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Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.
Borges, Beltran; Varthaliti, Antonia; Schwab, Marisa; Clarke, Maria T; Pivetti, Christopher; Gupta, Nalin; Cadwell, Cathryn R; Guibinga, Ghiabe; Phillips, Shirley; Del Rio, Tony; Ozsolak, Fatih; Imai-Leonard, Denise; Kong, Lingling; Laird, Diana J; Herzeg, Akos; Sumner, Charlotte J; MacKenzie, Tippi C.
Afiliación
  • Borges B; Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Varthaliti A; UCSF Center for Maternal-Fetal Precision Medicine, San Francisco, CA 94158, USA.
  • Schwab M; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Clarke MT; Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Pivetti C; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Gupta N; Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Cadwell CR; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Guibinga G; Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Phillips S; UCSF Center for Maternal-Fetal Precision Medicine, San Francisco, CA 94158, USA.
  • Del Rio T; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Ozsolak F; Department of Surgery, University of California, Davis, Davis, CA 95817, USA.
  • Imai-Leonard D; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Kong L; Department of Pediatrics and Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Laird DJ; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Herzeg A; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Sumner CJ; Weill Neurohub, University of California, San Francisco, San Francisco, CA 94158, USA.
  • MacKenzie TC; Novartis Institutes for BioMedical Research Biologics Center, San Diego, CA 92121, USA.
Mol Ther Methods Clin Dev ; 32(2): 101263, 2024 Jun 13.
Article en En | MEDLINE | ID: mdl-38827250
ABSTRACT
Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend toward elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select proto-oncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders, but warrant caution for exposure of female germ cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos