Microdystrophin gene therapy can prevent heart damage in DMD mice

Gene therapy maintained long-term heart function in preclinical study

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Illustration of a group of mice.

Microdystrophin gene therapy effectively maintained long-term heart function in a mouse model of severe Duchenne muscular dystrophy (DMD), a study has found.

The treatment prevented scar formation and inflammation in heart tissue, and maintained normal heart function over 18 months.

These findings support the ongoing clinical trials evaluating several microdystrophin gene therapies in patients with DMD.

The mouse study, “Micro-dystrophin gene therapy demonstrates long-term cardiac efficacy in a severe Duchenne muscular dystrophy model,” was published in the journal Molecular Therapy – Methods & Clinical Development.

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Several gene therapy clinical trials ongoing in young DMD patients

Dystrophin is one of a group of muscle proteins that work together to strengthen muscle fibers and protect them from damage as muscles contract and relax. Mutations in the DMD gene result in a lack of dystrophin protein, leading to muscle damage and scarring in skeletal muscles (those attached to tendons and bones) as well as heart muscle.

Several gene therapy clinical trials are ongoing in young DMD patients using versions of a truncated DMD gene called microdystrophin. Such genes are delivered to muscle cells using an adeno-associated virus, modified to be harmless, to make a shorter yet functional dystrophin protein.

Previously, researchers from the University of Washington engineered a novel set of enhanced microdystrophins and demonstrated their ability to enhance muscle strength and function in DMD preclinical models. Building on these findings, one such microdystrophin, called SGT-001, is currently being evaluated in the Phase 1/2 clinical trial IGNITE DMD (NCT03368742), sponsored by Solid Biosciences.

Early data indicated that SGT-001 leads to sustained improvements in physical functioning, disease-related biomarkers, patient-reported outcomes, and lung function in boys with DMD.

However, outcomes related to the heart will not be known for years because heart function decline in DMD typically begins in the late teens to early 20s. Moreover, microdystrophins have been thoroughly tested in skeletal muscles using animal models, but studies in models of impaired whole heart function still need to be completed.

To evaluate the preclinical efficacy of gene therapies for the heart and further understand DMD heart disease, researchers at Ohio State University and the University of Washington tested the microdystrophin-based gene therapy (here called microDys5) in a new mouse model that progresses to heart failure.

The mice were treated at one month of age, with heart assessments starting at six months and conducted every three months for 18 months.

At both six and nine months, treated mice had significantly higher ejection fraction, or the percentage of blood pumped from the heart with each contraction, than untreated mice (mean 61% vs. 44%). An ejection fraction above 50% is considered in the normal range.

At the same time, the fractional shortening, or the percentage change in the heart’s left ventricular size during each contraction, was significantly larger in treated than untreated mice (mean 32% vs. 22%). A fractional shortening higher than 28% is considered in the normal range.

With treatment, the mice maintained an ejection fraction greater than 55% and a fractional shortening greater than 27% from six to 18 months, “demonstrating long-term efficacy of the gene therapy on maintaining whole heart pump function,” the team wrote.

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Heart strain was reduced, with improvements in heart muscle performance

At 18 months, echocardiograms showed heart strain was significantly reduced, with improvements in heart muscle performance. Furthermore, 94% of tissue samples in all treated mice had heart muscle cells testing positive for microdystrophin protein.

Heart tissue in untreated mice had large areas of fibrosis (scarring), similar to 12-month-old mice, suggesting that improvements were “not due to an absence of cardiac damage in these mice at 18 months,” the team added. Treatment was able to prevent accumulation of heart muscle damage.

Collagen protein, a component of connective tissue and scarring, was more tightly packed in heart tissue in untreated mice at 18 months versus 12 months, demonstrating progressive scar formation. Treatment led to more loosely packed collagen at 18 months.

Finally, there were significantly reduced levels of white blood cells, a marker for inflammation, in the heart tissue of treated mice at 18 months compared with untreated animals (2.4% vs. 5%), which showed signs of active inflammation.

“Mice treated at 4 weeks-of-age with [micro]Dys5 were spared from cardiac pathology [disease], including fibrosis and inflammation, and maintained normal heart function throughout the 18 month period,” the researchers wrote.

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