Second Patient Death After Gene Therapy: Implications For The Future

Forbes

17-06-2025

As we continue our series exploring genetic medicine, both in this story and in Destiny's Child No Longer: Rewriting Genetic Fate, gene therapy stands at a crossroads. On June 16, Sarepta Therapeutics announced a second patient death following treatment with its gene therapy, Elevidys, for Duchenne muscular dystrophy. This news has sent shockwaves through the rare disease and biotech communities. It raises questions about the safety of adeno-associated virus-based gene therapies. The latest fatality, a 15-year-old, died from acute liver failure, a recognized but rare complication of adeno-associated virus-based gene transfer. This death follows a similar case reported in March.
These recent tragedies have profound implications. Elevidys, Sarepta's gene therapy, was among the first to receive approval for the treatment of Duchenne muscular dystrophy. Yet, the deaths of two patients treated with Elevidys now force us to confront a difficult question. Do the potential benefits of this therapy truly outweigh the risks, particularly for those who can no longer walk and may be at higher risk of complications?
Every advance in medicine brings new challenges, and gene therapy is no exception. The deaths associated with Elevidys have raised the regulatory bar for all investigational gene therapies that use adeno-associated virus vectors. This means more stringent safety monitoring, more careful patient selection, and better reporting of outcomes. This heightened scrutiny is not unwelcome, even if these measures may slow the pace of development in the short term. They are essential for ensuring safety and responsibility.
Adeno-associated virus-based vectors have become the workhorse of gene therapy due to their efficiency and relatively low risk of complications. The field has long recognized that high-dose adeno-associated virus-based administration can trigger severe, sometimes fatal, immune-mediated toxicities. These primarily affect the liver.
In 1999, Jesse Gelsinger died after receiving an adenoviral gene therapy. His tragic death marked a turning point in the field and led to decades of increased scrutiny and regulation. While adeno-associated viruses are generally less immunogenic than adenoviruses, high doses can activate the body's immune system. This leads to inflammation, liver injury, and, in rare cases, organ failure. Recent studies highlight that immune responses can contribute to toxicity, particularly in the liver. However, not all patients are impacted equally.
Recent findings underscore that age and disease status can significantly influence a patient's response to adeno-associated virus-based gene therapy. Clinical studies reveal that individual factors, such as underlying infections, pre-existing liver disease, or genetic predispositions, can amplify the risks. For example, in the first reported Elevidys death, a concurrent infection may have played a role in the patient's rapid decline.
Research from the University of Bristol indicates that in ocular gene therapy trials, older patients, particularly females, are more likely to experience severe inflammatory responses. However, in the Elevidys cases, both fatalities involved males who had lost the ability to walk due to advanced disease progression. This is a critical factor linked to heightened immune vulnerability. This underscores that risks are context-specific, depending on therapy type, delivery site, and patient health status.
To address the pressing safety concerns, Sarepta is investigating several strategies. One approach under consideration is the addition of sirolimus, an immunosuppressant widely used in organ transplantation. While this aims to reduce immune-mediated liver damage, experience from liver transplant patients warns that sirolimus can nearly triple infection risk, even at low doses. Its use in gene therapy remains experimental and demands careful evaluation before it can be widely adopted.
At the same time, non-viral delivery methods are emerging as a promising alternative. Lipid nanoparticles offer a way to bypass many of the immune challenges posed by viral vectors. Their ability to be tailored for precise tissue targeting and the absence of pre-existing immunity in patients make them particularly attractive for conditions like Duchenne muscular dystrophy, where repeated dosing may be necessary. Though still less efficient than viral vectors in some applications, the technology is advancing quickly.
The second death following Elevidys for Duchenne muscular dystrophy is a sobering reminder of the risks inherent in adeno-associated virus-based gene transfer, particularly for older or more severely affected patients. Still, these tragedies are not new to the field. We have seen similar inflection points before.
The history of gene therapy is marked by moments of triumph and tragedy. Each shapes the path forward. As we reflect on these recent events, it is clear that the field stands at another such crossroads—one that will require careful balancing of hope, caution, and scientific rigor to chart the best course for patients and the future of medicine.
For a deeper exploration of these issues, including real-world patient stories and the latest scientific advances, see Destiny's Child No Longer: Rewriting Genetic Fate, which provides a detailed examination of this therapy and other gene therapies.