Therapeutic expression of human clotting factors IX and × following adeno‐associated viral vector‐mediated intrauterine gene transfer in early‐gestation fetal macaques

What is it about?

Children born with single-gene disorders can develop clinical illness and complications due to missing or deficient proteins soon after birth or even during fetal development. Correction can be achieved with gene therapy, transferring the correct copy of the gene to the affected tissues with a non-pathogenic viral vector. Clinical trials have demonstrated encouraging outcomes in infants with progressive spinal muscular atrophy. Young recipients have a better chance of cure than older recipients with more advanced disease, demonstrating the efficacy of treating affected infants as early as possible. Gene therapy in fetuses can be safely performed and successfully corrects pathology in a range of knockout animal models. Intrauterine gene therapy (IUGT) performed in our non-human primate (NHP) model in early gestation results in sustained therapeutic levels of the replaced protein lasting up to 5 years after birth. A single dose of adeno-associated viral vectors (AAV) expressing human clotting factors 9 and 10 produced stable protein levels persisting at therapeutic levels despite the rapid growth of NHP infants. Repeat dosing after birth in low-responding infants was well-tolerated and long-term surveillance of all recipients showed little organ or immune-toxicity, unlike adult gene therapy recipients. AAV integrated widely into the host genome and by 4 years of age almost 90% of persistent vectors were integrated. Of the many integrated sequences we studied none were retrieved from or near cancer-associated genes. We anticipate that our long-term data demonstrating efficacy and safety will encourage the consideration of IUGT to treat early-onset incurable or debilitating single-gene diseases.

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