KR-20260062947-A - Treatment of muscle disorders using polyculin-interacting protein 1 (FNIP1) inhibitors and/or polyculin (FLCN) inhibitors

Abstract

The present disclosure generally relates to the treatment of subjects who have muscle disorders or are at risk of developing muscle disorders by administering a polyculin-interacting protein 1 (FNIP1) inhibitor and/or a polyculin (FLCN) inhibitor to the subjects.

Inventors

• 로타, 루카 안드레아
• 힌디, 조지
• 구사로바, 빅토리아
• 슬리먼, 마크
• 애덤, 르네 크리스티안

Assignees

• 리제너론 파마슈티칼스 인코포레이티드

Dates

Publication Date

20260507

Application Date

20240828

Priority Date

20230829

Claims (20)

1. A method for treating a subject having a muscle disorder or at risk of developing a muscle disorder, the method comprising the step of administering a polyculin interacting protein 1 (FNIP1) inhibitor and/or a polyculin (FLCN) inhibitor to the subject.
2. A method according to claim 1, wherein the muscle disorder comprises sarcopenia, Duchenne muscular dystrophy, or Pompe disease.
3. A method according to claim 1 or 2, wherein the FNIP1 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an FNIP1 nucleic acid molecule.
4. In paragraph 3, the method wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, small interfering RNA (siRNA), and/or short hairpin RNA (shRNA).
5. In paragraph 4, the method wherein the inhibitory nucleic acid molecule comprises siRNA.
6. In paragraph 4, the method wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.
7. A method according to any one of claims 1 to 6, wherein the FLCN inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to a FLCN nucleic acid molecule.
8. In claim 7, the method wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, small interfering RNA (siRNA), and/or short hairpin RNA (shRNA).
9. In claim 8, the method wherein the inhibitory nucleic acid molecule comprises siRNA.
10. In claim 8, the method wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.
11. A method of administering a muscle disorder treatment agent to the subject in any one of claims 1 to 10.
12. A method according to any one of claims 1 to 11, further comprising the step of detecting the presence or absence of FNIP1 variant nucleic acid molecules and/or FLCN variant nucleic acid molecules in a biological sample from the subject.
13. A method according to claim 12, comprising the step of administering a muscle disorder treatment agent to the subject at a standard dose when the FNIP1 variant nucleic acid molecule and/or FLCN variant nucleic acid molecule are absent from the biological sample.
14. A method according to claim 12, further comprising the step of administering a muscle disorder treatment agent to a subject in an amount equal to or less than the standard dose, where the subject is heterozygous with respect to the FNIP1 variant nucleic acid molecule and/or FLCN variant nucleic acid molecule.
15. A method according to any one of claims 12 to 14, wherein the FNIP1 variant nucleic acid molecule and/or FLCN variant nucleic acid molecule comprises a splice-site variant, a termination-gain variant, an initiation-loss variant, a termination-loss variant, a frameshift variant, a missense variant, an inframe indel variant, and/or a variant encoding a truncated FNIP1 variant polypeptide or a truncated FLCN variant polypeptide.
16. A method according to any one of claims 12 to 14, wherein the FNIP1 variant nucleic acid molecule comprises one or more of the genetic variants of Table 8.
17. A method according to any one of claims 12 to 14, wherein the FLCN variant nucleic acid molecule comprises one or more of the genetic variants of Table 9.
18. A method for treating a subject who has a muscle disorder or is at risk of developing a muscle disorder by administering a muscle disorder treatment agent, wherein the method Obtaining or causing to obtain a biological sample from the above-mentioned subject; By performing or causing sequencing analysis on the biological sample to determine whether the subject has a genotype comprising polyculin interacting protein 1 (FNIP1) variant nucleic acid molecules and/or polyculin (FLCN) variant nucleic acid molecules, A step of determining or determining whether the above-mentioned object has FNIP1 variant nucleic acid molecules and/or FLCN variant nucleic acid molecules; and A step of administering or continuing to administer the muscle disorder therapeutic agent to a subject who is an FNIP1 reference type and/or an FLCN reference type in an amount equal to or less than the standard dose, and/or an FNIP1 inhibitor and/or an FLCN inhibitor; A step of administering or continuing to administer the muscle disorder therapeutic agent to a subject heterozygous to the FNIP1 variant nucleic acid molecule and/or FLCN variant nucleic acid molecule in an amount equal to or less than the standard dose, and/or an FNIP1 inhibitor and/or FLCN inhibitor; or The method includes the step of administering the muscle disorder therapeutic agent at a standard dose or continuously administering it to a subject who is homozygous for the FNIP1 variant nucleic acid molecule and/or FLCN variant nucleic acid molecule; A method in which the presence of the above FNIP1 variant nucleic acid molecule and/or FLCN variant nucleic acid molecule indicates that the subject has a reduced risk of developing muscle disorder.
19. In paragraph 18, the above muscle disorder includes sarcopenia, Duchenne muscular dystrophy, or Pompe disease.
20. The method of claim 18 or 19, wherein the FNIP1 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an FNIP1 nucleic acid molecule.

Description

Treatment of muscle disorders using polyculin-interacting protein 1 (FNIP1) inhibitors and/or polyculin (FLCN) inhibitors See sequence list The present application contains a sequence list electronically written in an XML file named 381204286SEQ, created on August 21, 2024, with a size of 106,382 bytes. The sequence list is incorporated herein by reference. field The present disclosure relates to a method for treating a subject who has a muscle disorder or is at risk of developing a muscle disorder by administering a polyculin interacting protein 1 (FNIP1) inhibitor and/or a polyculin (FLCN) inhibitor, and a method for identifying a subject at increased risk of developing a muscle disorder. Causes of muscle disorders include injury or overuse such as sprains or muscle strains, spasms or tendinitis; genetic diseases such as muscular dystrophy; some cancers; inflammation such as myositis, neurological diseases affecting muscles; infections; and certain drugs. Muscle disorders include sarcopenia, Duchenne muscular dystrophy, and Pompe disease. Polyculin (FLCN) is encoded by a 25 kb gene located at 17p11.2. FLCN is a 64 kDa multifunctional protein with a length of 579 amino acids that is involved in both the cellular response to amino acid availability and the regulation of glycolysis. Specifically, FLCN regulates the mTORC1 signaling cascade, which controls the MiT/TFE factors TFEB and TFE3 in the cellular response to amino acid availability, and regulates glycolysis by binding to LDHA, a lactate dehydrogenase that acts as a non-competitive inhibitor. Additionally, FLCN stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD and activates mTORC1 by acting as a GTPase-activating protein, which facilitates the conversion of RRAGC/RagC or RRAGD/RagD to a GDP-bound state, thereby activating the kinase activity of mTORC1. Polyculin Interacting Protein 1 (FNIP1) is encoded by a 155 kb gene located at 5q31.1. FNIP1 is a 130 kDa protein with a length of 1166 amino acids that participates in the regulation of cellular metabolism and nutrient sensing by regulating targets of the AMP-activated protein kinase (AMPK) and rapamycin signaling pathways. Additionally, FNIP1 not only binds to the tumor suppressor protein polyculin but also negatively regulates ATPase activity by associating with the molecular chaperone heat shock protein-90 (Hsp90) and facilitating its binding to polyculin. The present disclosure provides a method for treating a subject who has a muscle disorder or is at risk of developing a muscle disorder, the method comprising the step of administering an FNIP1 inhibitor and/or FLCN inhibitor to the subject. The present disclosure also provides a method for treating a subject having a muscle disorder or at risk of developing a muscle disorder by administering a muscle disorder therapeutic agent, wherein the method comprises the steps of: obtaining or causing to obtain a biological sample from the subject; determining or causing to determine whether the subject has an FNIP1 variant nucleic acid molecule and/or an FLCN variant nucleic acid molecule by performing or causing to perform sequencing analysis on the biological sample to determine whether the subject has a genotype comprising an FNIP1 variant nucleic acid molecule and/or an FLCN variant nucleic acid molecule; and administering or continuing to administer a muscle disorder therapeutic agent at a standard dose and/or an FNIP1 inhibitor and/or an FLCN inhibitor to a subject who is a FNIP1 reference type and/or an FLCN reference type; administering or continuing to administer a muscle disorder therapeutic agent at an amount equal to or less than the standard dose to a subject who is heterozygous for an FNIP1 variant nucleic acid molecule and/or an FLCN variant nucleic acid molecule; and/or administering an FNIP1 inhibitor and/or an FLCN inhibitor. or includes the step of administering a muscle disorder treatment agent to a subject who is homozygous for FNIP1 variant nucleic acid molecules and/or FLCN variant nucleic acid molecules at an amount equal to or less than the standard dose, or continuing to administer; wherein the presence of FNIP1 variant nucleic acid molecules and/or FLCN variant nucleic acid molecules indicates that the subject has a reduced risk of developing muscle disorder. The present disclosure also provides a method for identifying a subject at increased risk of developing a muscle disorder, the method comprising the step of determining or causing to determine the presence or absence of FNIP1 variant nucleic acid molecules and/or FLCN variant nucleic acid molecules in a biological sample obtained from the subject; wherein if the subject is FNIP1 reference type and/or FLCN reference type, the subject has an increased risk of developing a muscle disorder; and if the subject is heterozygous or homozygous for FNIP1 variant nucleic acid molecules and/or FLCN variant nucleic acid molecules, the subject has a reduced risk of developing a muscle