Drs. George and Ahern have teamed up to create a treatment that will be useful for many different diseases. They leverage basic biology to create a tool that will “read through” a premature stop within a protein. Who does this help? In fact, many of the Syngap1 pathogenic variants (and pathogenic variants for many diseases) are caused by single-base changes in the DNA that result in premature termination of the protein. The changes that will be targeted by their treatment are called nonsense variants because they do not code for an amino acid at that point, but encode a “stop” instead so that the protein-making machinery stops before synthesizing the complete protein.
Dr. George gives a great overview of the basic biology behind the tRNA read-through concept. Dr. Ahern discusses how a treatment might get delivered with an Adeno-Associated Virus (AAV), and importantly shows that the treatment does not have off-target effects. Dr. Ahern describes the next steps in developing a clinical treatment, including making mouse models with protein-truncating variants to test.
The initial results showing no off-target effects are stunning, are applicable to many genes and many patients.