AAV9-CMV-GFP-2A-FLuc

Intravenous administration is considered the most attractive route for drug delivery due to its high patient acceptance, low cost, and low risk of complications. However, systemic administration of viral vectors for CNS gene therapy is challenging because most vectors are unable to penetrate the blood-brain barrier. The discovery of a specific serotype in rAAV vectors that can effectively penetrate the blood-brain barrier after intravenous administration has triggered a large number of studies using rAAV for CNS gene therapy. The neurotropic serotype rAAV9 has been identified as being able to transduce cells within the CNS, and studies have considered the impact of the blood-brain barrier on transduction. Evaluations involving intravenous administration of AAV9-Gfp vectors to newborn and adult mice with a fully formed blood-brain barrier yielded different results, suggesting that the blood-brain barrier plays a role in limiting the delivery of substances to the CNS. In newborns, where the blood-brain barrier is not fully developed, AAV9 preferentially transduces neurons, particularly motor neurons. In contrast, in mature individuals, the transduction profile points to astrocytes, which primarily constitute the structural components of the BBB.

In 2019, the FDA approved the first gene therapy for children with SMA under the age of 2. The therapy, called Zolgensma, uses an intravenous gene formulation with a rAAV9 vector as the carrier of a fully functional SMN1 gene. This approach effectively delivers the correct copy of the gene to spinal motor neurons. A single dose of Zolgensma has been shown to improve muscle function and survival in SMA patients. To date, rAAV9 is the primary unmodified viral vector used for CNS targeting following intravenous administration of the drug. It effectively transduces spinal motor neurons, resulting in significant reductions in clinical symptoms, improved quality of life, and increased longevity in SMA patients.