Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy
Copyright © 2023 Massachusetts Medical Society..
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.).
| Errataetall: |
CommentIn: N Engl J Med. 2023 Dec 7;389(23):2210-2211. - PMID 38055267 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:389 |
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| Enthalten in: |
The New England journal of medicine - 389(2023), 13 vom: 28. Sept., Seite 1203-1210 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lek, Angela [VerfasserIn] |
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| Anmerkungen: |
Date Completed 15.12.2023 Date Revised 15.12.2023 published: Print CommentIn: N Engl J Med. 2023 Dec 7;389(23):2210-2211. - PMID 38055267 Citation Status MEDLINE |
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| doi: |
10.1056/NEJMoa2307798 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362506116 |
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| 500 | |a CommentIn: N Engl J Med. 2023 Dec 7;389(23):2210-2211. - PMID 38055267 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Massachusetts Medical Society. | ||
| 520 | |a 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.) | ||
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| 700 | 1 | |a Wong, Brenda |e verfasserin |4 aut | |
| 700 | 1 | |a Keeler, Allison |e verfasserin |4 aut | |
| 700 | 1 | |a Blackwood, Meghan |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Kaiyue |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Shushu |e verfasserin |4 aut | |
| 700 | 1 | |a Sylvia, Katelyn |e verfasserin |4 aut | |
| 700 | 1 | |a Batista, A Rita |e verfasserin |4 aut | |
| 700 | 1 | |a Artinian, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Kokoski, Danielle |e verfasserin |4 aut | |
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