US-12622916-B2 - Use of H3K9me3 modulation for enhancing cognitive function

Abstract

Use of H3K9me3 modulation for enhancing cognitive function and treating anxiety related disorders is presented. A composition is administered to the subject comprising a therapeutically effective amount of a SUV39H1 inhibitor comprising analogs of ETP69. The therapeutically effective amount is effective in treating cognitive dysfunction in aging and age-related disorders.

Inventors

• Carl Cotman
• Larry Overman
• Shikha SNIGDHA

Assignees

• THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date

20260512

Application Date

20240214

Claims (20)

1. 1 . A method of treating, preventing, or alleviating a cognitive dysfunction, comprising: administering to a subject suspected of having the cognitive dysfunction a therapeutically effective amount of a histone methylation inhibitor ETP69.
2. 2 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 inhibits a histone methyltransferase.
3. 3 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 inhibits histone lysine methylation.
4. 4 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 inhibits a histone trimethylation.
5. 5 . The method of claim 1 , wherein the subject is a human.
6. 6 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 inhibits a histone 3 methylation.
7. 7 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 inhibits a histone 3 lysine 9 (H3K9) methylation.
8. 8 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 inhibits a H3K9 trimethylation (H3K9me3).
9. 9 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 does not significantly inhibit a histone acetyltransferase.
10. 10 . The method of claim 9 , wherein the histone acetyltransferase comprises p300.
11. 11 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 does not significantly inhibit a DNA methyltransferase.
12. 12 . The method of claim 11 , wherein the DNA methyltransferase comprises DMT1.
13. 13 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 is more selective against a methyltransferase than a chaetocin A.
14. 14 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 increases phosphorylation of a Akt or a CREB.
15. 15 . The method of claim 1 , wherein the histone methylation inhibitor ETP69 is administered as a pharmaceutical composition.
16. 16 . The method of claim 15 , wherein the administration prevents the cognitive dysfunction in the subject.
17. 17 . The method of claim 1 , wherein the subject has the cognitive dysfunction.
18. 18 . The method of claim 17 , wherein the administration slows, stops, or reverses the cognitive dysfunction in the subject.
19. 19 . The method of claim 1 , wherein the administration improves neuronal survival or increases neuronal spine density in the subject.
20. 20 . The method of claim 1 , wherein the administration improves memory in the subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is a continuation of U.S. application Ser. No. 17/697,893 which is a continuation of U.S. application Ser. No. 17/072,539, filed on Oct. 16, 2020, which is a continuation of U.S. application Ser. No. 16/354,996, filed on Mar. 15, 2019, now U.S. Pat. No. 10,849,910, which is a continuation of U.S. application Ser. No. 15/580,419, filed on Dec. 7, 2017, now U.S. Pat. No. 10,272,093, which is a U.S. National Phase of PCT/US2016/035764, filed on Jun. 3, 2016, which claims the benefit of U.S. Provisional Application Ser. No. 62/172,690, filed on Jun. 8, 2015, which is herein incorporated by reference for completeness of disclosure. STATEMENT AS TO RIGHTS TO INVENTION MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under Grant No. AG000538 and AG012694 awarded by the National Institute of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Field of the Invention Embodiments of the invention relates to treating cognitive dysfunction in aging, age-related and brain derived neurotrophic factor (BDNF)-dependent disorders. More specifically, the invention relates to treating cognitive dysfunction via administration of a SUV39H1 inhibitor referred to as ETP69 (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) either alone, or in combination with other cognitive enhancers. Description of the Related Art Epigenetic dysregulation is known to contribute to several aspects of age related memory deficits. In the past few years many studies have identified changes in histone methylation states in aging. Methylation of the histone tail typically occurs at specific lysine residues, such as H3K4, H3K9, H3K27, H3K36, H3K79 and H4K20, and can either activate or repress transcription. In particular, trimethylation of H3K9 (H3K9me3) is an important repressive histone mark, and is implicated in gene silencing. Establishment of H3K9me3 depends on the activity of the histone methyl transferase SUV39H1 which regulates H3K9 trimethylation at the peri-centric heterochromatin. While variations in H3K9 methylation have been suggested to be the underlying epigenetic mechanism for several age-related changes such as sustained vascular inflammation, diabetes, and metabolic memory, the direct effect of aging on regulation of histone lysine methylation in the brain has not been explored previously. Nor have there been any studies, which directly address the effect of SUV39H1 inhibition, and the corresponding downregulation of H3K9me3 on memory and cognitive function. Recent progress in the development of small molecule inhibitors of methyltransferases and demethylases which regulate the function of enzymes that contribute to histone methylation may thus be a powerful means to offset age-related deficits. There is an urgent need to identify therapies and therapeutic regimes for cognitive dysfunction, e.g., cognitive deficits related to aging, aged-related disorders and Alzheimer's disease. BRIEF SUMMARY OF THE INVENTION One or more embodiments of the invention are directed to use of H3K9me3 modulation for enhancing cognitive function in aging and for treatment of age-related disorders, e.g. dementia and other defects related to brain and neural functions. Some recent studies have revealed that histone methyltransferases and demethylases are implicated in aging and longevity. Methyltransferases catalyze histone methylation of specific genomic loci. And yet, how histone methylation contributes to learning and memory in aging has never been explored. Trimethylation of H3K9 (H3K9me3) is an important repressive histone mark, and is typically implicated in gene silencing. Embodiments of the present invention identify for the first time an essential role for histone H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged animals, and improved performance in the object location memory task, fear conditioning task and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased GluR1-containing AMPA receptors levels at spine surface, a key index of long-term potentiation (LTP). In addition, there were changes at the BDNF gene promoter regions, in concert with overall BDNF protein levels in the hippocampus of drug treated animals compared with control animals. BDNF is a key member of the neurotrophin family, and is involved in a wide range of neurodegenerative diseases including mood disorders, depression, bipolar disorder and neuropsychiatric conditions such as schizophrenia, apart from aging. Through variou