yet further consists of a peptide selected from SEQ ID NOs: 1-28. [0011] In some embodiments, the CST or the equivalent thereof further comprises a nonnatural amino acid at position R8 of SEQ ID NO: 1, or an equivalent thereof wherein the non- naturally amino acid at position R8 is retained. [0012] In some embodiments, the CST or the equivalent thereof further comprises a fatty acid and/or an acyl group, wherein the fatty acid has 10, 12, 14, 16, or 18 carbons. [0013] In some embodiments, the CST or the equivalent thereof further comprises at least one polyethylene glycol (PEG) moiety. [0014] In some embodiments, the equivalent of CST comprises, or alternatively consists essentially of, or consists of, or yet further consists of a retro-inverso peptide of any of the sequences selected from SEQ ID NOs: 1-28 [0015] In some embodiments, the CST or an equivalent thereof is administered every 12 hours, once every day, once every three days, once every week, once in two weeks or once every month. [0016] In some embodiments, the subject is a mammal, optionally a human patient. 2 4867-5418-2384.2 Aty. Dkt. No.: 114198-3450 [0017] In some embodiments, the CST or an equivalent thereof is administered by an enteral route, buccal route, intraperitoneal route, inhalation route, intravenous route, subcutaneous route or intramuscular route. BRIEF DESCRIPTION OF THE FIGURES [0018] FIGS. 1A-1I. Biochemical determination of CST in human samples. CST content was found to have decreased (A) a -36% decrease in AD frontal cortex, (B) a -19% decrease AD hippocampus, (C) a -29% decrease in CBD frontal cortex, and (D) a -37% decrease in PSP basal ganglia. AD patients were diagnosed as having Braak