More Data Support Gene Therapy for DMD Exon Duplications

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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New data from a Phase 1/2 clinical trial of an exon-skipping gene therapy suggest it may help preserve muscle function if delivered early on to Duchenne muscular dystrophy (DMD) patients with exon duplications.

This is the first time a clinical trial has shown production of full-length dystrophin, the protein lacking in people with Duchenne, as a result of gene therapy, according to the researchers.

“In this study of only three subjects, we are clearly seeing that the younger the age at dosing, the better result in terms of dystrophin expression,” Megan Waldrop, MD, said in a press release. Waldrop is a pediatric neurologist at Nationwide Children’s Hospital in Columbus, Ohio, where the trial is underway.

“I am looking forward to following our youngest subject to assess the persistence of response, and to conducting an additional study focused on dosing additional younger subjects to better assess this potential age-associated effect,” added Waldrop, the study’s lead investigator.

Study data support the therapy’s potential to safely and effectively increase full-length dystrophin protein levels in DMD patients with exon duplications.

“This is a landmark. We’re very gratified to show — for the first time ever — the therapeutic expression of full-length dystrophin as a result of a human gene therapy,” said Kevin Flanigan, MD, director of the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children’s and a leading expert in developing gene therapies for DMD.

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Waldrop presented the findings, “Safety and Outcomes of Intravenous scAAV9.U7-ACCA for the Treatment of Duchenne Muscular Dystrophy Caused by Exon 2 Duplications” at the 2022 Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), which concluded today in Washington, D.C.

DMD is caused by mutations in the DMD gene, which contains the instructions to produce a key protein for muscle health called dystrophin.

A type of mutation, called exon duplication, accounts for nearly 11% of cases of DMD. Duplication of exon 2 is the most frequent. Exons are sections of genetic information needed to make proteins. There are 79 exons in the DMD, the largest human gene.

The protein-making machinery requires that the information in genes is converted into an intermediate molecule called messenger RNA (mRNA). Only the information of exons is used to guide protein production. Exons are stitched together in the mRNA molecule before it is translated into a protein. Exon duplication impairs this process, disrupting the production of a working dystrophin protein.

Exon-skipping therapies are meant to guide the cell’s machinery to pass over a specific exon. As a result, the remaining exons can be stitched together, allowing for the production of a working, but usually shorter, form of dystrophin.

In exon 2 duplications, skipping one exon 2 copy leads to the normal production of full-length dystrophin.

The exon-skipping therapy developed by researchers at Nationwide Children’s uses a modified and harmless virus (called scAAV9.U7-ACCA) to deliver the genetic information of four molecules that force exon 2 skipping in the DMD gene’s mRNA.

The treatment is administered only once and directly into the bloodstream.

“In contrast to approved exon-skipping therapies, this is not a weekly treatment, and it induces exon skipping at much higher levels,” said Flanigan, who directs the neuromuscular clinical program at Nationwide Children’s. “And unlike microdystrophin gene therapies, this makes a complete, wild-type version of the protein.”

The investigational therapy’s safety and preliminary effectiveness is being assessed in a Phase 1/2 study (NCT04240314) with three boys with exon 2 duplication in the DMD gene. The trial is being conducted in collaboration with Audentes Gene Therapies.

At dosing, the first boy was 8 years old, the second was 13 and the third boy was dosed at 7 months, before symptpom onset. According to the press release, this is the youngest patient ever dosed with a DMD gene therapy.

All participants received a 3×1013 vector genomes per kilogram dose. No serious adverse events or toxicity issues have been reported.

The new data report the latest follow-up after dosing — 18 months for patient one, 12 months for patient two, and 60 days for patient three.

The first boy continues to do well, the researchers said. His levels of creatine kinase (CK), a marker of muscle damage, dropped to 31% of the levels before the start of the trial (baseline), a similar drop to the one seen in the second boy (29% of baseline), who shows clinical stability. The younger boy has experienced a significant drop — by 91% — in CK levels.

Functional outcome measures, namely the percentage-predicted 100-meter walk time, remained stable over time in the first boy, while it increased slightly in the second boy.

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The first boy showed a decline (worsening) in his scores on the North Star Ambulatory Assessment (NSAA), a measure of motor function in DMD. His score dropped from 25 to 23 points, which, according to the researchers, was due to increasing heel cord tightness. This was accompanied by an increase in the time to climb four stairs from 2.17 to 2.4 seconds

The second boy also showed a slight drop in his NSAA scores — from 22 points to 20 points — but his time to climb four stairs remained stable at 4.1 seconds.

In both cases, lung and heart function remain normal. The third boy is achieving developmental milestones on time.

Muscle biopsies of the first two boys, made at 12 months (first boy) and six months (second boy) of follow-up, confirmed the presence of an apparently full-length dystrophin protein. In the first boy, analysis detected levels around 6%, and in the second boy at around 1–2%.

A biopsy at four months after dosing in the youngest patient showed that 99% of his muscle fibers produced the full-length dystrophin. His dystrophin levels were 70% of normal.

“The newest gene therapy results from Flanigan and colleagues are extremely exciting and provide several important new tools in the fight against DMD,” said Jeff Chamberlain, PhD, a leader in the microdystrophin program and gene therapy for DMD patients.

“The full, intact dystrophin protein is likely to be significantly more beneficial than the miniaturized versions. Furthermore, the efficiency of gene delivery is a significant limitation on current methods, so the ability to safely treat young patients could transform the field of muscular dystrophy therapeutics,” said Chamberlain.

The viral vector’s development and production were supported by the CureDuchenne Foundation and the Beauhawks Foundation.