Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome.
Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome.
复制标题
AAV9 介导的 SGPL1 基因转移在 S1P 裂解酶不足综合征小鼠模型中的功效。
DOI：
10.1172/jci.insight.145936
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Saba,JulieD
中科院分区：
文献类型：
--
作者：
Zhao,Piming;Tassew,GizachewB;Lee,JoannaY;Oskouian,Babak;Muñoz,DeniseP;Hodgin,JeffreyB;Watson,GordonL;Tang,Felicia;Wang,Jen-Yeu;Luo,Jinghui;Yang,Yingbao;King,Sarah;Krauss,RonaldM;Keller,Nancy;Saba,JulieD
鞘氨醇-1-磷酸裂解酶不足综合征（SPLIS）是一种罕见的代谢紊乱，由鞘氨醇-1-磷酸裂解酶1（SGPL 1）失活突变引起，这是鞘脂代谢的最后一步所必需的。SPLIS的特征包括类固醇耐药肾病综合征和神经、内分泌和造血系统的损害。许多受影响的人在头两年内死亡。目前尚无针对SPLIS的靶向治疗。我们假设SGPL 1基因替换将解决SPLIS的根本原因，从而作为该疾病的通用治疗方法。作为概念的证明，我们评估了给予新生Sgpl 1-KO小鼠的腺相关病毒9介导的人SGPL 1转移（AAV-SPL）的功效，所述新生Sgpl 1-KO小鼠模拟SPLIS并在生命的第一周死亡。治疗显著延长了生存期，并预防了肾病、神经发育迟缓、贫血和高胆固醇血症。在KO肾脏中观察到的STAT 3途径活化和促炎性和促纤维化细胞因子升高通过治疗减弱。与未处理的KO幼仔相比，处理的KO幼仔的血浆和组织鞘脂减少。SGPL 1表达和活性可测量至少40周。总之，早期AAV-SPL治疗预防SPLIS小鼠模型中的肾病、肾损害和神经损伤。我们的研究结果表明，SGPL 1基因替代有望成为SPLIS的持久和通用靶向治疗。
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years. No targeted therapy for SPLIS is available. We hypothesized that SGPL1 gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9–mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with untreated KO pups. SGPL1 expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis, and neurological impairment in a mouse model of SPLIS. Our results suggest that SGPL1 gene replacement holds promise as a durable and universal targeted treatment for SPLIS.