The significance of triple-capsid-mutant AAV8 for treatment of Sanfilippo Syndrome Type B.

ABSTRACT

Sanfilippo Syndrome Type-B remains an untreatable childhood neurodegenerative disease with great burden for both patient and caregiver. Very few clinical trials have been undertaken to treat the disease, and none of these have yet yielded clinically obtainable products for patients. Caused by a simple enzyme function deficiency, Sanfilippo Syndrome Type-B has been considered a great prospect for gene-therapy interventions. Adeno-associated virus (AAV) remains a major choice for therapeutic gene delivery due to its relatively low-immunogenicity, versatility and tissue tropism. However, many clinical trials with AAV continue to use wild-type capsids, which in many cases are not able to reach stable transgene expression for long enough to be clinically effective in most cases. Previous research in AAV gene-therapy has created a litany of novel AAV capsids that can improve overall transduction efficiency far above that of wild-type AAV capsids. One such example is the triple-capsid mutant AAV8 (TCM8), which has been shown to exhibit transgene expression far superior to other capsids in Sanfilippo mouse models, specifically. Originally designed to bypass capsid ubiquitination intracellularly, mouse studies suggest this TCM8 vector outperforms both AAV5 and AAV9 when delivered to the central nervous system. This implies it as an ideal contender for an effective gene-therapy clinical trial candidate and has the potential to advance the progress of Sanfilippo Syndrome treatment. Here we provide commentary on the TCM8 vector and its context in the field of Sanfilippo Syndrome Type-B research.