PDF(Pubmed)
Abstract：
GM2 gangliosidosis is a group of genetic disorders that result in the accumulation of GM2 ganglioside (GM2) in brain cells, leading to progressive central nervous system (CNS) atrophy and premature death in patients. AB-variant GM2 gangliosidosis (ABGM2) arises from loss-of-function mutations in the GM2 activator protein (GM2AP), which is essential for the breakdown of GM2 in a key catabolic pathway required for CNS lipid homeostasis. In this study, we show that intrathecal delivery of self-complementary adeno-associated virus serotype-9 (scAAV9) harbouring a functional human GM2A transgene (scAAV9.hGM2A) can prevent GM2 accumulation in in GM2AP-deficient mice (Gm2a-/- mice). Additionally, scAAV9.hGM2A efficiently distributes to all tested regions of the CNS within 14 weeks post-injection and remains detectable for the lifespan of these animals (up to 104 weeks). Remarkably, GM2AP expression from the transgene scales with increasing doses of scAAV9.hGM2A (0.5, 1.0 and 2.0 × 1011 vector genomes (vg) per mouse), and this correlates with dose-dependent correction of GM2 accumulation in the brain. No severe adverse events were observed, and comorbidities in treated mice were comparable to those in disease-free cohorts. Lastly, all doses yielded corrective outcomes. These data indicate that scAAV9.hGM2A treatment is relatively non-toxic and tolerable, and biochemically corrects GM2 accumulation in the CNS-the main cause of morbidity and mortality in patients with ABGM2. Importantly, these results constitute proof-of-principle for treating ABGM2 with scAAV9.hGM2A by means of a single intrathecal administration and establish a foundation for future preclinical research.
摘要：
GM2神经节苷脂是一组导致GM2神经节苷脂（GM2）在脑细胞中积累的遗传性疾病，导致患者进行性中枢神经系统（CNS）萎缩和过早死亡。AB变体GM2神经节苷脂（ABGM2）是由GM2激活蛋白（GM2AP）的功能丧失突变引起的，这对于CNS脂质稳态所需的关键分解代谢途径中GM2的分解至关重要。在这项研究中,我们显示鞘内递送自身互补的腺相关病毒血清型9（scAAV9），其具有功能性人类GM2A转基因（scAAV9）。hGM2A）可以防止GM2AP缺陷小鼠（Gm2a-/-小鼠）中的GM2积累。此外,scAAV9.hGM2A在注射后14周内有效地分布到CNS的所有测试区域,并且在这些动物的寿命(长达104周)内保持可检测。值得注意的是,来自转基因的GM2AP表达随着scAAV9剂量的增加而缩放。hGM2A（每只小鼠0.5、1.0和2.0×1011个载体基因组（vg）），这与脑中GM2积累的剂量依赖性校正相关。没有观察到严重的不良事件，治疗小鼠的合并症与无病队列中的合并症相当。最后,所有剂量均产生纠正性结果.这些数据表明scAAV9。hGM2A治疗相对无毒且可耐受，和生化校正GM2在中枢神经系统的积累-ABGM2患者发病和死亡的主要原因。重要的是,这些结果构成了用scAAV9治疗ABGM2的原理证明。hGM2A通过单次鞘内给药的方式，为今后的临床前研究奠定了基础。
