Table 2.

Summary of using AAV in perinatal gene therapy and its clinical implication.

AAV transduction efficiency

• The ability of AAV serotypes to cross the BBB highlights its systemic transduction capabilities.

• Intravenous administration of AAV9 at either fetal or neonatal stage of development in rodents and NHP targets different cell types within the nervous system; neurons via fetal intravenous (iv) and astrocytes and microglia via neonatal iv administration.

• The iv approach is ideal for systemic neurodegenerative disorders.

Advantages of perinatal gene delivery

• Efficient gene delivery is achieved due to; large vector to cell ratio, induction of immune-tolerance (at least in rodents) to foreign protein expression.

• Ideal for early lethal neurodegenerative diseases as it allows for therapeutic transduction of cells and organs prior to disease pathology manifestation.

Potential disadvantages of perinatal gene therapy

• Lack of diagnostic technologies or infrastructure to identify disease in patients early enough.

• In utero ultrasound or exposed surgical procedure may impose risk such as fetal loss or preterm birth.

• Over expression of the therapeutic transgene in the fetus may cause developmental abnormalities.

• Fetal iv preferentially targets neurons and not astrocytes.

Clinical implication

• Perinatal gene therapy has been successful in a number of animal CNS diseases.

• Intravenous route of administration is favorable for its ability to cross the BBB and target other peripheral organs.

• Particular AAV serotypes ability to cross the BBB provides and alternative to intracranial administration which would require surgery and its attendant risks.

• Successful clinical trials have taken place where systemic delivery of AAV and disease specific transgene has been delivered topically and intravenously to patients.