Final go-ahead for the trial awaits U.S. Food and Drug Administration (FDA) approval of an Investigational New Drug (IND) application made for the therapy and its testing. But Mendell is confident that his team met all criteria and guidelines laid out by the FDA, and he anticipates regulatory approval.
Mendell, and Louise Rodino-Klapac, the trial’s other principal investigator, along with Nationwide were granted $2.2 million by Parent Project Muscular Dystrophy for this work. Mendell presented the design of the genetically engineered virus used in this therapy, along with plans for the trial, in a Sept. 6 webinar hosted by PPMD.
Mendell is the director of the Center for Muscle Health & Neuromuscular Disorders at the Ohio hospital, and a principle investigator at Nationwide’s Center for Gene Therapy, as is Rodino-Klapac. Both are also professors and specialists in pediatric medicine and care.
If all goes well and approval is granted, the researchers plan to begin the trial in late October or early November, Mendell said.
Mendell said that his team has “clear plans to conquer Duchenne” and is expecting to get “very good” study results. Novartis’ Kymriah, a gene therapy to treat an aggressive form of leukemia, was recently approved by the FDA, becoming the first such therapy with regulatory backing in the U.S. Its approval is expected to pave the way for other gene therapies for genetic diseases, such as DMD.
The trial will test whether the therapy is safe and whether it works. Two groups of six patients, based on age, will be included. Those in one group will be infants and toddlers, ages 3 months to 3 years, and the other will be children ages 4 to 7 years.
Most boys with DMD are diagnosed at 4 years old or later, with diagnoses at earlier ages often arriving inadvertently, before clear disease symptoms are evident. Mendell said he is “hopeful that the trial will change the playing field so much that there will be screening [for DMD] in newborns.”
The trial will run for three to 3.5 years, but the researchers expect to have a good idea of whether the treatment works by 18 weeks of it being administered.
Between months 12 and 18 post-treatment, Mendell expects to have clear signs of whether the therapy is affecting unintended targets and its potential side effects.
DMD is caused by a mutation in the dystrophin gene that codes for a protein essential in the development of muscle fibers. The therapy, AAVrh74.MHCK7.Micro-dystrophin (known as AAVrh74), uses a virus to carry a healthy version of part of this gene to muscle cells. In laboratory mice with a form of DMD, the therapy restored muscle fibers in skeletal muscle, and in heart and diaphragm muscles.
The therapy has been used in pilot clinical studies at Nationwide Children’s Hospital, including this one —NCT02376816 — in DMD patients. The planned trial will also take place at the Ohio hospital.
AAVrh74 only carries a part of the whole dystrophin gene, and is designed to treat patients with mutations in the part of the gene that the therapy replaces, exons 18–58. (Exons are units of DNA within the gene.) This includes most DMD patients — but developing future therapies, working in much the same way, to treat patients with mutations elsewhere in the dystrophin gene is entirely feasible, Mendell said.
Two questions still to be answered — possibly in the not-too-distant future — are whether the therapy will need to be administered multiple times and if older boys will be treatable.
“I’d be very eager to expand the trial to be able to reach more patients,” Mendell said.
Support for Mendell and Rodino-Klapac’s work, as well as a deeper exploration of CRISPR/Cas9 technology as a potential therapeutic approach for Duchenne, is part of PPMD’s new Gene Transfer Initiative.
“There would be no clinical trial without Parent Project, which put up the bulk of the funding to do the clinical trial,” Mendell said, thanking the organization for its considerable support in concluding the webinar.
In addition to PPMD, the therapy and its development are supported by Sarepta Therapeutics, the National Institutes of Health, and Jesse’s Journey, a Duchenne MD association in Canada, according to a PPMD presentation on the micro-dystrophin therapy given by Rodino-Klapac in June.
Sarepta, in fact, has rights to the microdystrophin therapy program; the company entered a research and licensing option agreement with Nationwide Children’s in January.
PPMD is likely to post the Sept. 6 webinar on its site soon, possibly with answers to participants’ questions that could not be addressed during the session, much as the association did for a similar presentation in August on CRISPR/Cas9 gene editing.