In this presentation, Dr. Gao provides an overview of current trends in gene therapy, beginning with definitions of in vivo gene therapies and ex vivo modification of patient cells. Gene therapy includes four major approaches: gene replacement, gene therapy, gene addition, and gene activation.

An example of successful gene replacement is Canavan’s disease, where a gene therapy approach was developed to systemically deliver AAV9 across the blood-brain barrier (BBB) to deliver a transgene encoding the missing enzyme needed to break down N-acetyl aspartate in neuronal cell mitochondria. A clinical trial involving a single two-year-old child with Canavan’s disease demonstrated high efficacy, a good safety profile, and most importantly, the child is alive today with a good quality of life.

Nonhuman primates (NHPs) offer more translational value than rodents for gene therapy when using multiple AAV serotypes, including AAV3, AAV8, and AAV9. NHPs are primarily used for safety studies; however, because disease state NHP models are lacking, efficacy studies are not typically conducted.

RNA-based therapies can be broadly classified as RNA editing, RNA silencing, and readthrough therapy to reverse premature translational termination. AAV-based therapies can address premature translation termination by delivering suppressor tRNAs. Suppressor tRNA differs from normal tRNA by one nucleotide, and a library of suppressor tRNAs can be developed for different amino acids. It is important to note that efficacy is typically determined by delivery efficiency rather than tRNA binding.