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  • Writer's pictureSaeed Anwar Anuj

The promise and perils of gene therapy in Duchene muscular dystrophy: insights from Terry's story

Following my recent blog post on Elevidys and its potential in Duchenne Muscular Dystrophy (DMD) treatment, many of you have reached out with concerns and questions, particularly regarding the safety of gene therapies. A recent study published in the New England Journal of Medicine has brought these issues into sharp focus, requiring our thoughtful consideration and understanding.


I personally have been closely following this particular case since before the approval of Elevidys, as I came across a pre-print version of the study in May. The paper details an N-of-1 clinical trial involving 27-year-old Terry Horgan, who had been bravely battling DMD since his diagnosis at 5.5 years old. For 21 years, Terry's treatment regimen included a daily dose of 1.1 mg deflazacort, a corticosteroid used to manage inflammation in DMD patients. By 18, he was reliant on a wheelchair, with progressively worsening cardiopulmonary dysfunction. In October 2022, Terry underwent a high-dose gene therapy using recombinant adeno-associated virus serotype 9 (rAAV9), which included a modified 'dead' Staphylococcus aureus Cas9 (dSaCas9) fused to VP64, aimed at up-regulating cortical dystrophin. The administered dose was quite substantial, at 1 × 10^14 vector genomes per kilogram of body weight, equating to 100 trillion vector genomes. To put this into perspective, a 30 kg individual would receive an injection containing 3000 trillion copies of the viral genome, each carrying a miniature version of the human dystrophin gene. However, Terry soon developed mild cardiac dysfunction and pericardial effusion, which escalated to acute respiratory distress syndrome (ARDS) and, ultimately, cardiac arrest, leading to his premature passing. This tragic turn of events, resulting from cytokine-mediated cardiopulmonary toxic effects, underscores the profound complexities and inherent risks associated with gene therapy, particularly for those in advanced stages of DMD.


Now, let's try to contextualize the treatment and its implications: First of all, this patient, at 27 years old, was within the mean life expectancy for DMD, a stage where cardiac and pulmonary complications are more common. This scenario may represent a 'perfect storm', combining the advanced stage of DMD with high-dose gene therapy. It's crucial to note that the treatment in this study differs significantly from the FDA-approved Elevidys. Elevidys is intended for pediatric patients with mutations outside a certain region of the gene's N-terminal part. In contrast, the therapy in this study targeted an adult patient with a mutation in the promoter and exon 1 region of the N-terminal part, which is distinct from the region where Elevidys is contraindicated.


This recent incident has brought critical safety issues associated with AAV-mediated gene therapies into sharp focus. Our immune system, skilled at identifying and reacting to foreign entities, e.g., pathogenic viruses and bacteria, might recognize the viral vectors used in gene therapy as foreign. This can lead to a spectrum of immune responses, ranging from mild reactions, which might slightly impact the therapy's efficacy, to severe complications like inflammation or organ damage, as seen in the 27-year-old DMD patient's case. Individual variability in immune systems means that people can respond differently to the same viral vector. Additionally, some individuals may have pre-existing antibodies against certain AAV serotypes from previous exposure to viruses, which can neutralize the viral vectors, reducing their effectiveness or provoking an immune reaction. This pre-existing immunity can necessitate using different AAV serotypes or alternative delivery methods in treatment plans. Besides, determining the optimal dosage for gene therapy is a significant challenge. While higher doses may seem more effective in delivering the therapeutic gene, they also increase the risk of a stronger immune response. In such cases, the immune system may view the viral vectors as a considerable threat, leading to an aggressive reaction that could be more harmful than the condition being treated. The timing of gene therapy administration is equally crucial, as it should ideally align with a patient’s capacity to tolerate the therapy and the disease's progression. In response, the scientific community is deeply engaged in understanding the complexities of immune responses to AAV-mediated gene therapies. Our work includes developing viral vectors less prone to triggering strong immune responses and finding a balance where the therapy effectively delivers necessary genes without causing adverse immune reactions. This pursuit involves continuous studies and trials, aiming to better comprehend how varying dosages and timings impact different patients.


This incident also brings to light the intricate challenges associated with the human immune system in the context of biotherapeutics. The immune response to gene therapy can be unpredictable and complex, a fact that is sometimes underacknowledged in the industry. For instance, the history of recombinant human Erythropoietin (rhEPO) in therapeutics offers a crucial lesson. Differing immunogenicity rates for the same drug in different indications led regulators to adopt a stance of biosimilarity rather than bio-genericity. This instance is a stark reminder that our understanding of human biology, while advanced, remains incomplete. The scientific community is acutely aware of these gaps in knowledge, despite the optimistic narratives often presented by the marketing arms of biotherapeutic companies.


In addressing the complexities of gene therapy, the scientific community is deeply invested in enhancing the safety and efficacy of these treatments. Researchers are refining gene-editing technologies like CRISPR to ensure precise genetic modifications, thereby minimizing the risks of off-target effects that could have unforeseen health implications. This precision is being achieved through rigorous testing and refinement of gene-editing protocols. Additionally, scientists are engineering viral vectors, such as AAVs, to be less detectable by the immune system by altering their surface proteins, reducing the likelihood of immune responses. In addition, new vectors are being developed. Personalization of these vectors based on individual patients’ immune profiles is also being explored, aiming to tailor treatments more effectively and reduce adverse reactions. Understanding long-term effects is crucial; thus, scientists are committed to extended monitoring of patients post-treatment to detect any delayed adverse effects. This involves detailed data collection and analysis, which will guide future adjustments in treatment protocols, dosages, and vector designs. The approach is inclusive, involving patient communities in the research process to ensure research aligns with their experiences and needs, and we maintain open communication channels to share findings and gather feedback. The evolving nature of this field calls for collaboration and innovation. We work alongside global researchers, clinicians, and patient advocacy groups, sharing knowledge and exploring new technologies and methods. This multifaceted approach, combining meticulous research, patient-centric strategies, and collaborative efforts, underscores our dedication to advancing gene therapies safely and effectively, always prioritizing the voices and experiences of those most impacted by these conditions.


As we face these challenges, your questions and concerns guide our path forward. Developing safe and effective treatments is a journey marked by both challenges and progress. Each step, whether a success or a setback, contributes crucially to our collective understanding and guides our future endeavors. We, as researchers, are steadfast in our commitment to this journey, driven by the resilience and hopes of the DMD community. Our collective efforts, informed by ongoing learning and patient experiences, are crucial as we navigate this intricate landscape. Together, we strive towards a future where gene therapy not only treats but significantly improves the lives of those with DMD.



13 October 2023 Saeed Anwar

Edmonton, Canada

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