Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy.
Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy.
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DOI：
10.1016/j.omtm.2022.09.014
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发表时间：
2022-12-08
期刊：
影响因子：
--
通讯作者：
Mcilroy, George D.
中科院分区：
文献类型：
--
作者：
Sommer, Nadine;Roumane, Ahlima;Han, Weiping;Delibegovic, Mirela;Rochford, Justin J.;Mcilroy, George D.
先天性全身性脂肪营养不良2型是一种严重的多系统疾病，治疗选择有限。它是由影响BSCL 2基因的突变引起的，BSCL 2基因编码蛋白质seipin。患有先天性全身性脂肪营养不良2型的患者缺乏代谢性和机械性脂肪组织，并发生严重的代谢并发症，包括肝脂肪变性、脂肪萎缩性糖尿病和心血管疾病。基因疗法正在成为可行的治疗方法，有助于减轻遗传性和获得性人类疾病。我们的目的是确定基因治疗是否可以为脂肪营养不良提供一种有效的医学干预形式。我们研究了系统性腺相关病毒递送人BSCL 2是否可以逆转seipin敲除小鼠的代谢疾病，其中没有白色脂肪组织。我们发现腺相关病毒基因治疗靶向体内脂肪祖细胞，并在成年seipin基因敲除小鼠中显著恢复白色脂肪组织发育。这导致在该先天性全身性脂肪营养不良2型临床前小鼠模型中对代谢健康的快速和长期有益作用。高血压在治疗后2周内正常化，严重胰岛素抵抗也正常化。我们认为，基因治疗提供了巨大的潜力，作为一种治疗策略，以纠正先天性脂肪营养不良患者的多种代谢并发症。脂肪营养不良是一种罕见的脂肪组织缺乏症，伴有严重的代谢并发症。我们证明，AAV介导的基因治疗恢复了先天性全身性脂肪营养不良的临床前小鼠模型中的脂肪组织发育并改善了代谢健康。基因治疗作为脂肪营养不良患者的治疗策略提供了巨大的潜力。
Congenital generalized 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 generalized 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 that 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 generalized lipodystrophy type 2. Hyperglycemia was normalized within 2 weeks post-treatment together with normalization 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. Lipodystrophy is a rare disorder of adipose tissue deficiency with severe metabolic complications. We demonstrate that AAV-mediated gene therapy restores adipose tissue development and improves metabolic health in a pre-clinical mouse model of congenital generalized lipodystrophy. Gene therapy offers great potential as a therapeutic strategy for patients suffering from lipodystrophy.
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影响因子：
29
作者：
Jeffery E;Wing A;Holtrup B;Sebo Z;Kaplan JL;Saavedra-Peña R;Church CD;Colman L;Berry R;Rodeheffer MS
通讯作者：
Rodeheffer MS
DOI：
10.1016/j.omtm.2020.09.009
发表时间：
2020-12-11
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Bates R;Huang W;Cao L
通讯作者：
Cao L
影响因子：
7.7
作者：
Dollet, Lucile;Levrel, Clara;Prieur, Xavier
通讯作者：
Prieur, Xavier
影响因子：
29
作者：
Cawthorn WP;Scheller EL;Learman BS;Parlee SD;Simon BR;Mori H;Ning X;Bree AJ;Schell B;Broome DT;Soliman SS;DelProposto JL;Lumeng CN;Mitra A;Pandit SV;Gallagher KA;Miller JD;Krishnan V;Hui SK;Bredella MA;Fazeli PK;Klibanski A;Horowitz MC;Rosen CJ;MacDougald OA
通讯作者：
MacDougald OA
影响因子：
4.8
作者：
Chen, Weiqin;Zhou, Hongyi;Chan, Lawrence
通讯作者：
Chan, Lawrence