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N Engl J Med ; 389(13): 1203-1210, 2023 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-37754285

RESUMEN

We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., "dead" Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).


Asunto(s)
Distrofina , Terapia Genética , Distrofia Muscular de Duchenne , Síndrome de Dificultad Respiratoria , Transgenes , Adulto , Humanos , Anticuerpos , Distrofina/genética , Terapia Genética/efectos adversos , Terapia Genética/métodos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/inmunología , Transgenes/genética , Transgenes/inmunología , Resultado Fatal , Inmunidad Innata/genética , Inmunidad Innata/inmunología
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