Congenital generalised lipodystrophy type 2 is a serious multisystem disorder with limited treatment options. It is caused by mutations affecting the BSCL2 gene, which encodes the protein seipin. Patients with congenital generalised lipodystrophy type 2 lack both metabolic and mechanical adipose tissue and develop severe metabolic complications including hepatic steatosis, lipoatrophic diabetes and cardiovascular disease. Gene therapies are becoming viable treatments, helping to alleviate inherited and acquired human disorders. We aimed to determine whether gene therapy could offer an effective form of medical intervention for lipodystrophy. We examined whether systemic adeno-associated virus delivery of human BSCL2 could reverse metabolic disease in seipin knockout mice, where white adipose tissue is absent. We reveal adeno-associated virus gene therapy targets adipose progenitor cells in vivo and substantially restores white adipose tissue development in adult seipin knockout mice. This resulted in both rapid and prolonged beneficial effects to metabolic health in this pre-clinical mouse model of congenital generalised lipodystrophy type 2. Hyperglycaemia was normalised within two weeks post-treatment, together with normalisation of severe insulin resistance. We propose that gene therapy offers great potential as a therapeutic strategy to correct multiple metabolic complications in patients with congenital lipodystrophy.
Original languageEnglish
Pages (from-to)206-216
Number of pages11
JournalMolecular Therapy - Methods & Clinical Development
Early online date19 Oct 2022
Publication statusPublished - 8 Dec 2022

Bibliographical note

The authors are extremely grateful to Dr Donna MacCallum (University of Aberdeen) for assistance with AAV vector i.v. tail vein injections and Pat Bain (University of Aberdeen) for design and generation of the graphical abstract. The authors would also like to thank the staff at the University of Aberdeen’s Microscopy and Histology Core Facility and the Medical Research Facility for support with animal breeding and maintenance. This research was supported by funding from the EFSD/Lilly Young Investigator Research Award Programme, Wellcome Trust ISSF Fellowship Support Fund, and Diabetes UK RD Lawrence Fellowship (21/0006280) awarded to G.D.M. and Diabetes UK (18/0005884) awarded to J.J.R.


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