Biferi Maria Grazia, Cohen-Tannoudji Mathilde, García-Silva Andrea, Souto-Rodríguez Olga, Viéitez-González Irene, San-Millán-Tejado Beatriz, Fernández-Carrera Andrea, Pérez-Márquez Tania, Teijeira-Bautista Susana, Barrera Soraya, Domínguez Vanesa, Marais Thibaut, González-Fernández África, Barkats Martine, Ortolano Saida
Sorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, 75013 Paris, France.
Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Hospital Álvaro Cunqueiro, 36312 Vigo, Spain.
Mol Ther Methods Clin Dev. 2020 Oct 22;20:1-17. doi: 10.1016/j.omtm.2020.10.016. eCollection 2021 Mar 12.
Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse model.
法布里病是一种罕见的X连锁疾病，影响α-半乳糖苷酶A，这是糖鞘脂溶酶体分解代谢中的一种限速酶。目前的治疗方法存在重要局限性，如半衰期短和分布有限，而基因治疗可以克服这些问题。这项工作的目的是测试一种新型腺相关病毒载体，血清型9（AAV9），其可普遍表达人α-半乳糖苷酶A以治疗法布里病（scAAV9-PGK-GLA）。该载体在法布里病小鼠模型的新生小鼠中进行了初步测试。治疗5个月后，在包括中枢神经系统在内的分析组织中可检测到α-半乳糖苷酶A活性。此外，我们通过单次静脉注射在不同性别、两种剂量和疾病阶段（症状前和有症状）的成年动物中测试了该载体。我们发现，外源性α-半乳糖苷酶A在周围组织以及中枢神经系统中均有活性，并在注射后长达5个月的时间内防止了治疗动物体内糖鞘脂的积累。在32只接受治疗的动物中，有9只产生了针对α-半乳糖苷酶A的抗体，不过组织中的酶活性并未受到显著影响。这些结果表明，scAAV9-PGK-GLA可驱动α-半乳糖苷酶A的广泛持续表达，在全身给药后可穿过血脑屏障，并减轻法布里病小鼠模型的病理症状。
