Progress Update: 3rd Gen Oligonucleotide Targeting DUX4 in Mouse Model

by Yi-Wen Chen
See grant: Investigation of a third generation oligonucleotide targeting DUX4 using a new mouse model of FSHD

This report summarizes our recent research activities in testing in vivo efficacy of 3GA2 using an FSHD mouse model called FLExDUX4. We conducted short term trials using either intramuscular (i.m.) or subcutaneous (s.c.) delivery and showed that 3GA2 delivered by s.c. injections (every other day for six injections) successfully reduced DUX4 expression in the triceps muscles in comparison to the muscles collected from the control FLExDUX4 mice, which only received saline injections. Afterwards, we would like to determine whether the longer treatment will improve muscle function measured by grip strength testing in addition to the DUX4 reduction. We injected (30mg/kg, s,c, twice a week) six male and six female mice with the 3GA2. The control mice (six males and six females) received saline injections. The wildtype siblings (six males and six females) also received saline injections during the period of time. We performed the first muscle functional testing at three weeks after the first injection and found that the grip strength of the FLExDUX4 mice was improved significantly to a level similar to the wildtype mice. Muscle strength of both formlimbs and hindlumbs in both genders was significantly improved. We repeated the grip strength measurements after additional three weeks (six weeks after the initial injection). The improvement was more significant and the muscle strength reached the same level as the wildtype littermates. The improvement was observed in both forelimbs and hindlimbs and in both male and female mice. The results showed that the 3GA2 treatment quickly improved muscle function within three weeks (six injections) and completely restore the muscle strength by week six after the initial injection. The study demonstrated strong in vivo efficacy of the 3GA treatment for both male and female mice. Several follow-up studies are currently ongoing to validate molecular and pathological improvement and safety of the treatments. We thank the Friends of FSH Research for supporting the study.