Comper Fabrizio, Miranda Carlos J, Liou Benjamin, Dodev Tihomir, Jeyakumar Jey M, Canavese Miriam, Cocita Clement, Khoshrou Khashayar, Tiscornia Gustavo, Chisari Elisa, Stotter Emmaline, Shehu Erald, Sridharan Sudharsan, Yu I-Mei, Pandya Jalpa, Khinder Jaminder, Northcott Natalie, Kalcheva Petya, Correia Samantha, Sun Ying, Dane Allison P, Sheridan Rose, Nathwani Amit C, Corbau Romuald
Spur Therapeutics, Stevenage SG1 2BP, UK.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Mol Ther. 2025 May 7. doi: 10.1016/j.ymthe.2025.05.003.
Gaucher disease type 1 (GD1) is caused by mutations in the GBA1 gene, which result in deficient enzyme β-glucocerebrosidase (GCase) activity and production with the harmful accumulation of the lipid substrate glucocerebroside. Replacement of GCase is current standard of care for GD1; however, GCase has a relatively short active half-life at both physiological and lysosomal pH and biweekly intravenous administration does not provide a consistent exposure to active enzyme. FLT201 is the first adeno-associated virus (AAV) gene therapy in clinical trials for treatment of GD1. FLT201 consists of a rationally designed AAV capsid (AAVS3) containing an expression cassette with an engineered GBA1 transgene that encodes a unique glucocerebrosidase variant (GCase85). GCase85 includes an engineered disulfide, which results in a >6-fold increase in active half-life in human serum and a >21-fold increase in active half-life at lysosomal pH conditions, with similar catalytic properties to those of wild-type and exogenous GCase. Preclinical data indicate that FLT201 could offer a durable treatment for Gaucher disease type 1, addressing unmet needs related to substrate accumulation in tissues poorly treated by current enzyme replacement therapy. The improved stability of the engineered GCase85 variant is predicted to be crucial for FLT201's therapeutic effectiveness.
1型戈谢病（GD1）由GBA1基因突变引起，该突变导致酶β-葡萄糖脑苷脂酶（GCase）活性和产量不足，脂质底物葡萄糖脑苷脂有害蓄积。GCase替代疗法是目前GD1的标准治疗方法；然而，GCase在生理pH值和溶酶体pH值下的活性半衰期相对较短，每两周进行一次静脉给药并不能持续提供活性酶。FLT201是首个用于治疗GD1的正在进行临床试验的腺相关病毒（AAV）基因疗法。FLT201由一个经过合理设计的AAV衣壳（AAVS3）组成，该衣壳包含一个表达盒，带有一个经过工程改造的GBA1转基因，其编码一种独特的葡萄糖脑苷脂酶变体（GCase85）。GCase85包含一个工程化二硫键，这导致其在人血清中的活性半衰期增加6倍以上，在溶酶体pH条件下活性半衰期增加21倍以上，其催化特性与野生型和外源性GCase相似。临床前数据表明，FLT201可为1型戈谢病提供持久治疗，满足当前酶替代疗法治疗效果不佳的组织中底物蓄积相关的未满足需求。工程化GCase85变体稳定性的提高预计对FLT201的治疗效果至关重要。
