CAG-FLEX-GCaMP6f AAV (Serotype 9)

Almost all large molecule drugs and approximately 98% of small molecule drugs cannot cross the blood-brain barrier, which limits the development of drugs for many central nervous system diseases. Gene therapy has been proposed as a means of crossing the blood-brain barrier. However, widespread delivery to the brain and spinal cord has proven challenging. Successful gene therapy for motor neuron disease is expected to require widespread transduction within the spinal cord and motor cortex.

AAV vectors (e.g., AAV2) have shown promise in several recent clinical trials for neurological diseases, demonstrating sustained transgene expression, a relatively safe profile, and promising functional responses, but require surgical intraparenchymal injection. Newly discovered AAV serotypes, particularly AAV6, AAV8, and AAV9, have led to advances in delivery, allowing widespread transduction in multiple tissues (e.g., skeletal and cardiac muscle) after simple systemic intravenous or intraperitoneal injections. These serotypes have all been shown to effectively cross the vascular endothelial cell barrier. Compared to other AAV serotypes, AAV9 is more easily transported within the brain after intraparenchymal injection. In neonates, a single intravascular injection of AAV9 resulted in widespread transduction of dorsal root ganglia and motor neurons in the spinal cord and neurons in most brain regions. In adults, transduction occurred primarily in astrocytes in the spinal cord and brain.