Borges, Beltran, Varthaliti, Antonia, Schwab, Marisa, Clarke, Maria/T, Pivetti, Christopher, Gupta, Nalin, Guibinga, Ghiabe, Phillips, Shirley, Del Rio, Tony, Ozsolak, Fatih, Imai-Leonard, Denise, Kong, Lingling, Laird, Diana/J, Herzeg, Akos, Sumner, Charlotte/J and Mackenzie, Tippi/C (2024) Prenatal administration of AAV9-GFP in fetal lambs results in widespread distribution into brain and spinal cord and transduction of female germ cells. Molecular therapy - methods and clinical development. ISSN 2329-0501

Abstract

Prenatal somatic cell gene therapy could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy or muscular dystrophy. Given the current clinical use of adeno-associated virus serotype 9 (AAV9) vectors, we tested the safety and biodistribution of AAV9-GFP in fetal lambs after umbilical vein (UV) or intracranial (IC) injection at embryonic day 75 (E75) and harvest at E96 or E140 (term=E150). We detected widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses. There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), with no evident DRG toxicity. There was excellent transduction of diaphragm and quadriceps muscles. However, we noted several findings indicative of systemic toxicity including growth restriction and transient elevation of total bilirubin (in ewes and lambs). There were no antibodies against GFP but there were elevations in anti-AAV9 antibodies in ewes and lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with a low level of integration-specific reads , without integration in protooncogenes . These results support using the sheep model for further preclinical development and suggest potential therapeutic benefit for neuromuscular disorders; however, observed toxicities, particularly transduction of female germ cells, warrant caution.

Item Type:	Article
Keywords:	prenatal somatic cell gene therapy; adeno-associated virus; germ-cell transduction, spinal muscular atrophy
Date Deposited:	10 Jul 2024 00:46
Last Modified:	10 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/51786