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CN-122003238-A - Methods for the combined treatment of spinal muscular atrophy

CN122003238ACN 122003238 ACN122003238 ACN 122003238ACN-122003238-A

Abstract

Methods of treating Spinal Muscular Atrophy (SMA) using a combination of a 15-hydroxyprostadil dehydrogenase (15-PGDH) inhibitor and an agent that increases the expression of a motor neuron Survival (SMN) protein are provided. Further, provided herein is a composition, pharmaceutical formulation, or kit comprising a 15-hydroxy prostaglandin dehydrogenase (15-PGDH) inhibitor and an agent that increases the expression of a motor neuron Survival (SMN) protein.

Inventors

  • Maika Webster
  • Alexander. Castine
  • Bruce Fall

Assignees

  • 埃皮里姆生物股份有限公司

Dates

Publication Date
20260508
Application Date
20240712
Priority Date
20230714

Claims (20)

  1. 1. A method of treating Spinal Muscular Atrophy (SMA), the method comprising: administering to a subject in need thereof an amount effective to treat the SMA, (I) 15-hydroxy prostaglandin dehydrogenase (15-PGDH) inhibitor, and (Ii) An agent that increases the expression of a motor neuron Survival (SMN) protein, Thereby treating the SMA.
  2. 2. The method of claim 1, wherein the SMN protein is selected from the group consisting of a motor neuron survival 1 (SMN 1) protein, a motor neuron survival 2 (SMN 2) protein, and any combination thereof.
  3. 3. The method of claim 1 or 2, wherein the agent that increases the expression of SMN protein is an agent that increases the expression of SMN2 protein.
  4. 4. The method of claim 3, wherein the agent that increases expression of SMN2 protein is an agent that modulates splicing of motor neuron survival 2 (SMN 2) pre-mRNA.
  5. 5. The method of claim 4, wherein the agent that modulates the splicing of SMN2 pre-mRNA increases exon 7 inclusion in SMN2 mRNA transcripts.
  6. 6. The method of claim 4 or 5, wherein the agent that modulates the splicing of SMN2 pre-mRNA is selected from the group consisting of Li Sipu orchid, SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, bunapolan, sodium noocina, and any combination thereof.
  7. 7. The method of claim 3, wherein the agent that increases the expression of SMN2 protein is RG3039.
  8. 8. The method of claim 1 or 2, wherein the agent that increases the expression of SMN protein is an agent that increases the expression of SMN1 protein.
  9. 9. The method of claim 8, wherein the agent that increases the expression of SMN1 protein is onasemnogene abeparvovec.
  10. 10. The method of any one of claims 1-9, wherein the agent that increases the expression of SMN protein is selected from the group consisting of a small molecule, an antisense oligonucleotide, siRNA, miRNA, shRNA, a gene therapy agent, an antigen binding unit, a peptide, an aptamer, and any combination thereof.
  11. 11. The method of claim 10, wherein the agent that increases expression of SMN protein is a small molecule.
  12. 12. The method of claim 10, wherein the agent that increases expression of SMN protein is an antisense oligonucleotide.
  13. 13. The method of claim 10, wherein the agent that increases expression of SMN protein is a gene therapy agent.
  14. 14. The method of any one of claims 1-13, wherein the SMA is selected from SMA type 0, SMA type 1 (Werdnig-Hoffmann disease), SMA type 2 (Dubowitz disease), SMA type 3 (Kugelberg-Welander disease), and SMA type 4.
  15. 15. The method of any one of claims 1-14, wherein the administering the 15-PGDH inhibitor, the agent that increases the expression of SMN protein, or both is selected from the group consisting of oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intraarterial administration, intradermal administration, subcutaneous administration, and any combination thereof.
  16. 16. The method of any one of claims 1-15, wherein the administering the 15-PGDH inhibitor, the agent that increases the expression of SMN protein, or both is selected from acute administration, chronic administration, intermittent administration, and continuous administration.
  17. 17. The method of any one of claims 1-16, wherein the administering comprises administering the 15-PGDH inhibitor and the agent that increases the expression of SMN protein as a single formulation to the subject in need thereof.
  18. 18. The method of any one of claims 1-16, wherein the administering comprises sequentially administering the 15-PGDH inhibitor and the agent that increases the expression of SMN protein in separate formulations to the subject in need thereof.
  19. 19. The method of any one of claims 1-16, wherein the administering comprises administering the 15-PGDH inhibitor prior to administering the agent that increases the expression of SMN protein to the subject in need thereof.
  20. 20. The method of any one of claims 1-16, wherein the administering comprises administering the agent that increases SMN protein expression prior to administering the 15-PGDH inhibitor to the subject in need thereof.

Description

Methods for the combined treatment of spinal muscular atrophy Cross reference The present application claims the benefit of U.S. provisional application No. 63/513,814, filed on 7.14 of 2023, which provisional application is incorporated herein by reference in its entirety. Background Muscle disorders or conditions occur in a variety of forms and may range from relatively mild to extremely severe. The muscle disorder or condition may be inherited (e.g., muscular dystrophy), or obtained. Spinal Muscular Atrophy (SMA) is an autosomal recessive genetic disease that involves loss of motor neurons, affecting the nervous system and voluntary muscle movements. There is an unmet need for treatment of SMA. Incorporation by reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. Disclosure of Invention There is an unmet need for treatment of Spinal Muscular Atrophy (SMA). The present disclosure meets this unmet need. In one aspect, the present disclosure provides a method of treating Spinal Muscular Atrophy (SMA), the method comprising administering to a subject in need thereof (i) a 15-hydroxy prostaglandin dehydrogenase (15-PGDH) inhibitor, and (ii) an agent that increases expression of a motor neuron Survival (SMN) protein, in an amount effective to treat the SMA. In some embodiments, the SMN protein is selected from the group consisting of a motor neuron survival 1 (SMN 1) protein, a motor neuron survival 2 (SMN 2) protein, and any combination thereof. In some embodiments, the agent that increases the expression of SMN protein is an agent that increases the expression of SMN2 protein. In some embodiments, the agent that increases expression of SMN2 protein is an agent that modulates splicing of motor neuron survival 2 (SMN 2) pre-mRNA. In some embodiments, the agent that modulates splicing of SMN2 pre-mRNA increases exon 7 inclusion in the SMN2 mRNA transcript. In some embodiments, the agent that modulates splicing of SMN2 pre-mRNA is selected from the group consisting of Li Sipu orchid (risdiplam), SMN-C2, SMN-C3, SMN-C5, RG-7916, RG7800, SMN-C1, SMN-C8, bunapolan (Branaplam), sodium norcinal (nusinersen), and any combination thereof. In some embodiments, the agent that increases expression of the SMN2 protein is RG3039. In some embodiments, the agent that increases the expression of SMN protein is an agent that increases the expression of SMN1 protein. In some embodiments, the agent that increases the expression of SMN1 protein is onasemnogene abeparvovec. In some embodiments, the agent that increases the expression of the SMN protein is selected from the group consisting of a small molecule, an antisense oligonucleotide, siRNA, miRNA, shRNA, a gene therapeutic agent, an antigen binding unit, a peptide, an aptamer, and any combination thereof. In some embodiments, the agent that increases the expression of SMN protein is a small molecule. In some embodiments, the agent that increases the expression of SMN protein is an antisense oligonucleotide. In some embodiments, the agent that increases the expression of SMN protein is a gene therapy agent. In some embodiments, the SMA is selected from the group consisting of SMA type 0, SMA type 1 (Werdnig-Hoffmann disease), SMA type 2 (Dubowitz disease), SMA type 3 (Kugelberg-Welander disease), and SMA type 4. In some embodiments, the 15-PGDH inhibitor is administered, the agent that increases the expression of SMN protein is administered, or both, is selected from the group consisting of oral administration, intramuscular administration, intrathecal administration, intravenous administration, intraperitoneal administration, intra-arterial injection, intradermal administration, subcutaneous administration, and any combination thereof. In some embodiments, the 15-PGDH inhibitor is administered, the agent that increases the expression of SMN protein is administered, or both, are selected from the group consisting of acute administration, chronic administration, intermittent administration, and continuous administration. In some embodiments, administering comprises administering to a subject in need thereof a 15-PGDH inhibitor and an agent that increases the expression of SMN protein in a single formulation. In some embodiments, administering comprises sequentially administering to a subject in need thereof a 15-PGDH inhibitor and an agent that increases the expression of SMN protein in separate formulations. In some embodiments, administering comprises administering a 15-PGDH inhibitor to a su