Dose-Limiting AAV Toxicity Responsible for Cure Rare Disease’s DMD Trial Death


Unforeseen complications may arise when treating older patients with gene therapy.

Investigations by Cure Rare Disease (CRD) into the death of the first and only patient with Duchenne muscular dystrophy (DMD) treated with a CRISPR-based adeno-associated virus vector (AAV9) gene therapy delivering dCas9-VP64 transgene in a single patient trial (NCT05514249) have revealed that the patient died from acute respiratory distress syndrome (ARDS) caused by an innate immune reaction after high dose rAAV gene therapy.

The research elucidated the innate immune signaling with capillary leak dose-limiting toxicity that led to the patient’s death and has been published in New England Journal of Medicine.1

“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,” first author Angela Lek, PhD, vice president, research, Muscular Dystrophy Association, and colleagues wrote in the paper.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. 

Terry Horgan, the 27-year-old primary patient in the trial and the brother of CRD founder Rich Horgan, died 8 days after receiving the gene therapy in November 2022. Six days after dosing, the patient acutely decompensated and sustained cardiac arrest after showing signs of mild cardiac dysfunction and pericardial effusion, dying 2 days later. The new, post-mortem findings revealed severe acute-respiratory distress syndrome with diffuse alveolar damage. Investigators also assessed transgene expression and found minimal expression of the transgene in liver. There was no evidence of AAV9 antibodies or effector T cell reactivity in the organs.

READ MORE: Duchenne Muscular Dystrophy Cell Therapy CAP-1002 Demonstrates Improvements in LVEF

“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 wrote.1

The FDA previously gave CRD approval to proceed with the single patient trial in August 2022.3 The gene therapy was intended to treat muscle promotor and exon 1 mutations on the dystrophin gene that would upregulate an isoform of the dystrophin protein in hopes of stabilizing an potentially reversing symptom progression 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 about the death.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. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med. 2023 (389): 1203-1210
doi: 10.1056/NEJMoa2307798
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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