Muscular Dystrophy
Credit: © Studio Pookini/Fotolia

In a striking collaboration, four companies shared laboratory and clinical data to find what was causing certain serious adverse events (SAEs) in Duchenne Muscular Dystrophy (DMD) gene therapy trials. The companies, all frontrunners in this field, are Pfizer, Sarepta, Solid Biosciences, and Genethon. Based on this work, they propose these SAEs are caused by an anti-transgene mechanism that is determined by the patient’s genotype.  

The team presented their findings as an abstract at the American Society of Gene and Cell Therapy meeting this week. The presentation was made by Carsten G. Bonnemann, MD, a principal investigator in the Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH.Dusponsors chose to collaborate, share data, and convene an international panel of experts to analyze the SAEs, find ways to minimize their recurrence, and assess potential therapeutic and preventative strategies.

These SAEs included extremity and bulbar muscle weakness, occurring approximately 3–7 weeks following gene therapy infusion. Some individual patients also had severe respiratory muscle compromise or increased cardiac troponin-I levels. The patients did recover.  Following various immunosuppressive and supportive therapies, muscle strength improved, and cardiac enzyme levels normalized over 6–8 weeks after onset.

In their abstract, the researchers noted that “Given that similar events were observed across multiple investigational gene therapy products with different capsids, promoters, and transgene sequences, they are most likely to be a specific transgene/genotype-related ‘class effect.’”

They propose that the mechanism involves a T-cell mediated immune response to the expressed transgene protein in a cross-reactive immunological material (CRIM)-negative setting, determined by the patient’s genotype. 

The researchers pointed to three key pieces of evidence. First, the SAEs only occurred in patients with genomic deletions including N-terminal epitopes present in the transgene protein. Second, when positive ELISpot (T-cell) tests were recorded in patients with SAEs, they were reactive specifically to the corresponding N-terminal peptide pool. Finally, preliminary epitope mapping of anti-dystrophin antibodies from one patient suggests a prominent signal at the transgene Hinge1 segment within the N-terminus of dystrophin.

The researchers note that, “The unique open, collaborative working group including four sponsors of the ongoing studies and multiple academic experts was instrumental in being able to quickly identify an anti-transgene mechanism and the associated risk factors for observed SAEs.”

A plan for further investigation is underway to better define the immune mechanism and associated risk factors behind these SAEs. 

And, as the researchers write, “This collaborative approach and its conclusions may have implications to mitigate risks in gene therapy development programs beyond DMD.”

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