Analysis of unilateral parenchymal AAV9-BBS1 hypothalamic delivery to rescue obesity and metabolic phenotypes in a Bardet-Biedl Syndrome mouse model (Bbs1 M390R/M390R)

Abstract

Bardet-Biedl Syndrome (BBS) is a rare heterogeneous autosomal recessive genetic disorder that is classified under ciliopathies, presenting with a spectrum of clinical manifestations including obesity, photoreceptor degeneration, cognitive impairment, and various organ abnormalities. Among the 26 identified genes associated with BBS, the predominant causative gene is BBS1, with a single missense mutation (M390R) accounting for 80% of BBS1 cases. Bbs1M390R/M390R mouse models have replicated human BBS phenotypes, including obesity and central nervous system (CNS) abnormalities. Currently, clinical management of BBS is limited to symptomatic treatment due to the absence of specific therapeutic interventions. Recent studies have shown that gene therapy using adeno-associated viral vectors (AAV) can be effective in treating CNS dysfunction in other monogenic disorders. This thesis investigates the efficacy of CNS gene therapy in preventing the development of neurometabolic syndrome in a juvenile BBS1 mouse model. AAV9 vectors carrying the BBS1 transgene were administered intracranially into the hypothalamus of 30-day-old mice. Biodistribution studies revealed efficient bilateral transduction of the hypothalamus and adjacent thalamic regions, with remarkable tropism for the hippocampal dentate gyrus granular layer. Morphometric analysis following AAV9-CAG-hBBS1 treatment demonstrated prevention of the development of excessive body weight, adiposity, and metabolic syndrome in Bbs1M390R/M390R mice, comparable to the results obtained in younger mice from previous studies conducted by our group, offering promising insights into therapeutic avenues for BBS. It was also found in this study that wild-type mice overexpressing BBS1 in the CNS developed obesity, further highlighting the role of CNS dysfunction in the development of obesity. This study demonstrates the potential of hypothalamic gene therapy in preventing the development of obesity and metabolic syndrome associated with BBS. However, the presence of off-target effects and transgene over-expression causing adverse effects necessitate further investigation to ensure the safety and efficacy of this approach. In conclusion, these findings lay the foundation for future research and clinical applications in developing novel specific therapeutic strategies for BBS and other monogenic disorders with CNS dysfunction.