Department of Pediatrics, Division of Genetics, University of California, 9500 Gilman Drive, MC 0734, La Jolla, San Diego, CA, 92093-0734, USA.
Pediatr Nephrol. 2019 Jun;34(6):965-973. doi: 10.1007/s00467-018-3974-7. Epub 2018 May 22.
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). Initial symptoms of cystinosis correspond to the renal Fanconi syndrome. Patients then develop chronic kidney disease and multi-organ failure due to accumulation of cystine in all tissue compartments. LSDs are commonly characterized by a defective activity of lysosomal enzymes. Hematopoietic stem and progenitor cell (HSPC) transplantation is a treatment option for several LSDs based on the premise that their progeny will integrate in the affected tissues and secrete the functional enzyme, which will be recaptured by the surrounding deficient cells and restore physiological activity. However, in the case of cystinosis, the defective protein is a transmembrane lysosomal protein, cystinosin. Thus, cystinosin cannot be secreted, and yet, we showed that HSPC transplantation can rescue disease phenotype in the mouse model of cystinosis. In this review, we are describing a different mechanism by which HSPC-derived cells provide cystinosin to diseased cells within tissues, and how HSPC transplantation could be an effective one-time treatment to treat cystinosis but also other LSDs associated with a lysosomal transmembrane protein dysfunction.
胱氨酸贮积症是一种常染色体隐性遗传代谢疾病，属于溶酶体贮积症（LSD）家族。胱氨酸贮积症的初始症状与肾范可尼综合征相对应。随后，由于胱氨酸在所有组织隔室中的积累，患者会发展为慢性肾脏病和多器官衰竭。LSD 通常的特征是溶酶体酶活性缺陷。基于其后代将整合到受影响的组织中并分泌功能性酶，而周围缺乏的细胞将重新捕获该酶并恢复生理活性的前提，造血干细胞和祖细胞（HSPC）移植是几种 LSD 的治疗选择。然而，在胱氨酸贮积症的情况下，缺陷蛋白是一种跨膜溶酶体蛋白，即胱氨酸酶。因此，胱氨酸酶不能被分泌，但我们发现 HSPC 移植可以挽救胱氨酸贮积症小鼠模型中的疾病表型。在这篇综述中，我们描述了 HSPC 衍生细胞向组织内患病细胞提供胱氨酸酶的另一种机制，以及 HSPC 移植如何成为治疗胱氨酸贮积症以及其他与溶酶体跨膜蛋白功能障碍相关的 LSD 的有效一次性治疗方法。
