Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus

Molecular Therapy: Methods & Clinical Development, 2024 · DOI: https://doi.org/10.1016/j.omtm.2024.101263 · Published: June 1, 2024

Neurology Genetics Women's Health

Simple Explanation

This study explores using gene therapy before birth to treat severe genetic disorders like spinal muscular atrophy (SMA) or muscular dystrophy. Researchers tested a clinical-grade AAV9-GFP viral vector in fetal lambs to see how safe it is and where it goes in the body after injection into the umbilical vein or brain. The treatment showed good results in targeting the brain, spinal cord, and muscles, but also revealed potential risks such as affecting the mother and the developing reproductive cells in female fetuses.

Study Duration

E75 to E96/E140 (21 or 65 days)

Participants

30 fetal lambs from 15 pregnancies

Evidence Level

Not specified

Key Findings

1
Umbilical vein injection of AAV9-GFP resulted in widespread biodistribution in lamb tissues and maternal uteruses.
2
GFP expression was detected in female germ cells, but not male germ cells, raising concerns about potential germline transduction.
3
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) was observed.

Research Summary

This study investigated the safety and efficacy of prenatal AAV9-GFP administration in fetal lambs for potential treatment of neuromuscular disorders. The results showed broad biodistribution and transgene expression in CNS and peripheral tissues, but also highlighted safety concerns like maternal exposure and female germ cell transduction. The findings suggest potential therapeutic benefits but warrant caution for exposure of female germ cells and the need for further studies to optimize dosage and injection techniques.

Practical Implications

Therapeutic Potential

AAV9 PSCGT may offer a therapeutic option for early-onset neuromuscular disorders like SMA and muscular dystrophy, given the robust transgene expression in the CNS and muscles.

Safety Concerns

The maternal exposure and transduction of female germ cells highlight the need for caution and further investigation into the risks associated with AAV9-based prenatal gene therapy.

Dosage and Technique Optimization

Future research should focus on dose titration and less invasive injection techniques to mitigate potential toxicities and improve the safety profile of prenatal AAV9 administration.

Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus

Simple Explanation

Key Findings

Research Summary

Practical Implications

Therapeutic Potential

Safety Concerns

Dosage and Technique Optimization

Study Limitations

Your Feedback

Was this summary helpful?

Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus

Simple Explanation

Key Findings

Research Summary

Practical Implications

Therapeutic Potential

Safety Concerns

Dosage and Technique Optimization

Study Limitations

Your Feedback

Was this summary helpful?