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.
Reference
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.
Dan Pietersen says
November 22, 2018 at 10:08 amWow! What a breakthrough. I suspect my 12 year old son has FSHD, as certain symptoms are starting to show. It is an illness in my family, as my 52 year old brother and his 23 year old son was diagnosed with the condition a couple of years ago.
Raj Badiani says
November 26, 2018 at 5:54 pmHello Harper and team, this is great news around the research and conclusions you have reached with this mouse model. It would be great to know what happens next? Will there be combined forces with the Ace-083 trials to see if there are synergies/ additional benefits?
Diane Scher says
January 4, 2019 at 10:48 amI am looking forward to seeing a.successful conclusion, and therefore inclusion for those of us who are headed for extinction without a positive.treatment and result or the luxury of a cure before our passing.
On another subject, personally, I would like to use this opportunity to express myself as in a forum mode.
Background History.
Pass it on if appropriate to the studies any any colleagues who may be interested.
I was diagnosed with FSHD at age 14 after taking the electronic needles test r and subsequent muscle biopsy performed at Henry Ford Hospital in Detroit.
I am 76 years old, having survived with a slow progressive muscle degeneration, and fortunately still mobile.
The FSHD DNA gene has been traced and confirmed in the matrilineal family line, skipping only a few generations.
However, at this stage, the progression and effects of aging are making their marks. Ironically, I am in excellent health.
I can walk on my own, drive because I am shored up with back supports to give me the ability to walk, stand up, do chores and drive–and to maintain my posture when maneuvering.
I use a cane or rollator/walker for any lengthy strolls and strength management in carrying heavier items for any distance.
I DO NOT USE OR NEED A WHEELCHAIR thus far at this juncture.
I attend senior exercise classes and use flexibility and gentle stretching exercises, plus use the pool for aquatic therapy.
My strength in terms of lifting or reaching is waning because of the weakness in my shoulders (winged) and arms.
For years, I have been actively interested in participating in a clinical trial. I signed up. No responses to date.
(Member of the FSH Society/Rochester NYdate.
I am definitely nterested in donating my body to science, specifically to FSHD studies after my death.
Thank you for the nformative and inspirational article.
Diane Scher
Age 76
Charleston South Carolina
June Kinoshita says
January 24, 2019 at 12:48 pmThanks for sharing your story! We’re glad to know you are doing so well. At age 76 you are above the age limit for the current clinical studies and trials, but when treatments become available, you should be able to benefit from them. In the meantime, thanks for being part of the national registry in Rochester. We don’t see you in our member database. You might want to join so that you can receive timely news and alerts from the FSH Society.
Gopi says
January 4, 2019 at 7:53 pmI am also FSHD Patient, please provide treatment details as of now available in market any where in world.and future also.
June Kinoshita says
January 24, 2019 at 12:45 pmIf you join the FSH Society, you’ll receive notifications about any new trials. Joining is free; we just need your contact information.
Ronald D Ferguson DVM says
January 5, 2019 at 1:27 pmI would like to try Ace-083 or any other treatment foe FSHD.
June Kinoshita says
January 24, 2019 at 12:44 pmIf you join the FSH Society, you’ll receive notifications about any new trials. Joining is free; we just need your contact information.