CN-121986167-A - Glial targeted relief of hyperexcitability in neurodegenerative diseases

Abstract

The present disclosure relates to relief of hyperexcitability and related therapeutic agents and methods for treating neurodegenerative diseases.

Inventors

• S. Goldman
• M. Nedegaard
• C.Long

Assignees

• 罗切斯特大学

Dates

Publication Date

20260505

Application Date

20241022

Priority Date

20231023

Claims (20)

1. 1. A method of (i) reducing brain hyperexcitation in a subject in need thereof, or (ii) treating a condition mediated by brain hyperexcitation, the method comprising increasing the level or activity of Na + ,K + atpase in glial cells of the subject.
2. 2. A method of reducing the level of cerebral interstitial potassium in a subject in need thereof, the method comprising increasing the level or activity of Na + ,K + atpase in glial cells of the subject.
3. 3. The method of claim 1 or 2, wherein the subject has a condition mediated by neuronal hyperexcitability.
4. 4. The method of claim 2 or 3, wherein the brain interstitial potassium level is restored to ±30% of the brain interstitial potassium level of a normal healthy adult brain.
5. 5. The method of any one of the preceding claims, wherein the increasing comprises decreasing the expression level of FXYD1 gene in the glial cell.
6. 6. The method of claim 5, wherein the reducing comprises administering to the subject an agent that reduces the expression level of the FXYD1 gene in the glial cell.
7. 7. The method of claim 6, wherein the agent comprises or encodes an inhibitory nucleic acid or CRISPR/Cas system.
8. 8. The method of claim 7, wherein the inhibitory nucleic acid comprises an RNA molecule (small interfering RNA (siRNA), short hammerhead RNA (shRNA), or microrna (miRNA)).
9. 9. The method of claim 7, wherein the agent is an expression cassette or vector comprising a sequence encoding the inhibitory nucleic acid or encoding one or more components of the CRISPR/Cas system.
10. 10. The method of claim 9, wherein the sequence is operably linked to a cell type-selective or cell type-specific regulatory sequence.
11. 11. The method of claim 10, wherein the cell type selective or cell type specific regulatory sequence comprises a promoter or an enhancer or both.
12. 12. The method of claim 11, wherein the promoter is a glial cell specific promoter or a regulatable promoter.
13. 13. The method of any one of claims 9 to 12, wherein the vector is a viral vector.
14. 14. The method of any one of the preceding claims, wherein the glial cell is an astrocyte.
15. 15. The method of any one of the preceding claims, wherein the glial cells are glial progenitor cells.
16. 16. The method of any one of claims 1 and 3 to 15, wherein the condition is a neurodegenerative disease.
17. 17. The method of any one of claims 1 and 3 to 15, wherein the condition is Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, frontotemporal dementia, huntington's disease, or schizophrenia.
18. 18. The method of any one of claims 7 to 17, wherein the inhibitory nucleic acid or siRNA molecule comprises or encodes a sequence that is at least 75% complementary to a segment of the FXYD1 gene or RNA.
19. 19. The method of any one of claims 7 to 17, wherein the CRISPR/Cas system comprises or encodes a guide RNA (gRNA) sequence that is at least 75% complementary to a segment of the FXYD1 gene or RNA.
20. 20. An inhibitory nucleic acid or siRNA molecule comprising or encoding a sequence that is at least 75% complementary to a segment of the FXYD1 gene or RNA.

Description

Glial targeted relief of hyperexcitability in neurodegenerative diseases Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/592,271, filed on day 23, 10, 2023. The contents of said application are incorporated herein by reference in their entirety. Benefit of government The present invention was carried out under the AG072298 awarded by the national institutes of health (National Institutes of Health) with government support. The government has certain rights in this invention. Reference to an electronic sequence Listing The contents of the electronic sequence Listing (161118.04901 SeqList. Xml; size: 7,578 bytes; and date of creation: 10 month 15 of 2024) are incorporated herein by reference in their entirety. Technical Field The present disclosure relates to relief of hyperexcitability and related therapeutic agents and methods for treating neurodegenerative diseases. Background Neurodegenerative diseases are characterized by a gradual loss of structure or function of neurons in the brain or peripheral nervous system, which affects millions of people worldwide. Neurodegenerative disorders can be found in many different levels of neuronal circuits in the brain, ranging from molecules to the whole body. Aging is the most important risk factor for developing neurodegenerative diseases. Both the incidence and prevalence of neurodegenerative diseases including Alzheimer's disease and Huntington's disease, frontotemporal dementia (FTD) and FTD amyotrophic lateral sclerosis complex, and Parkinson's disease, lewy body disease (Lewy body disease) and multisystem atrophy increase with age. Each of these disorders is characterized by progressive neuronal loss, which is intimately associated with symptomatic disease progression and functional deterioration. In contrast, however, normal aging has been demonstrated to cause synaptic loss without a significant decrease in neuronal density. Despite intensive research in this area (focusing mainly on the potential neurotoxicity of amyloid, tau and synuclein and on neuroinflammation), understanding of the pathobiology of neuronal loss in neurodegenerative disorders remains limited. The need for new therapeutic agents for neurodegenerative diseases and methods for treating neurodegenerative diseases has not been met. Disclosure of Invention The present disclosure addresses the above-described needs in several aspects. In one aspect, the present disclosure provides a method of (i) reducing brain hyperexcitability in a subject in need thereof, or (ii) treating a condition mediated by brain hyperexcitability. The method comprises increasing the level or activity of Na +,K+ atpase in glial cells of the subject. In another aspect, the disclosure features a method of reducing the level of cerebral interstitial potassium in a subject in need thereof. The method comprises increasing the level or activity of Na +,K+ atpase in glial cells of the subject. In each of the methods described above, the subject may have a condition mediated by neuronal hyperexcitability. In some embodiments, the brain interstitial potassium level is restored to about ±30% of the brain interstitial potassium level of a normal healthy adult brain. In each of the methods described above, the increasing may comprise decreasing the expression level of FXYD1 gene in the glial cell. In one embodiment, the reducing comprises administering to the subject an agent that reduces the expression level of the FXYD1 gene in the glial cell. In some embodiments, the agent may comprise or encode an inhibitory nucleic acid or a CRISPR/Cas system. In some embodiments, the inhibitory nucleic acid comprises an RNA molecule, such as a small interfering RNA (siRNA), short hammerhead RNA (shRNA), or microrna (miRNA). In some embodiments, the agent is or comprises an expression cassette or vector comprising a sequence encoding the inhibitory nucleic acid or encoding one or more components of the CRISPR/Cas system. In some embodiments, the sequence is operably linked to a cell type-selective or cell type-specific regulatory sequence. In some embodiments, the cell type selective or cell type specific regulatory sequence comprises a promoter or an enhancer or both. The promoter may be a glial cell specific promoter or a regulatable promoter. The vector may be a viral vector. In each of the methods described above, the glial cells may be astrocytes, glial progenitor cells, or oligodendrocytes. The condition mentioned above may be a neurodegenerative disease. Examples of such conditions or neurodegenerative diseases include Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, frontotemporal dementia, huntington's disease, and schizophrenia. In some embodiments, the inhibitory nucleic acid or siRNA molecule comprises or encodes a sequence that is at least 75% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100) complementary to a segment of the