Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy

Sommer, Nadine; Roumane, Ahlima; Han, Weiping; Delibegović, Mirela; Rochford, Justin J.; Mcilroy, George D.

doi:10.1016/j.omtm.2022.09.014

Cited by 11 publications

(33 citation statements)

References 43 publications

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“…Beneficial metabolic improvements included the reversal of insulin resistance, glucose intolerance and reduction of hepatomegaly, along with significant elevations in circulating leptin and adiponectin levels. These changes were rapidly observed and remained apparent 5 months after treatment 50 . Our findings also indicated that AAV8 vectors are capable of targeting both visceral and subcutaneous white adipose tissue progenitor cells in vivo.…”

Section: Therapeutic Strategies To Restore Adipose Tissue Functionalitysupporting

confidence: 68%

“…These changes were rapidly observed and remained apparent 5 months after treatment. 50 Our findings also indicated that AAV8 vectors are capable of targeting both visceral and subcutaneous white adipose tissue progenitor cells in vivo. Curiously however, only visceral adipose tissue depots (gonadal and retroperitoneal) were restored under these conditions, whilst subcutaneous adipose tissue remained absent.…”

Section: Gene and Cell Therapysupporting

confidence: 62%

“…The critical research efforts performed by others 46 led our laboratory to investigate whether AAV‐mediated gene therapy could be a viable therapeutic approach to restore adipose tissue development in lipodystrophy disorders. Our research has been the first to report that AAV‐mediated gene therapy is highly effective in a mouse model of CGL2 50 . A single systemic injection of AAV serotype 8 overexpressing human BSCL2 from the cytomegalovirus promoter was able to effectively restore adipose tissue development and reverse metabolic disease in this pre‐clinical mouse model.…”

Section: Therapeutic Strategies To Restore Adipose Tissue Functionalitymentioning

confidence: 78%

“…Our research has been the first to report that AAV-mediated gene therapy is highly effective in a mouse model of CGL2. 50 A single systemic injection of AAV serotype 8 overexpressing human BSCL2 from the cytomegalovirus promoter was able to effectively restore adipose tissue development and reverse metabolic disease in this pre-clinical mouse model. Beneficial metabolic improvements included the reversal of insulin resistance, glucose intolerance and reduction of hepatomegaly, along with significant elevations in circulating leptin and adiponectin levels.…”

Section: Gene and Cell Therapymentioning

confidence: 86%

“…Our findings also indicated that AAV8 vectors are capable of targeting both visceral and subcutaneous white adipose tissue progenitor cells in vivo. Curiously however, only visceral adipose tissue depots (gonadal and retroperitoneal) were restored under these conditions, whilst subcutaneous adipose tissue remained absent 50 . Further work will be required to determine if additional adipose development can be achieved using AAV‐mediated gene therapy.…”

Section: Therapeutic Strategies To Restore Adipose Tissue Functionalitymentioning

confidence: 99%

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From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy

Tiwari,

Mcilroy

2023

Diabet Med

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AimsLipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life‐threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality.MethodsExtensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders.ResultsA wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground‐breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting‐edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy.ConclusionsLipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.

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Section: Therapeutic Strategies To Restore Adipose Tissue Functionalitysupporting

confidence: 68%

Section: Gene and Cell Therapysupporting

confidence: 62%

Section: Therapeutic Strategies To Restore Adipose Tissue Functionalitymentioning

confidence: 78%

Section: Gene and Cell Therapymentioning

confidence: 86%

Section: Therapeutic Strategies To Restore Adipose Tissue Functionalitymentioning

confidence: 99%

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From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy

Tiwari,

Mcilroy

2023

Diabet Med

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Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28–29 September 2023

Ceccarini,

Akinci,

Araujo-Vilar

et al. 2024

Annales d'Endocrinologie

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Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy

Tiwari,

Roumane,

Sommer

et al. 2024

Gene Ther

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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.

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Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy

Cited by 11 publications

References 43 publications

From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy

From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy

Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28–29 September 2023

Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy

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