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EP-4736867-A1 - COMPOSITION FOR TREATING SPINAL CORD INJURY DISEASES AND USE THEREOF

EP4736867A1EP 4736867 A1EP4736867 A1EP 4736867A1EP-4736867-A1

Abstract

The present disclosure relates to a composition for treating spinal cord injury disorders and a method of using the same.

Inventors

  • CHANG, Yujung
  • KIM, Chunggu
  • IM, HYEONJOO
  • YOO, JUN SANG
  • SHIM, HYUN SOO

Assignees

  • Standup Therapeutics Inc.
  • Yoo, Jun Sang
  • Shim, Hyun Soo

Dates

Publication Date
20260506
Application Date
20230706

Claims (20)

  1. A pharmaceutical composition for treating a spinal cord injury disorder, the composition comprising: a nucleic acid sequence encoding a Gsta4 (Glutathione S-Transferase Alpha 4) protein; a nucleic acid sequence encoding an Lhx3 (LIM homeobox 3) protein; and a nucleic acid sequence encoding an MNX1 (Motor neuron and pancreas homeobox 1) protein.
  2. The pharmaceutical composition according to Claim 1, wherein the spinal cord injury disorder is selected from the group consisting of paraplegia, quadriplegia, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive pseudobulbar palsy, progressive muscular atrophy, progressive bulbar palsy, and post-polio syndrome.
  3. The pharmaceutical composition according to Claim 1, wherein the nucleic acid sequence encoding the Gsta4 protein, the nucleic acid sequence encoding the Lhx3 protein, and the nucleic acid sequence encoding the MNX1 protein are independently contained in a vector, or two or more of the nucleic acid sequences are combined and contained in a vector.
  4. The pharmaceutical composition according to Claim 3, wherein the vector is an adeno-associated virus (AAV).
  5. The pharmaceutical composition according to Claim 4, wherein the adeno-associated virus is a type selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV-DJ, AAV-DJ/8, AAV-Rh10, AAV-retro, AAV-PHP.B, AAV-PHP.eB, and AAV-PHP.S.
  6. The pharmaceutical composition according to Claim 5, wherein the adeno-associated virus is AAV2.
  7. The pharmaceutical composition according to Claim 1, wherein the nucleic acid sequence encoding the Gsta4 protein is the sequence of SEQ ID NO: 12.
  8. The pharmaceutical composition according to Claim 1, wherein the nucleic acid sequence encoding the Lhx3 protein is the sequence of SEQ ID NO: 16.
  9. The pharmaceutical composition according to Claim 1, wherein the nucleic acid sequence encoding the MNX1 protein is the sequence of SEQ ID NO: 14.
  10. The pharmaceutical composition according to Claim 3, wherein the vector further comprises at least one selected from the group consisting of a promoter, an enhancer, a polyadenylation signal, a Kozak consensus sequence, an inverted terminal repeat (ITR), a long terminal repeat (LTR), a terminator, an internal ribosome entry site (IRES), and a 2A self-cleaving peptide.
  11. The pharmaceutical composition according to Claim 3, wherein the vector further comprises a promoter, a 2A self-cleaving peptide, and an inverted terminal repeat (ITR).
  12. The pharmaceutical composition according to Claim 11, wherein the promoter is a CMV promoter, and the 2A self-cleaving peptide is P2A or T2A.
  13. The pharmaceutical composition according to Claim 1, wherein the pharmaceutical composition is formulated as an injectable preparation.
  14. The pharmaceutical composition according to Claim 4, wherein the AAV contained in the pharmaceutical composition is administered to a subject in a dose ranging from 1×10 5 GC/kg to 1×10 15 GC/kg.
  15. The pharmaceutical composition according to Claim 14, wherein the AAV is administered to a subject in a dose ranging from 1×10 6 GC/kg to 1×10 12 GC/kg.
  16. The pharmaceutical composition according to Claim 1, wherein the pharmaceutical composition is administered to an injured spinal cord region of a subject having a spinal cord injury disorder, and the injured spinal cord region is selected from the group consisting of L1 (lumbar 1), L2 (lumbar 2), L3 (lumbar 3), L4 (lumbar 4), L5 (lumbar 5), T1 (thoracic 1), T2 (thoracic 2), T3 (thoracic 3), T4 (thoracic 4), T5 (thoracic 5), T6 (thoracic 6), T7 (thoracic 7), T8 (thoracic 8), T9 (thoracic 9), T10 (thoracic 10), T11 (thoracic 11), T12 (thoracic 12), T13 (thoracic 13), C1 (cervical 1), C2 (cervical 2), C3 (cervical 3), C4 (cervical 4), C5 (cervical 5), C6 (cervical 6), C7 (cervical 7), C8 (cervical 8), S1 (sacrum 1), S2 (sacrum 2), S3 (sacrum 3), and S4 (sacrum 4).
  17. The pharmaceutical composition according to Claim 1, wherein the pharmaceutical composition is administered to a subject in a volume ranging from 10 µL to 100 µL per administration.
  18. A pharmaceutical composition for treating a spinal cord injury disorder, the composition comprising: a nucleic acid sequence encoding a Gsta4 (Glutathione S-Transferase Alpha 4) protein.
  19. The pharmaceutical composition according to Claim 18, wherein the spinal cord injury disorder is selected from the group consisting of paraplegia, quadriplegia, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive pseudobulbar palsy, progressive muscular atrophy, progressive bulbar palsy, and post-polio syndrome.
  20. The pharmaceutical composition according to Claim 18, wherein the nucleic acid sequence encoding the Gsta4 protein is contained in a vector.

Description

[Technical Field] The present disclosure relates to a composition for treating spinal cord injury disorders and a method for treating spinal cord injury disorders using the same. [Background Art] The spinal cord, which is a part of the central nervous system located within the spine, is difficult to recover once it is damaged. In particular, damage to the spinal cord disrupts neural transmission between the brain and the body, resulting in loss of motor function and sensory function. Various neuronal cells and glial cells, including astrocytes, microglia, and motor neurons, are present in the spinal cord. When motor neurons are destroyed, progressive degeneration occurs in motor nerves, which may affect upper motor neurons that transmit signals from the brain to the medulla or spinal cord, or lower motor neurons that transmit signals from the spinal cord to muscles. In addition, it has been reported that astrocytes form a glial scar at the site of spinal cord injury, thereby blocking ascending and descending neural signal transmission. Spinal cord injury, which is a damage to the central nervous system, has not yet been provided with a clearly established therapeutic regimen despite advances in medical and surgical treatments. To date, when the spinal cord is damaged, treatments such as steroid therapy that may cause severe side effects and invasive surgical procedures have been frequently employed. Furthermore, although cell-based therapies using stem cells and compound-based therapies have been developed as therapeutic agents for spinal cord injury, stem cell therapies involve the risk of teratoma formation or tumorigenesis, and compound-based therapies only exhibit temporary improvement in motor function and are insufficient to restore the damaged spinal cord. Accordingly, there is a need to develop new therapeutic agents for spinal cord injury. [Detailed Description of the Invention] [Technical Problem] An object of the present disclosure is to provide a composition for treating spinal cord injury disorders. In particular, the composition comprises differentiation factors for directly converting somatic cells into motor neurons. Specifically, the composition comprises a Gsta4 (Glutathione S-transferase A4) protein or a nucleic acid encoding the same. In another object of the present disclosure, a further composition for treating spinal cord injury disorders is provided. In particular, the composition comprises a Gsta4 (Glutathione S-transferase A4) protein or a nucleic acid encoding the same, an Hb9 (MNX1) protein or a nucleic acid sequence encoding the same, and an Lhx3 protein or a nucleic acid sequence encoding the same, as differentiation factors for directly converting somatic cells into motor neurons. In another object of the present disclosure, a method for preparing the composition is provided. Another object of the present disclosure is to provide a method for treating spinal cord injury disorders. A further object of the present disclosure is to provide various uses of the composition. [Technical Solution] In order to solve the above-described objects, according to one aspect of the present disclosure, there is provided a pharmaceutical composition for treating a spinal cord injury disorder. The pharmaceutical composition for treating a spinal cord injury disorder may comprise: a nucleic acid sequence encoding a Gsta4 (Glutathione S-Transferase Alpha 4) protein;a nucleic acid sequence encoding an Lhx3 (LIM homeobox 3) protein; anda nucleic acid sequence encoding an MNX1 (Motor neuron and pancreas homeobox 1) protein. At this time, the spinal cord injury disorder may be selected from the group consisting of paraplegia, quadriplegia, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive pseudobulbar palsy, progressive muscular atrophy, progressive bulbar palsy, and post-polio syndrome. The nucleic acid sequence encoding the Gsta4 protein, the nucleic acid sequence encoding the Lhx3 protein, and the nucleic acid sequence encoding the MNX1 protein may be independently contained in a vector, or two or more of the nucleic acid sequences may be combined and contained in a vector. At this time, the vector may be an adeno-associated virus (AAV). The adeno-associated virus may be selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV-DJ, AAV-DJ/8, AAV-Rh10, AAV-retro, AAV-PHP.B, AAV-PHP.eB, and AAV-PHP.S. The nucleic acid sequence encoding the Gsta4 protein may be the sequence of SEQ ID NO: 12, the nucleic acid sequence encoding the Lhx3 protein may be the sequence of SEQ ID NO: 16, and the nucleic acid sequence encoding the MNX1 protein may be the sequence of SEQ ID NO: 14. The vector may further comprise a promoter, a 2A self-cleaving peptide, and an inverted terminal repeat (ITR). In this case, the promoter may be a CMV promoter, and the 2A self-cleaving peptide may be P2A or T2A. In addition, the CMV pro