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Title: Analysis of unilateral parenchymal AAV9-BBS1 hypothalamic delivery to rescue obesity and metabolic phenotypes in a Bardet-Biedl Syndrome mouse model (Bbs1 M390R/M390R)
Other Titles: Hypothalamic gene therapy prevents the development of obesity and metabolic syndrome in Bardet-Biedl Syndrome 1 mouse model
Authors: Kesavan Nair Rema, Rakhi
Advisors: Hernandez, V
Themis, M
Keywords: Gene therapy in BBS1 mouse model;Stereotaxic targeting of the hypothalamus in mice;Analysis of morphometric parameters to assess obesity;Analysis of biomarkers to assess metabolic syndrome;Biodistribution of AAV9 vector in the mouse CNS
Issue Date: 2023
Publisher: Brunel University London
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.
Description: This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London
Appears in Collections:Biological Sciences
Dept of Life Sciences Theses

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