New Gene Therapy Shows Promise Treating DMD

Rebecca Willcocks, PhD

Stakeholders are hopeful a new gene therapy that utilizes magnetic resonance imaging (MRI) could be beneficial for adolescent patients with Duchenne Muscular Dystrophy (DMD).

A team, led by Rebecca J. Willcocks, PhD, Department of Physical Therapy, University of Florida, tested Microdystrophin gene transfer using recombinant adeno-associated virus serotype rh74 (rAAVrh74) driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7) as an effective therapy for patients with DMD.

Three Different Cohorts

In the open-label gene transfer study, the investigators found the treatment showed robust transgene expression on muscle biopsy (74-96%) of fibers, but biopsy data on reflects a small sample of muscle where muscle quality in large muscle groups can be objectively and noninvasively measured using quantitive MRI (qMRI) and spectroscopy (qMRS).

These 2 tools are often used for monitoring disease progression and therapeutic response in DMD, correlating with and identifying future loss of ambulatory function.

The researchers between qMRI and qMRS data, including muscle fat fraction and bulk MRI transverse relaxation time, could be reduce in children treated with SRP-9001 compared to an age-matched natural history cohort treated with standard of care, as well as a control group of individuals without DMD.

In the case-control trial dubbed the Systemic Gene Delivery Clinical Trial for Duchenne Muscular Dystrophy, 3 patients received qMRI and qMRS evaluation at the University of Florida between 2018-2020.

Treatment Parameters

Each participant was imaged once or twice following systemic delivery of SRP-9001. The imaging took place between 6-24 months following treatment, using the MR protocols implemented in the multicenter Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy (Imaging DMD) study.

The research team then drew a natural history comparison cohort retrospectively from the ImagingDMD study and identified 54 individuals who had a total of 110 study visits between 2011-2018.

The participants were aged between 4.9-7.9 years, matching the age of the participants who received SRP-9001.

Each individual in the natural history cohort was treated with corticosteroids, but none of them were treated with dystrophin restoration therapy.

The investigators also retrospectively identified 17 age-matched individuals without DMD for the comparison control cohort.

The qMRI and qMRS was used to measure leg muscle fat fraction qT_².

They also briefly acquired multiecho axial gradient echo images and multiecho spin echo images in the calves and thighs, while localizing single-voxel proton MRS (1H-MRS) in the vastus lateralis (VL) and soleus muscles.

Promising Results

Overall, minimal fat infiltration was observed on MR images from the SRP-9001 arm compared to participants from the natural history cohort, whose muscles have dark patterning throughout, especially in the biceps femoris long head and adductor magnus.

Similarly, the investigators found spectra from the VL showed a visible fat peak, reflecting accumulation of intramuscular fat (value, 0.13) in the participants from the natural history cohort. However, this was minimal in the control and SRP-9001 arms of the trial.

In the SRP-9001 cohort, the mean VL MRS fat faction was lower than what was found in the natural history cohort. Overall, there was 100 data points (0.02 [0.01] vs 0.11 [0/11]) and similar to the control cohort, which included 17 data points (0.02 [0.01]).

VL fat faction was stable over the course of 12 months (the time between MR visits) in 2 participants who received SRP-9001 and had repeated measurements (mean change, 0.00 [0.01]).

However, this was not found among the 42 participants in the natural history cohort with repeated measurements (mean change, 0.05 [0.07]).

The researchers also found qT₂ across 5 upper and lower leg muscles was greater in the natural history cohort than it was in the SRP-9001 or control cohorts (mean qT₂ for VL: natural history, 44.7 [7.7] ms; SRP-9001, 37.3 [2.2] ms; control, 35.1 [3.7] ms).

“These MR data indicate marked sparing and minimal fat infiltration in boys with DMD who received SRP-9001 compared with an age-matched natural history cohort,” the authors wrote. “qMRI and qMRS biomarkers are valuable adjuncts to clinical assessments because of their sensitivity to subclinical disease progression and lack of dependence on participant growth, maturation, and motivation.”

The study, “Assessment of rAAVrh.74.MHCK7.micro-dystrophin Gene Therapy Using Magnetic Resonance Imaging in Children With Duchenne Muscular Dystrophy,” was published online in JAMA Network Open.