AUSTIN—Gene therapy techniques under investigation show promise for the treatment of muscular dystrophy, according to research presented at the 2013 Annual Meeting of the Child Neurology Society. Treatment with eteplirsen, a phosphorodiamidate morpholino oligomer that modifies gene expression at the pre-mRNA level, promotes dystrophin expression in patients with Duchenne’s muscular dystrophy. The therapy also improves patients’ function, said Jerry R. Mendell, MD, Director of the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio.

In addition, injecting the follistatin gene into the quadriceps muscle may improve muscle strength and preserve ambulation in patients with Becker muscular dystrophy. By blocking the myostatin signaling pathway, the follistatin gene enlarges muscle fibers and increases muscle strength in experimental animals, said Dr. Mendell.

Eteplirsen Promoted Dystrophin Expression
Dr. Mendell and colleagues are conducting an ongoing trial of an exon-skipping treatment involving eteplirsen. The investigators randomized 12 patients with Duchenne’s muscular dystrophy to a high dose (50 mg/kg/week) of IV eteplirsen, a low dose (30 mg/kg/week) of IV eteplirsen, or placebo. At 12 weeks, the researchers performed biopsies of the high-dose patients and two control patients.

At six months, Dr. Mendell’s group performed biopsies of the low-dose patients and two control patients. At six months, all patients then entered an open-label trial, which is ongoing. The control participants began receiving eteplirsen, and the researchers performed biopsies of all patients at one year. For the placebo-controlled and open-label trials, the primary end points were dystrophin expression and distance walked on the Six-Minute Walk Test (6MWT).

The investigators observed virtually no dystrophin expression among the four high-dose patients at 12 weeks. At 24 weeks, however, the four low-dose patients had dystrophin expression. At 48 weeks, all patients had dystrophin expression. Patients who began receiving eteplirsen at the beginning of the trial had a 47% increase in dystrophin-expressing fibers at 48 weeks. Patients who received placebo for 24 weeks, followed by eteplirsen for 24 weeks had a 38% increase in dystrophin-expressing fibers at 48 weeks.

Patients receiving eteplirsen began to maintain a consistent level of dystrophin expression at approximately 12 weeks, while control patients declined until they began receiving eteplirsen. Dystrophin levels remained consistent among placebo-delayed patients beginning at 36 weeks, but levels were lower than those among patients who had received eteplirsen from the start of the study.

Patients receiving eteplirsen from the initiation of the study maintained their distance walked on the 6MWT throughout the study. For patients who originally received placebo before starting eteplirsen, distance on the 6MWT diverged from that of eteplirsen-treated patients at 12 weeks and declined until the former patients began producing dystrophin (at about week 36). After this time, distance on 6MWT remained consistent for placebo-delayed patients.

Two patients on eteplirsen and one control patient had transient proteinuria, which the investigators did not regard as a significant adverse event. “This is the first treatment to show gene correction [ie, dystrophin production] in Duchenne’s [muscular] dystrophy,” said Dr. Mendell.

Follistatin Increased the Distance Patients Walked
In a second ongoing study, Dr. Mendell and colleagues are injecting a low dose (6 × 1011 vg/kg) of follistatin, delivered by adeno-associated virus (AAV), into the quadriceps muscle of three patients with Becker muscular dystrophy. The primary end point is distance walked on the 6MWT, which patients undergo at baseline and at regular intervals during treatment. At one year, one patient had an increase of 56 m on the 6MWT, and a second patient had an increase of 111 m. A third patient had a 13-m increase at six months.

Because no participants had significant side effects, the researchers began testing a high dose (2 × 1012 vg/kg) of AAV follistatin on three participants. At one month, a patient receiving the high dose had an increase of 54 m on the 6MWT. Reverse-transcription polymerase chain reaction revealed dystrophin production among the patients. “I’ll be encouraged by this trial if there is a dose-dependent effect” of follistatin, said Dr. Mendell. “We’ll be able to establish this [result] over time.”

Two New Gene Therapy Trials Planned
Dr. Mendell and colleagues plan to initiate two additional gene therapy trials later this year. In one trial, the group will use AAV as a vehicle for the vascular delivery of the alpha-sarcoglycan gene in patients with limb-girdle muscular dystrophy type 2D. In spring 2014, the investigators plan to assess the vascular delivery of the microdystrophin gene as a treatment for Duchenne’s muscular dystrophy. “We will be careful to learn the lessons from our first gene therapy trial, where we saw an immune response to dystrophin,” concluded Dr. Mendell.

—Erik Greb

Emerging Gene Therapy Techniques May Help Patients With Muscular Dystrophy