Pathogenesis informs therapy in the GM1 and GM2 Gangliosidoses

GM 2神经节苷脂沉积症、泰-萨二氏病和桑德霍夫病分别由HEXA和HEXB基因突变引起的异聚体溶酶体水解酶β-己糖胺酶A的酶缺乏引起。 这些常染色体隐性遗传疾病是从婴儿发病到晚期或成人发病的连续体，并且表型基于残余酶活性的量，而残余酶活性又由HEXA或HEXB基因中的特定突变决定。 所有亚型的特征是进行性神经变性，婴儿型疾病在4-6个月时出现症状，发育停滞，然后在12个月前迅速下降并出现顽固性癫痫发作，24个月时进展为植物人状态。 3至6岁之间的死亡通常是由于吸入性肺炎。 对于GM 2神经节苷脂沉积症的任何亚型都没有有效的治疗方法。 该项目旨在了解神经节苷脂储存对GM 2神经节苷脂沉积症患者大脑发育的最早影响。 我们假设，我们的工作将对这些毁灭性疾病的治疗类型和时机产生影响。 自20世纪70年代中期以来，人们已经知道，早在妊娠中期，受影响患者的大脑中就可以看到GM 2储存。 然而，储存对早期大脑发育的影响尚未得到正式研究。 我们对两个17周妊娠TSD胎儿的4个脑区和年龄匹配的对照组织进行了转录组分析。 我们的初步结果表明，TSD大脑缺乏神经元突触发生的转录物，并且与我们先前的发现一致，即来自婴儿Sandhoff病患者的iPS细胞的人类大脑类器官缺乏神经元分化。 大脑类器官，其表达谱对应于人类发育的前三个月，也显示出神经元增殖的差异。 Sandhoff病类器官明显大于正常对照类器官，并显示出更大程度的神经元增殖。 这是有趣的，因为桑德霍夫（和泰-萨克斯）婴儿有进行性巨脑畸形。 使用从GM 2神经节苷脂沉积症的动物模型（小鼠，猫和羊）在妊娠的定义点的胎儿组织，我们计划采用一种新的技术，空间转录组学，探测年龄和区域特异性差异的基因表达相比，控制。 TSD婴儿早期脑发育的显著差异将对治疗的类型和时机产生明显的影响。我们的研究表明，即使在新生儿期开始的治疗可能不足以改变婴儿发病疾病的结局。尽管如此，最近已经提交了用于婴儿Tay-Sachs和Sandhoff疾病基因治疗的研究性新药申请，并且试验正在进行中或在未来几个月内开始招募。 了解产前溶酶体贮积对神经发育的影响将提高我们对疾病发病机制的理解，并可能提出替代治疗时机或方法。

The GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease are caused by enzyme deficiency of the heteromeric lysosomal hydrolase beta-hexoaminidase A due to mutations in the HEXA and HEXB genes respectively. These autosomal recessive diseases are a continuum from infantile onset to late or adult-onset and phenotype is based on the amount of residual enzyme activity which is in turn determined by specific mutations in the HEXA or HEXB genes. All subtypes feature progressive neurodegeneration and the infantile forms of the diseases have onset of symptoms by 4-6 months with developmental arrest and then rapid decline and onset of intractable seizures before 12 months with progression to a vegetative state by 24 months. Death between 3 and 6 years is typically due to aspiration pneumonia. There are no effective therapies for any of the subtypes of the GM2 gangliosidoses. This project aims to understand the earliest impact of ganglioside storage on brain development in patients with GM2 gangliosidosis. We postulate that our work will have implications for the type and timing of therapy for these devastating disorders. It has been known since the mid-1970s that GM2 storage in the brains of affected patients can be seen as early as the second trimester of gestation. However, the impact of storage on early brain development has not been formally studied. We have performed transciptome analysis on 4 brain regions from two 17-week gestation fetuses with TSD and age-matched control tissues. Our preliminary results show that TSD brains are deficient in transcripts of neuronal synaptogenesis and align with our previous findings of lack of neuronal differentiation in human cerebral organoids derived from iPS cells from a patient with infantile Sandhoff disease. Cerebral organoids, whose expression profile corresponds to the first trimester of human development, also show differences in neuronal proliferation. Sandhoff disease organoids are significantly larger than normal control organoids and show a greater degree of neuronal proliferation. This is interesting, as Sandhoff (and Tay-Sachs) infants have progressive megalencephaly. Using fetal tissues from animal models of GM2 gangliosidosis (mice, cats, and sheep) at defined points in gestation we plan to employ a new technology, spatial transcriptomics, to probe age- and region-specific differences in gene expression compared to controls. Significant differences in early brain development of TSD infants will have obvious implications for type and timing of therapy. Our studies suggest that treatment initiated even in the newborn period may be insufficient to modify outcome in infantile onset disease. Despite this, investigational new drug applications for gene therapy for infantile Tay-Sachs and Sandhoff diseases have been recently filed and trials are either in progress or commencing enrollment in the coming months. Understanding the impact of lysosomal storage on neural development prenatally will improve our understanding of disease pathogenesis and may suggest alternative timing or approaches to therapy.