Compounds and methods for treating Friedreich's ataxia

Compounds targeting GAA trinucleotide repeats in the FXN gene modulate FXN expression to treat Friedreich's ataxia, addressing the lack of effective treatments by enhancing binding affinity and selectivity, thereby reversing disease progression.

JP2025502064APending Publication Date: 2025-01-24DESIGN THERAPEUTICS INC
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Patent Information

Application Number
JP2024540893
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2022-11-08
Filing Date
2023-01-06
Publication Date
2025-01-24

AI Technical Summary

Technical Problem

Current treatments for Friedreich's ataxia (FA), caused by deficient FXN gene expression due to GAA trinucleotide repeat expansions, lack efficacy in reversing the disease progression, leading to severe neurological and cardiac symptoms.

Method used

Development of compounds that selectively bind to the GAA trinucleotide repeat sequences in the FXN gene, recruiting regulatory proteins to modulate FXN gene expression, thereby adjusting its production and reducing disease symptoms.

Benefits of technology

The compounds effectively downregulate deficient FXN gene expression, potentially reversing FA progression and alleviating associated symptoms by enhancing binding affinity and selectivity.

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Abstract

The present disclosure relates to compounds and methods for regulating the expression of fxn and treating diseases and conditions in which fxn plays an active role. The compounds can be transcriptional modulator molecules having a first end, a second end, and an oligomeric backbone, a) the first end comprising a DNA binding moiety capable of non-covalently binding to the trinucleotide repeat sequence GAA, b) the second end comprising a protein binding moiety that binds to a regulatory molecule that regulates the expression of a gene comprising the nucleotide repeat sequence GAA, and c) the oligomeric backbone comprising a linker between the first end and the second end.
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Claims

【Request 1】 【Chemical 1-1】 【Chemistry 1-2】 【Chemistry 1-3】 【Chemistry 1-4】 【Chemistry 1-5】 or a pharma- ceutically acceptable salt thereof.

2. The compound is 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

3. The compound is 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

4. The compound is 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

5. The compound is 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

6. The compound is 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

7. The compound is 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

8. The compound is 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

9. The compound is 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

10. The compound is 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

11. The compound is 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

12. The compound is 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof.

13. The compound is 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof.

14. The compound is 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof.

15. The compound is 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof.

16. The compound is 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof.

17. The compound is 【Chemistry 17】 or a pharma- ceutically acceptable salt thereof.

18. The compound is 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof.

19. The compound is 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof.

20. The compound is 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

22. 22. A method of regulating expression of fxn, comprising contacting fxn with a compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.

23. 23. A method of treating a disease or condition caused by expression of defective fxn in a patient in need thereof, comprising administering to said patient a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

24. 24. The method of claim 23, wherein the disease is Friedreich's ataxia (FA).

25. 22. A method of treating Friedreich's ataxia (FA) in a patient in need thereof, comprising administering to the patient a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21.

26. 26. The method of claim 25, wherein the method comprises reducing one or more of muscle atrophy, ataxia, fasciculation, or dementia.