The recent death of a 16-year-old boy who was undergoing gene therapy for Duchenne muscular dystrophy has sent shockwaves through the community. The teenager passed away from acute liver failure months after starting Elevidys, the only FDA-approved gene therapy for DMD developed by Sarepta Therapeutics. The company has not ruled out the possibility that the treatment, which utilizes an adeno-associated virus (AAV) vector to deliver the therapeutic gene payload, may have played a role in the fatal outcome.
Sharon Hesterlee, Chief Research Officer at the Muscular Dystrophy Association, stated that liver injury is a known side effect of AAV gene therapy, but the investigation into the specific cause of the death is ongoing. The patient also had a cytomegalovirus infection, which could have contributed to the outcome.
The tragic incident has raised concerns about the safety of gene therapies, particularly those using AAVs. Despite their benefits, AAVs come with their own set of challenges. These vectors are non-integrating, meaning they do not typically insert their genetic material into the cell’s chromosomal DNA, reducing the risk of cancer. However, the therapeutic gene may dilute quickly in tissues that rapidly divide, impacting the treatment’s effectiveness.
While AAVs are less likely to trigger immune responses compared to earlier vectors, they have limitations in terms of the payload they can carry and can be costly to manufacture. Patients with pre-existing immunity to AAV serotypes may experience side effects that make it unsuitable as a therapy option.
Companies are exploring alternative vector options, such as lentiviruses, retroviruses, lytic viruses, Herpes simplex virus, and poxvirus for gene therapy. Non-viral vectors like lipid nanoparticles and exosomes are also being investigated for their potential benefits, including the ability for repeat dosing and lower manufacturing costs.
Despite the risks associated with AAVs, they remain a promising delivery system for gene therapies. The industry is likely to continue developing AAV-based treatments while also exploring other options to enhance safety and efficacy in the long run. As research and technology advance, the field of gene therapy is continuously evolving to provide innovative solutions for genetic disorders like Duchenne muscular dystrophy.
