Animal models for prenatal gene therapy: the nonhuman primate model

Area of Science:

• Reproductive Biology
• Genetics
• Immunology

Background:

• Intrauterine gene therapy (IUGT) presents a potential cure for severe fetal monogenic diseases.
• Early gestation IUGT may correct disorders before irreversible damage and induce immune tolerance.
• Rodent models have limitations for assessing long-term IUGT efficacy and safety due to immune and gestational differences.

Purpose of the Study:

• To establish a nonhuman primate (NHP) model for investigating intrauterine gene therapy.
• To evaluate early versus late-gestation IUGT outcomes in Macaca fascicularis.
• To assess transgene expression longevity and potential adverse events in NHPs.

Main Methods:

• Development of a Macaca fascicularis model for intrauterine gene therapy.
• Utilized ultrasound and fetoscopic techniques for systemic vector delivery.
• Implemented longitudinal analyses to monitor treatment effects and safety.

Main Results:

• The NHP model allows for the study of critical IUGT parameters not feasible in rodents.
• Investigation of immune maturity, transgene expression, and adverse events in relation to gestation timing.
• Established a framework for vector administration and longitudinal monitoring in NHPs.

Conclusions:

• Nonhuman primates are essential for advancing intrauterine gene therapy research.
• This model facilitates the study of long-term efficacy, safety, and immune responses to IUGT.
• Further research in NHPs is critical for translating IUGT to clinical applications for fetal genetic disorders.