Identification of a candidate drug for the treatment of facioscapulohumeral muscular dystrophy

Identification of a candidate drug for the treatment of facioscapulohumeral muscular dystrophy

Takahiro Yoshizawa1,2, Yoshitaka Tomiyama3, Naoko Shiba4, Tomohide Takaya5, Daigo Miyazaki6,10, Tsutomu Nakada2, Yuji Shiba2,4, Akinori Nakamura6,7, Tomoki Kosho2,8,9,11.

  1. Shinshu Niversity, Japan.
  2. Research Center for Advanced Science and Technology, Shinshu University, Japan.
  3. Department of Druc Discovery Science, School of Medicine, Shinshu University, Japan.
  4. Department of Regenerative Science and Medicine, School of Medicine, Shinshu University, Japan.
  5. Department of Agriculture, Graduate School of Science and Technology, Shinshu University, Japan.
  6. Laboratory of Neurology and Rheumatology, Department of Medicine, School of Medicine, Shinshu University, Japan.
  7. Department of Neurology, National Hospital Organization Matsumoto Medical Center, Japan.
  8. Deparment of Medical Genetics, School of Medicine, Shinshu University, Japan.
  9. Center for Medical Genetics, SHinshu University Hospital, Japan.
  10. Division of Support for Intractable Disease, Shinshu Medical Care Collaboration Center, Shinshu University Hospital, Japan.
  11. Division of Clinical Sequencing, School of Medicine, Shinshu University, Japan.

Human Genetics Asia 2023 (Tokyo, Japan), 2023/10/13 (Poster).

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy caused by abnormal activation of the DUX4 gene. Overproduction of myotoxic protein DUX4 damages skeletal muscle cells and induces progressive and descending pattern of muscular weakness and atrophy in FSHD.

In this study, DUX4-overexpressing rhabdomyosarcoma cells (TE-671) were used for drug screening for FSHD. Then, we found "compound X", which showed concentration-dependent inhibition of DUX4-induced cell death. Tamoxifen-induced skeletal muscle-specific DUX4 overexpression (FLExDUX4;ACTA1-MCM) mice were used as an animal model for FSHD. Body weight, grip strength, and time of fatigue were significantly decreased in FLExDUX4;ACTA1-MCM mice. Serum CK and LDH, markers of muscular injuries, were significantly increased in this mouse model. In histological analysis, inflammatory cell infiltration was observed in gastrocnemius of the mice. Administration of compound X inhibited reduction of the myofunctions (e.g., increase of serum CK, LDH) and also inhibited inflammatory cell infiltration in FLExDUX4;ACTA1-MCM mice.

These results suggest that compound X is a promising candidate for the treatment of FSHD (Japanese Patent Application No. 2023-054469). Further model-based studies (e.g., larger animals) would be required in view of future physician-initiated clinical trial.