In a groundbreaking yet tragic turn of events, a recent study published in the New England Journal of Medicine has reported the death of a 27-year-old patient diagnosed with Duchenne’s muscular dystrophy (DMD) after undergoing a high-dose rAAV9 gene therapy treatment. This incident has raised concerns about the safety and potential risks associated with gene therapy treatments, particularly for those with advanced stages of DMD.
Duchenne’s muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys and leads to muscle degeneration and weakness. As researchers worldwide strive to find effective treatments for this debilitating condition, gene therapy has emerged as a promising avenue. However, the recent incident underscores the need for caution and thorough evaluation before administering such treatments.
The patient was treated with a recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9. For those unfamiliar with the terminology, dSaCas9 refers to a “dead” Staphylococcus aureus Cas9, where the Cas9 nuclease activity is inactivated. This particular transgene was innovatively designed as a custom CRISPR–transactivator therapy with the aim of up-regulating cortical dystrophin, a protein crucial for muscle function and often deficient in DMD patients.
Following the treatment, the patient’s health began to deteriorate. Initial symptoms included mild cardiac dysfunction and pericardial effusion, a condition where excess fluid accumulates around the heart. These symptoms rapidly escalated, and within six days post-treatment, the patient developed acute respiratory distress syndrome (ARDS), a severe lung condition that prevents adequate oxygen from reaching the lungs and into the bloodstream. Tragically, this was followed by a cardiac arrest, and the patient succumbed two days later.
A comprehensive postmortem examination was conducted to ascertain the cause of death. The findings revealed severe diffuse alveolar damage, a condition where the tiny air sacs in the lungs, responsible for oxygen exchange, become damaged. Interestingly, the examination showed minimal expression of the transgene in the liver.
Moreover, there was no evidence of the presence of AAV serotype 9 antibodies or any effector T-cell reactivity in the organs. These observations led the researchers to conclude that the patient’s ARDS was likely triggered by an innate immune reaction, possibly as a response to the high-dose rAAV gene therapy.
This incident, funded by Cure Rare Disease, serves as a somber reminder of the challenges and uncertainties that come with pioneering medical treatments. While gene therapy holds immense potential in treating a range of genetic disorders, it is crucial to approach it with caution, ensuring rigorous clinical evaluations and safety protocols.
The medical community and researchers are now tasked with delving deeper into understanding the potential risks associated with gene therapy treatments. It is essential to strike a balance between innovation and safety, ensuring that patients receive the best possible care without exposing them to undue risks.
In light of this incident, medical professionals, researchers, and stakeholders in the field of gene therapy are urged to collaborate, share insights, and work towards refining treatment protocols to prevent such tragic outcomes in the future.
Journal Reference
Lek, A., Wong, B., Keeler, A., Blackwood, M., Ma, K., Huang, S., … Flotte, T. (2023). New England Journal of Medicine, 389(13), 1203–1210. doi:10.1056/nejmoa2307798
