JP-2026075094-A - Methods to reduce HTT expression

Abstract

[Problem] To provide a method for mitigating Huntington's disease (HD), and a method for reducing HTT RNA and/or HTT protein in human subjects who require a reduction in HTT RNA and/or HTT protein. [Solution] A method for reducing HD in a human subject requiring reduction of HD is provided, the method comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide or a salt thereof. [Selection Diagram] None

Inventors

• ベネット，シー・フランク
• ノリス，ダニエル・エイ
• スミス，アン・ブイ
• レーン，ロジャー

Assignees

• アイオーニス ファーマシューティカルズ， インコーポレーテッド

Dates

Publication Date

20260507

Application Date

20251225

Priority Date

20200221

Claims (20)

1. A method for alleviating Huntington's disease (HD) in a human subject requiring alleviation of HD, wherein the method involves applying the following chemical structure to the human subject: The method comprising administering a therapeutically effective amount of a modified oligonucleotide or a salt thereof, in accordance with (Sequence ID 4).
2. The method according to claim 1, wherein the modified oligonucleotide is a sodium salt or a potassium salt.
3. A method for reducing HD in a human subject requiring HD reduction, wherein the method involves applying the following chemical structure to the human subject: The method comprising administering a therapeutically effective amount of a modified oligonucleotide in accordance with (Sequence ID 4).
4. A method for reducing HD in a human subject requiring reduction of HD, the method comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide, wherein the modified oligonucleotide has the following chemical notation (5'→3'): mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (Sequence ID 4), A = adenine nucleic acid base, mC = 5-methylcytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, e=2'-MOE sugar moiety, d = 2'-β-D-deoxyribosyl sugar moiety, The method wherein s = phosphorothioate nucleoside bond and o = phosphodiester nucleoside bond.
5. The method according to any one of claims 1 to 4, wherein at least one symptom of HD is alleviated.
6. The method according to claim 5, wherein the at least one symptom includes brain atrophy, decreased brain activity, decreased brain connectivity, muscle atrophy, neurodegeneration, heart failure, impaired glucose tolerance, weight loss, osteoporosis, testicular atrophy, general dysfunction, motor dysfunction, cognitive dysfunction, daily functioning impairment, decreased attention, impaired visual processing, decreased working memory, decreased psychomotor speed, impaired verbal motor output, decreased independence, decreased emotional blunting, decreased learning ability, impaired mental connectivity, speech impairment, depression, irritability, anger, motor dysfunction, self-care impairment, pain, discomfort, anxiety, suicidal ideation, suicidal behavior, or a combination thereof.
7. A method for reducing HTT RNA in a human subject requiring a reduction in HTT RNA, wherein the method involves applying the following chemical structure to the human subject: The method comprising administering a therapeutically effective amount of a modified oligonucleotide or a salt thereof, in accordance with (Sequence ID 4).
8. The method according to claim 7, wherein the modified oligonucleotide is a sodium salt or a potassium salt.
9. A method for reducing HTT RNA in a human subject requiring a reduction in HTT RNA, wherein the method involves applying the following chemical structure to the human subject: The method comprising administering a therapeutically effective amount of a modified oligonucleotide in accordance with (Sequence ID 4).
10. A method for reducing HTT RNA in a human subject requiring a reduction in HTT RNA, the method comprising administering a therapeutically effective amount of modified oligonucleotides to the human subject, wherein the modified oligonucleotides are chemically represented as follows (5'→3'): mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes It has mCe (SEQ ID NO: 4), A = adenine nucleic acid base, mC = 5-methylcytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, e=2'-MOE sugar moiety, d = 2'-β-D-deoxyribosyl sugar moiety, The method wherein s = phosphorothioate nucleoside bond and o = phosphodiester nucleoside bond.
11. A method for reducing HTT protein in a human subject requiring a reduction in HTT protein, wherein the method involves applying the following chemical structure to the human subject: The method comprising administering a therapeutically effective amount of a modified oligonucleotide or a salt thereof, in accordance with (Sequence ID 4).
12. The method according to claim 11, wherein the modified oligonucleotide is a sodium salt or a potassium salt.
13. A method for reducing HTT protein in a human subject requiring a reduction in HTT protein, wherein the method involves applying the following chemical structure to the human subject: The method comprising administering a therapeutically effective amount of a modified oligonucleotide in accordance with (Sequence ID 4).
14. A method for reducing HTT protein in a human subject requiring a reduction in HTT protein, the method comprising administering a therapeutically effective amount of a modified oligonucleotide to the human subject, wherein the modified oligonucleotide has the following chemical notation (5'→3'): mCes Teo mCeo Aeo Ges Tds Ads Ads mCds Ads Tds Tds Gds Ads mCds Aeo mCeo mCeo Aes mCe (Sequence ID 4), A = adenine nucleic acid base, mC = 5-methylcytosine nucleic acid base, G = guanine nucleic acid base, T = thymine nucleobase, e=2'-MOE sugar moiety, d = 2'-β-D-deoxyribosyl sugar moiety, The method wherein s = phosphorothioate nucleoside bond and o = phosphodiester nucleoside bond.
15. The method according to any one of claims 1 to 14, wherein the effective dose for the aforementioned treatment is 10 mg.
16. The method according to any one of claims 1 to 14, wherein the effective dose for the aforementioned treatment is 30 mg.
17. The method according to any one of claims 1 to 14, wherein the effective dose for the aforementioned treatment is 60 mg.
18. The method according to any one of claims 1 to 14, wherein the effective dose for the aforementioned treatment is 90 mg.
19. The method according to any one of claims 1 to 14, wherein the effective dose for the aforementioned treatment is 120 mg.
20. The method according to any one of claims 1 to 14, wherein the effective dose for the aforementioned treatment is approximately 10 mg.

Description

Sequence Listing This application has been filed electronically with a sequence listing. This sequence listing is provided as a file named BIOL0380WOSEQ_ST25.txt, 268KB in size, created on 18 February 2021. The electronic information of this sequence listing is incorporated herein by reference in its entirety. This specification provides a method for administering ISIS 443139 to alleviate Huntington's disease, reduce HTT RNA, reduce mHTT RNA, reduce HTT protein, or reduce mHTT protein in human subjects who require such treatment. In specific cases, the method is useful in alleviating at least one symptom of Huntington's disease. Such symptoms of Huntington's disease include, but are not limited to, brain atrophy, muscle atrophy, neurodegeneration, uncontrolled movements, dysphagia, dysarthria, anxiety, and depression. Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease characterized by progressive chorea, mental changes, and intellectual decline. HD affects both men and women equally and occurs in all races (Gusella and MacDonald, Curr. Opin. Neurobiol. 1995 5:656-62). Selective cell loss and fibrillary astrocytoma are observed in the brains of HD patients, particularly in the caudate nucleus and putamen of the striatum, as well as in the cerebral cortex (Vonsattel, J-P. et al., Neuropathol. Exp. Neurol. 1985, 44:559-577), and, less likely, in the hippocampus (Spargo, E. et al., J. Neurol. Neurosurg. Psychiatry 1993, 56:487-491) and the ventral thalamus (Byers, R.K. et al., Neurology 1973, 23:561-569). The symptoms of HD are due to neuronal death in many brain regions, but are most evident in the striatum, particularly the caudate nucleus, where patients suffer from a gradual, gradual decline in cell loss that ultimately kills the entire structure. HD is caused by an expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeat region in IT15, the gene encoding the huntingtin protein (HTT protein). The resulting expanded CAG repeat region encodes an abnormally long polyglutamine (PolyQ) tract within the HTT protein, leading to the expression of the mutant HTT (mHTT) protein. As a result of the excessive polyglutamine length, the mHTT protein forms aggregates in the cytoplasm and nucleus of CNS neurons (Davies). et al., Cell 1997, 90:537-548). Due to its genomic instability, the expanded CAG repeat region may expand further with age and during meiotic transmission, potentially containing additional CAG repeats. Individuals with 27–35 CAG repeats typically do not develop HD, but their children are at risk of HD progression. Individuals with 35–60 CAG repeats typically experience HD that begins in adulthood. Individuals with more than 60 CAG repeats typically experience adolescent HD progression, with HD symptoms being experienced before the age of 20. Individuals with a normal number of CAG repeats (<27) are not considered to be at risk of HD progression. This shows the mean reduction in cerebrospinal fluid (CSF) mHTT protein trough concentration as a percentage of baseline at multiple time points in human subjects treated every four weeks with the modified oligonucleotide ISIS 443139.This shows the mean reduction in cerebrospinal fluid (CSF) mHTT protein trough concentration as a percentage of baseline at multiple time points in human subjects treated every 8 weeks with the modified oligonucleotide ISIS 443139. This specification provides a method for alleviating Huntington's disease (HD), and a method for reducing HTT RNA and/or HTT protein in human subjects requiring a reduction in HTT RNA and/or HTT protein. In certain embodiments, HTT RNA is mHTT RNA. In certain embodiments, HTT protein is mHTT protein. In certain embodiments, the method comprises administering a therapeutically effective amount of modified oligonucleotide. In certain embodiments, the modified oligonucleotide is ISIS 443139. In certain embodiments, the therapeutically effective amount is in the range of about 40 mg to about 200 mg. In certain embodiments, the therapeutically effective amount is about 120 mg. In certain embodiments, the therapeutically effective amount is administered once every four weeks. In certain embodiments, the therapeutically effective amount is administered once every eight weeks. In certain embodiments, the therapeutically effective amount is administered once every sixteen weeks. In certain embodiments, the method includes administering a loading dose of approximately 120 mg of ISIS 443139 approximately once every four weeks, followed by a maintenance dose of 120 mg of ISIS 443139 approximately once every eight weeks or approximately once every sixteen weeks. Please understand that both the general description above and the detailed description below are illustrative and descriptive only, and not limiting. In this specification, the use of the singular includes the plural unless otherwise explicitly stated. Where used herein, the use of "or" means "and/or" unless otherwise e