An experimental gene therapy has been shown to enlarge and strengthen muscles in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). The study was published on November 15 in the Journal of Clinical Investigation Insight by Scott Harper, PhD, and his team at Nationwide Children’s Hospital.
The study made use of mice developed by the Harper lab that are genetically engineered to express the DUX4 gene, which is implicated in FSHD. When DUX4 is switched on, “these animals develop progressive muscular dystrophy,” Harper said. “We extensively characterized their symptoms, which include walking problems, muscle weakness, and muscle damage.” Called TIC-DUX4, this mouse model was developed with funding from the FSH Society among others (see story).
Harper said the new study was designed to determine whether the TIC-DUX4 mouse could provide useful insights into the development of FSHD treatments. To do this, the lab engineered adeno-associated virus (AAV) to carry the gene for follistatin into muscle cells. There the gene integrates into the mouse DNA and the cells produce the protein follistatin. Follistatin is a naturally occurring protein that blocks another protein, myostatin, which inhibits muscle growth. Follistatin’s action is similar to that of ACE-083, an experimental therapy that is currently in a clinical trial in FSHD patients.
This follistatin-carrying AAV was injected into the leg muscles of the TIC-DUX4 mice, and resulted in increased muscle size and “improved overall strength,” Harper said.
The study noted it would “be interesting to test the impact of combining AAV1.Follistatin treatment with DUX4-inhibitory strategies, which could work to both suppress DUX4-associated damage and improve muscle mass and strength.”
“This proof-of-principle study provided encouraging evidence that DUX4 expressing muscle can be treated with AAV-delivered myostatin inhibition approaches to improve muscle function,” the study stated. “We conclude that TIC-DUX4 mice are a relevant model to study DUX4 pathogenicity and disease progression. Moreover, the TIC-DUX4 mouse develops numerous molecular, histological, and functional outcomes that can be used as powerful tools to test gene therapies and other therapeutic strategies for FSHD.”
Harper said his lab has initiated the depositing of these mice at the Jackson Laboratory (www.jax.org), where they can be obtained for use by other laboratories. Stock Number: 032779.
Funding for this research was provided by the FSH Society, MDA, Chris Carrino Foundation, Friends of FSH Research, and NIH.
AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. Carlee R. Giesige, Lindsay M. Wallace, Kristin N. Heller, Jocelyn O. Eidahl, Nizar Y. Saad, Allison M. Fowler, Nettie K. Pyne, Mustafa Al-Kharsan, Afrooz Rashnonejad, Gholamhossein Amini Chermahini, Jacqueline S. Domire, Diana Mukweyi, Sara E. Garwick-Coppens, Susan M. Guckes, K. John McLaughlin, Kathrin Meyer, Louise R. Rodino-Klapac, and Scott Q. Harper. JCI Insight. 2018;3(22):e123538.