Numerous pediatric neurogenetic diseases may be optimally treated by in utero gene therapy (IUGT); but advancing such treatments requires animal models that recapitulate developmental physiology relevant to humans. One disease that could benefit from IUGT is the autosomal recessive motor neuron disease spinal muscular atrophy (SMA). Current SMA gene-targeting therapeutics are more efficacious when delivered shortly after birth, however postnatal treatment is rarely curative in severely affected patients. IUGT may provide benefit for SMA patients. In previous studies, we developed a large animal porcine model of SMA using AAV9 to deliver a short hairpin RNA (shRNA) directed at porcine survival motor neuron gene (Smn) mRNA on postnatal day 5. Here, we aimed to model developmental features of SMA in fetal piglets and to demonstrate the feasibility of prenatal gene therapy by delivering AAV9-shSmn in utero. Saline (sham), AAV9-GFP, or AAV9-shSmn was injected under direct ultrasound guidance between gestational ages 77–110 days. We developed an ultrasound-guided technique to deliver virus under direct visualization to mimic the clinic setting. Saline injection was tolerated and resulted in viable, healthy piglets. Litter rejection occurred within seven days of AAV9 injection for all other rounds. Our real-world experience of in utero viral delivery followed by AAV9-related fetal rejection suggests that the domestic sow may not be a viable model system for preclinical in utero AAV9 gene therapy studies.
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We would like to express our profound gratitude for the generosity and altruism of donors and their families, whose gifts of tissues serve an integral role in advancing medical research and education. We are grateful to Arthur H.M. Burghes, Ph.D. and his laboratory for guidance and advice. We would like to thank Jose Otero and Denise Gamble for their pathology input.
This project was funded by CureSMA, the SMA Foundation and the NIH (R01 NS062269) to CJS.
SJK has received compensation for consultation from AveXis, Biogen, and Genentech. CJS receives grant support from Roche Ltd and has served as a paid advisor, consultant, and/or speaker to the SMA Foundation, Biogen, Ionis Pharmaceuticals, PTC Therapeutics, Roche/Genentech, Sarepta, NuraBio, AveXis, and Novartis. All other authors report no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Rich, K.A., Wier, C.G., Russo, J. et al. Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets. Gene Ther 29, 513–519 (2022). https://doi.org/10.1038/s41434-021-00305-2