Patients with mucopolysaccharidosis type IIIA (MPS IIIA) lack the lysosomal enzyme sulfamidase (SGSH), which is responsible for the degradation of heparan sulfate (HS). Build-up of undegraded HS results in severe progressive neurodegeneration for which there is currently no treatment. The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA. LYS-SAF302 was administered to 5-week-old MPS IIIA mice at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vector genomes [vg]/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct or significantly reduce HS storage, secondary accumulation of GM2 and GM3 gangliosides, ubiquitin-reactive axonal spheroid lesions, lysosomal expansion, and neuroinflammation at 12 weeks and 25 weeks post-dosing. To study SGSH distribution in the brain of large animals, LYS-SAF302 was injected into the subcortical white matter of dogs (1.0E+12 or 2.0E+12 vg/animal) and cynomolgus monkeys (7.2E+11 vg/animal). Increases of SGSH enzyme activity of at least 20% above endogenous levels were detected in 78% (dogs 4 weeks after injection) and 97% (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.

中文翻译：

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AAVrh10载体可纠正MPS IIIA小鼠的疾病病理并在大型动物大脑中实现SGSH的广泛分布。

IIIA型粘多糖贮积病（MPS IIIA）患者缺乏溶酶体酶磺酰胺酶（SGSH），后者负责硫酸乙酰肝素（HS）的降解。未降解HS的积累导致严重的进行性神经变性，目前尚无治疗方法。在MPS IIIA小鼠模型中评估了载体腺相关病毒（AAV）rh.10-CAG-SGSH（LYS-SAF302）纠正疾病病理的能力。将LYS-SAF302以5种不同剂量（8.6E + 08、4.1E + 10和9.0E + 10矢量基因组[vg] /动物）分别注射到5周大的MPS IIIA小鼠中，分别注入尾状壳核/纹状体和丘脑。LYS-SAF302能够剂量依赖性地纠正或显着降低HS储存，GM2和GM3神经节苷脂的二次蓄积，泛素反应性轴突球体病变，溶酶体扩张，给药后12周和25周出现神经炎症。为了研究大型动物大脑中SGSH的分布，将LYS-SAF302注射到狗（1.0E + 12或2.0E + 12 vg /动物）和食蟹猴（7.2E + 11 vg /动物）的皮质下白质中。在总脑容量的78％（注射后4周的狗）和97％（注射后6周的猴子）中，检测到的SGSH酶活性比内源水平至少高出20％。综上所述，这些数据验证了实质内AAV的施用是实现MPS IIIA中广泛的酶分布和疾病病理纠正的一种有前途的方法。2E + 11 vg /动物）。在总脑容量的78％（注射后4周的狗）和97％（注射后6周的猴子）中，检测到的SGSH酶活性比内源水平至少高出20％。综上所述，这些数据验证了实质内AAV的施用是实现MPS IIIA中广泛的酶分布和疾病病理纠正的一种有前途的方法。2E + 11 vg /动物）。在总脑容量的78％（注射后4周的狗）和97％（注射后6周的猴子）中，检测到的SGSH酶活性比内源水平至少高出20％。综上所述，这些数据验证了实质内AAV的施用是实现MPS IIIA中广泛的酶分布和疾病病理纠正的一种有前途的方法。