Genome editing research targets late-onset Tay Sachs

Base editing has been used to correct the mutation causing late-onset Tay-Sachs disease (LOTS) in mice and human cells.

LOTS is a rare form of Tay-Sachs disease, affecting around 500 people worldwide. Unlike the better known infantile form, symptoms can appear in childhood, adolescence or adulthood. LOTS results from a single base point mutation in the HEXA gene, which encodes the beta-hexosaminidase A enzyme. This mutation involves the substitution of a guanine with an adenine in the DNA sequence. Researchers from the United States National Institute of Health (NIH), in Bethesda, Maryland, used an adeno-associated virus (AAV) to deliver an adenine base editor (ABE), guided by a short RNA, to precisely correct this point mutation in the HEXA gene in mice with LOTS.

Dr Richard Proia, lead author of this study from the NIH's National Institute of Diabetes and Digestive and Kidney Diseases, explained, 'With LOTS, a slight correction will go a long way. This editing may only need to increase enzyme activity by about ten percent to keep symptoms from getting worse, and improve their quality of life.'

The beta-hexosaminidase A enzyme normally breaks down GM2 ganglioside, a fatty substance in the brain. In LOTS, GM2 accumulates, leading to muscle weakness, spasms, impaired coordination, and occasionally cognitive decline. In this study, published in the Journal of Clinical Investigation, the team used an ABE packaged within an AAV vector to switch the incorrect adenine back to guanine in the HEXA gene, both in a LOTS mouse model, and in cells from affected individuals.

Unlike traditional genome editing, which cuts DNA and risks introducing new mutations, base editing swaps the single incorrect base pair without breaking the DNA. In treated LOTS mice, beta-hexosaminidase A activity increased by 24 percentage points compared with control mice, accompanied by a 90 percent reduction in GM2 accumulation. These changes were also associated with prolonged lifespan and reduced neuroinflammation in the brains of the treated mice.

Although this work has been limited to cell cultures and animal models so far, the team aims to develop it into a therapy for humans. Dr Proia said, 'We've figured out that opening the door to increased enzyme activity is possible, now we have to figure out how to do it in a person.'

In future work, the group plans to explore the most effective way to deliver the ABE technology into the brain. Although AAV vectors have shown promise, their effectiveness is limited by pre-existing antibodies and their limited ability to cross into the human brain. The team believes that this base editing approach holds considerable promise, concluding in their paper that 'base editing opens the possibility for one-time, permanent treatments potentially halting the progression of these devastating disorders.'