Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator
An N-of-1 trial was developed to deliver a dCas9-VP64 transgene designed to upregulate the cortical dystrophin as a custom therapy for a Duchenne muscular dystrophy (DMD) patient. After showing signs of mild cardiac dysfunction and pericardial effusion, the patient acutely decompensated and sustained cardiac arrest six-days after dosing and succumbed two-days later. Post-mortem examination revealed severe acute-respiratory distress syndrome with diffuse alveolar damage. Vector biodistribution data was obtained and revealed minimal expression of transgene in liver. There was no evidence of AAV9 antibodies nor of effector T cell reactivity. These findings demonstrate innate immune signaling with capillary leak as a form of toxicity in an advanced DMD case treated with high-dose rAAV gene therapy..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 18. Mai Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lek, Angela [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2023.05.16.23289881 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI039574830 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI039574830 | ||
| 003 | DE-627 | ||
| 005 | 20231205145129.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230520s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.05.16.23289881 |2 doi | |
| 035 | |a (DE-627)XBI039574830 | ||
| 035 | |a (biorXiv)10.1101/2023.05.16.23289881 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lek, Angela |e verfasserin |0 (orcid)0000-0001-5889-2169 |4 aut | |
| 245 | 1 | 0 | |a Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a An N-of-1 trial was developed to deliver a dCas9-VP64 transgene designed to upregulate the cortical dystrophin as a custom therapy for a Duchenne muscular dystrophy (DMD) patient. After showing signs of mild cardiac dysfunction and pericardial effusion, the patient acutely decompensated and sustained cardiac arrest six-days after dosing and succumbed two-days later. Post-mortem examination revealed severe acute-respiratory distress syndrome with diffuse alveolar damage. Vector biodistribution data was obtained and revealed minimal expression of transgene in liver. There was no evidence of AAV9 antibodies nor of effector T cell reactivity. These findings demonstrate innate immune signaling with capillary leak as a form of toxicity in an advanced DMD case treated with high-dose rAAV gene therapy. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Wong, Brenda |0 (orcid)0000-0002-0971-9789 |4 aut | |
| 700 | 1 | |a Keeler, Allison |0 (orcid)0000-0002-5202-4616 |4 aut | |
| 700 | 1 | |a Blackwood, Meghan |4 aut | |
| 700 | 1 | |a Ma, Kaiyue |0 (orcid)0009-0001-4302-3371 |4 aut | |
| 700 | 1 | |a Huang, Shushu |0 (orcid)0000-0002-0220-4395 |4 aut | |
| 700 | 1 | |a Sylvia, Katelyn |4 aut | |
| 700 | 1 | |a Batista, Ana Rita |4 aut | |
| 700 | 1 | |a Artinian, Rebecca |4 aut | |
| 700 | 1 | |a Kokoski, Danielle |4 aut | |
| 700 | 1 | |a Parajuli, Shestruma |0 (orcid)0000-0003-0043-9673 |4 aut | |
| 700 | 1 | |a Putra, Juan |0 (orcid)0000-0002-3487-4641 |4 aut | |
| 700 | 1 | |a Carreon, Chrystalle Katte |0 (orcid)0000-0003-2152-7998 |4 aut | |
| 700 | 1 | |a Lidov, Hart |0 (orcid)0000-0002-1839-7603 |4 aut | |
| 700 | 1 | |a Woodman, Keryn |0 (orcid)0000-0002-4969-3026 |4 aut | |
| 700 | 1 | |a Pajusalu, Sander |0 (orcid)0000-0002-5435-0781 |4 aut | |
| 700 | 1 | |a Spinazzola, Janelle |0 (orcid)0000-0002-7141-5487 |4 aut | |
| 700 | 1 | |a Gallagher, Thomas |0 (orcid)0000-0001-6381-6902 |4 aut | |
| 700 | 1 | |a LaRovere, Joan |0 (orcid)0000-0003-3688-4971 |4 aut | |
| 700 | 1 | |a Baulderson, Diane |4 aut | |
| 700 | 1 | |a Black, Lauren |4 aut | |
| 700 | 1 | |a Sutton, Keith |4 aut | |
| 700 | 1 | |a Horgan, Richard |4 aut | |
| 700 | 1 | |a Lek, Monkol |0 (orcid)0000-0003-1227-6293 |4 aut | |
| 700 | 1 | |a Flotte, Terence |0 (orcid)0000-0002-8255-0588 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 18. Mai |
| 773 | 1 | 8 | |g year:2023 |g day:18 |g month:05 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.05.16.23289881 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 18 |c 05 | ||