Cure Rare Disease Identifies Toxicity Responsible for DMD Gene Therapy Death


Caution is warranted for older patients with Duchenne muscular dystrophy who are receiving gene therapy, according to details of a patient death in a single patient trial.

Angela Lek, PhD, vice president, research, Muscular Dystrophy Association,

Angela Lek, PhD

This content originally appeared on our sister site, CGTLive.

According to a recent preprint of non-peer-reviewed research, investigations by Cure Rare Disease (CRD) have elucidated that a gene therapy prompted an innate immune signaling with capillary leak dose-limiting toxicity, leading to a patient death in a single patient trial (NCT05514249).1 The patient with Duchenne muscular dystrophy (DMD) was treated with a CRISPR-based adeno-associated virus vector (AAV9) gene therapy that delivered Cas9-VP64 transgene.

“There are several novel aspects of our case that add to the body of knowledge relevant to future applications of AAV-mediated gene therapy to DMD; however, our interpretations and separation of what is due to the custom gene therapy administered, age of the patient, and severity of disease state is challenging because of the design of this trial with a unique AAV-mediated gene therapy for a single patient,” lead author Angela Lek, PhD, vice president, research, Muscular Dystrophy Association, and colleagues wrote.1 “The patient’s late stage of DMD progression at dosing may have limited his physiologic reserves to tolerate the cardiopulmonary stress associated with acute toxicity resulting from rAAV gene therapy, but this was not possible to fully demonstrate. 

In November 2022, 27-year-old Terry Horgan, primary patient and the brother of CRD founder Rich Horgan, died 8 days following treatment of the gene therapy in the trial. The patient showed signs of mild cardiac dysfunction and pericardial effusion and then 6 days following the dosage, the patient acutely decompensated and sustained cardiac arrest. Two days later, the patient died. The new post-mortem results from the patient showed severe acute-respiratory distress syndrome along with diffuse alveolar damage. Also, minimal expression of the transgene in the liver was observed when investigators assessed transgene expression. Overall, no evidence was observed of AAV9 antibodies or effector T cell reactivity in the patient.

READ MORE: Cell Therapy CAP-1002 Continues to Show Preservation of Cardiac Function in Open-Label Extension Study of DMD

“Unfortunately, the acute toxicity and shortened course of this patient prevented a substantive assessment of the safety and efficacy of the CRISPR-transactivator approach itself. It is well-known that the single-stranded rAAV genome requires weeks to form transcriptionally active double-stranded forms after in vivo gene therapy. In this case, the innate immune toxicity shortened the patient’s course to an extent that would not have been predicted to allow for significant transgene expression,” Lek and colleagues noted.1

In August 2022, the FDA granted CRD approval to continue with the single patient trial.3 The CRISPR-based gene therapy was intended to treat muscle promotor and exon 1 mutations on the dystrophin gene and ultimately upregulate an isoform of the dystrophin protein with the hope of stabilizing and potentially reversing the progression of symptoms in DMD.

"We know the CRD-TMH-001 trial and the outcome have been closely followed by the rare disease community and many are eager for more details. While these details are currently being studied by multiple teams across the country, this is a complex undertaking and could take up to four months," CRD said in a statement.2 "The comprehensive work these teams are doing is critical to gaining a clear understanding of the outcome of the CRD-TMH-001 trial and to shedding additional light on the challenges of gene therapy broadly."

1. Lek A, Wong B, Keeler AL, et al. Unexpected death of a Duchenne muscular dystrophy patient in an N-of-1 trial of rAAV9-delivered CRISPR-transactivator.medRxiv 2023. doi:10.1101/2023.05.16.23289881
2. An Update to the CRD community. News release. Cure Rare Disease. November 1, 2022. Accessed July 18, 2023.
3. Cure Rare Disease Receives FDA Approval to Administer First-in-Human CRISPR Therapeutic. News release. Cure Rare Disease. August 9, 2022. Accessed July 18, 2023.
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