Case Report of Patient Death Following High-Dose Gene Therapy for DMD

According to the findings of a case study of a patient living with advanced Duchenne muscular dystrophy (DMD) who received transgene therapy and died just over a week later, an innate immune reaction following the high-dose therapy led to fatal acute respiratory distress syndrome (ARDS).¹

The 27-year-old patient had received recombinant adeno-associated virus serotype 9 (rAAV9), which contained Staphylococcus aureus Cas9 with inactivated Cas9 nuclease activity, at a dose of 1x10¹⁴ vector genoms (vg)/kg. This therapy was meant to upregulate cortical dystrophin as a custom CRISPR–transactivator therapy, the authors noted.

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He was just 5.5 years of age when his DMD was diagnosed, and for 21 years he was treated with once-daily 1.1-mg deflazacort, a corticosteroid that acts as an anti-inflammatory and immunomodulatory agent.² He lost ambulatory function by age 18 years; had increasing cardiopulmonary dysfunction, with forced expiratory volume in 1 second and forced vital capacity of 36% each; and had left ventricular ejection fraction (LVEF) between 55% and 60%.

Their report was published recently in The New England Journal of Medicine.

Study investigators highlight that although several rAAV-based treatments have been developed for DMD, the large size of the dystrophin gene and high dose of rAAV needed present challenges to their effectiveness. Previous studies have evaluated the effectiveness of doses ranging from 5x10¹³ to 2x10¹⁴ vg/kg, after which patients developed several toxic syndromes; chief among them, hepatotoxicity, thrombocytopenia and thrombotic microangiopathy, and cardiotoxicity.

Of the Cas9 fusion protein and vector, the authors explained that a biopsy from the patient at age 23 “showed patchy dystrophin immunostaining that was approximately 3% of the control muscle value, as assessed by Western blot.” He also was shown to have inherited from his mother an approximate 30 kb hemizygous deletion encompassing the promoter and exon 1 of the muscle transcript variant of dystrophin.

“We hypothesized that the cortical isoform of dystrophin may be compensating for the absence of the muscle isoform on the basis of reports of exon 1 deletions in Dp427m observed in patients with X-linked dilated cardiomyopathy that resulted in no overt skeletal-muscle phenotype,” the investigators wrote.

It was because of his unique deletion mutation that they decided on the CRISPR–transactivator technology.

At the time of the patient’s 1x10¹⁴ vg/kg dose on October 4, 2022, he had severe generalized muscle weakness, a restrictive pulmonary defect, and mild left ventricular systolic dysfunction. The carvedilol and lisinopril he was on to stabilize his cardiac function were stopped prior to infusion of the gene therapy due to potential for drug-drug interactions causing worsening myocarditis and cardiogenic shock. He was also put on prophylactic immune-suppression therapy prior to the gene therapy, and this consisted of rituximab, glucocorticoids, and sirolimus, and underwent infectious disease evaluation.

Premature ventricular contractions were seen on the day after vector delivery, and they were followed by a downward trend in platelet counts and increasing B-type natriuretic peptide (BNP) and N-terminal proBNP by day 2. By day 5 post gene therapy delivery, he was on continuous ventilation because of a drop in LVEF to between 45% and 50%, at which point he was presumed to have myopericarditis. ARDS had developed by day 6, and mitigating therapies (glucocorticoids, eculizumab [anti-C5], tocilizumab [anti–interleukin-6R], and anakinra) were administered. Cardiopulmonary arrest followed, and the patient had died from multiorgan failure and severe hypoxic ischemic neurologic injury.

Autopsy findings showed a marked decrease in heart and skeletal muscle, severe cardiomyopathy, heavy and edematous lungs, infarctions across the cerebral cortex and cerebellum regions of the brain, and widespread neuronal injury.

“ARDS is not commonly described in association with AAV gene therapy, and other persons treated with the same dose of the recombinant AAV9 vector have not had this toxic effect,” the authors concluded, “which suggests that both host factors and inherent properties of the vector led to unexpectedly high levels of vector genome in the lung and may have contributed to the outcome.”

References

1. Lek A, Wong B, Keeler A, et al. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med. 2023;389(13):1203-1210. doi:10.1056/NEJMoa2307798

2. Deflazacort tablets. Cleveland Clinic. Accessed October 18, 2023. https://my.clevelandclinic.org/health/drugs/20103-deflazacort-tablets