Single, off-the-shelf treatment of Neuropathic Mucopolysaccharidoses with iPSC-derived microglia [bulk RNA-seq]

Lysosomal storage disorders (LSDs) are a group of inherited metabolic disorders . A subgroup of LSDs is called Mucopolysaccharidoses (MPS), where accumulation of glycosaminoglycans causes a progressive degenerative disorder. The central nervous system (CNS) is particularly impacted with developmental delays, neurological regression, and early mortality. Current treatments are often insufficient to fully address the clinical need. Here we report the use of microglia derived from healthy human induced pluripotent stem cells (hiPSCs) as a potential one-time, allogeneic off-the-shelf cell therapy for several MPS. iPSC-derived microglia, termed MG01 , are replete with wild-type levels of lysosomal enzymes and we show that MG01 can deliver the functional enzyme into four different MPS knockout cell lines via mannose-6-phosphate receptor-mediated endocytosis in vitro. We then show that a single administration of MG01 provides sufficient enzyme to prevent behavioral deficits in two different animal models of MPS, efficacious to at least eight months after transplantation. Overall design: Bulk RNAseq of MG01 xenograft in the brain of NSG-Quad mouse. Tissue obtained from formalin fixed cryosections.

溶酶体贮积症（Lysosomal storage disorders, LSDs）是一类遗传性代谢疾病。其亚类之一为黏多糖贮积症（Mucopolysaccharidoses, MPS），该类疾病因糖胺聚糖异常蓄积引发进行性退行性病变。中枢神经系统（CNS）尤其容易受累，患者可出现发育迟缓、神经退行性变及早期死亡。当前临床治疗手段往往难以完全满足此类疾病的诊疗需求。
本研究报道了源自健康人诱导多能干细胞（hiPSCs）的小胶质细胞作为潜在的一次性异体现货细胞疗法，用于治疗多种MPS亚型。本研究中命名为MG01的诱导多能干细胞源性小胶质细胞，其溶酶体酶水平符合野生型标准；实验证实，MG01可通过甘露糖-6-磷酸受体介导的内吞作用，在体外将功能性酶递送至4种不同的MPS基因敲除细胞系中。
后续研究表明，单次输注MG01即可提供足量的功能性酶，能够在两种不同的MPS动物模型中预防行为缺陷，其疗效可持续至移植后至少8个月。
整体实验设计：对NSG-Quad小鼠脑内的MG01异种移植物开展批量RNA测序，实验组织取自福尔马林固定冰冻切片。