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Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy
Mansi Tiwari1,2, Ahlima Roumane1,2, Nadine Sommer1,2
1The Rowett Institute, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
Abstract:
Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model of Bscl2 deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing human BSCL2 restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1 × 1012 GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1 × 1010 GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.
Insights
Gene therapy using adeno-associated virus (AAV) vectors successfully restored adipose tissue and metabolic health in a lipodystrophy mouse model. Tissue-selective targeting to adipose tissue proved effective, offering a potential new treatment for this rare disorder.
Area of Science:
- Molecular Biology
- Genetics
- Metabolic Disorders
Background:
- Lipodystrophy is a rare, life-threatening disorder characterized by loss of adipose tissue and severe metabolic complications like hepatic steatosis and diabetes.
- Current treatment options for lipodystrophy are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of tissue-selective adeno-associated virus (AAV) vectors for targeted gene therapy in a preclinical model of lipodystrophy.
- To determine if adipose tissue-selective gene delivery can restore metabolic health in lipodystrophic mice.
Main Methods:
- Development of AAV vectors with adipose-selective (mini/aP2 promoter) or liver-selective (thyroxine-binding globulin promoter) promoters.
- Incorporation of a liver-specific microRNA-122 target sequence in AAV-aP2 vectors to restrict hepatic expression.
- Systemic delivery of AAV vectors overexpressing human BSCL2 in a Bscl2-deficient lipodystrophic mouse model.
Main Results:
- Systemic delivery of adipose-tissue-selective AAV-aP2 vectors restored adipose tissue development and improved metabolic health in lipodystrophic mice without significant liver expression.
- High doses of liver-selective vectors resulted in off-target expression and some adipose tissue development.
- Low doses of liver-selective vectors showed robust liver expression but did not ameliorate metabolic dysfunction.
Conclusions:
- Adipose tissue-selective AAV-mediated gene therapy is sufficient to restore metabolic health in generalized lipodystrophy.
- Targeted gene therapy offers a promising, potentially safer therapeutic avenue for lipodystrophy compared to non-selective approaches.
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