Development of antisense therapy for facioscapulohumeral muscular dystrophy


Preclinical Trial Design & Biomarker Development

Poster Number: 148


Aiping Zhang, PhD, Sreetama Sen Chandra, PhD, Hunain Khawaja, Kenji Rowel Q. Lim, PhD, Rika Maruyama, PhD, Takako Jones, PhD, Peter L. Jones, PhD, Toshifumi Yokota, PhD, Yi-Wen Chen, PhD


1. Children's National Hospital, 9. Children's Research Institute (CNMC)

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscular dystrophies with an incidence of 1:8,000 to 1:20,000. Studies showed that FSHD is caused by aberrant expression of double homeobox 4 (DUX4) due to epigenetic changes of the D4Z4 macrosatellite repeat region at chromosome 4q35. Antisense oligonucleotides (AONs) therapy has shown promise for treating an array of disorders and can be used to reduce DUX4 in FSHD.
Objective: To develop antisense strategies to reduce the pathogenic DUX4 mRNA in affected muscles and identify AONs that are suitable for therapeutic development.

Approach: LNA and 2’-MOE gapmers were delivered by either intramuscular injections (i.m.) or subcutaneous injections (s.c.) to the DUX4-expressing FLExDUX4 mouse model. The reduction of DUX4 transcripts was determined by qRT-PCR. Changes in disease phenotypes were determined by grip strength and pathology.

Results: Our results showed that i.m. injections (20ug) of gapmers into the tibialis anterior muscles significantly reduced DUX4 transcripts in the muscles of the FLExDUX4 mice. Short-term treatment by s.c. injections (20mg/kg) of the gapmers reduced DUX4 expression in the muscles. In a long-term 10-week trial, s.c. injections (20mg/kg) twice a week significantly reduced DUX4 expression. In addition, muscle function measured by grip strength testing showed significant improvement after the treatment. Muscle fibrosis was reduced by the LNA treatment and elevated active TGFβ1in the disease model returned to baseline.

Conclusion: Our findings showed that the gapmers targeting DUX4 significantly reduced DUX4 transcripts. The reduction of DUX4 was accompanied by recovery of muscle functional deficits and improvement of muscle pathology in the FLExDUX4 mice. We conclude that the gapmers are suitable therapeutic candidates for FSHD.