Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.

中文翻译：

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造血干细胞移植导致两种酸性神经酰胺酶缺乏症小鼠模型的生化和功能纠正


法伯病 （FD） 和脊髓性肌萎缩症伴进行性肌阵挛性癫痫 （SMA-PME） 是由酸性神经酰胺酶 （ACDase） 活性缺陷引起的超罕见溶酶体贮积症。尽管这两种情况都是由 ASAH1 基因突变引起的，但临床表现差异很大。FD 患者通常在儿童期死亡，而 SMA-PME 患者可以活到成年。FD 或 SMA-PME 没有治疗方法。正在研究造血干细胞移植 （HSCT） 和治疗 ACDase 缺乏症的基因治疗策略。我们之前已经生成并表征了 FD 和 SMA-PME 的小鼠模型，这些模型概括了患者描述的症状。在这里，我们表明 HSCT 改善了两种 ACDase 缺陷小鼠模型的寿命、行为、造血系统异常和浆细胞因子水平，并显着减少了整个研究组织（包括 CNS）的组织细胞浸润和神经酰胺积累。HSCT 还成功地防止了 SMA-PME 小鼠的病变发展和脊髓的显着脱髓鞘。重要的是，我们注意到只有早期和通常症状前的治疗是有效的，并且两种模式的肾功能损害都没有改善。