Successful treatment of the murine model of cystinosis using bone marrow cell transplantation

Abstract

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in every organ in the body and leads to organ damage and dysfunction, including renal defects. Using the murine model for cystinosis, Ctns ؊/؊ mice, we performed syngeneic bone marrow cell (BMC), hematopoietic stem cell (HSC), and mesenchymal stem cell transplantation. Organ-specific cystine content was reduced by 57% to 94% in all organs tested in the BMC-treated mice. Confocal microscopy and quantitative polymerase chain reaction revealed a large quantity of transplanted BMC in all organs tested, from 5% to 19% of the total cells. Most of these cells were not from the lymphoid lineage but part of the intrinsic structure of the organ. The natural progression of renal dysfunction was prevented, and deposition of corneal cystine crystals was significantly improved in the BMC-treated mice. HSC had the same therapeutic effect as whole BMC. In contrast, mesenchymal stem cell did not integrate efficiently in any organ. This work is a proof of concept for using HSC transplantation as a therapy for cystinosis and highlights the efficiency of this strategy for a chronic, progressive degenerative disease. (Blood. 2009;

Upregulation of the Rab27a-Dependent Trafficking and Secretory Mechanisms Improves Lysosomal Transport, Alleviates Endoplasmic Reticulum Stress, and Reduces Lysosome Overload in Cystinosis

“…The cystine content in murine fibroblasts was analyzed as previously described (44). Briefly, fibroblasts were resuspended in 750 l N-ethylmaleimide (Fluka Biochemika) at 650 g/ ml.…”

Expression Patterns and Function of Chromatin Protein HMGB2 during Mesenchymal Stem Cell Differentiation

“…Mouse MSC Isolation and Culture-MSC were generated as described previously (32). Hmgb2 Ϫ/Ϫ mice were provided by M. E. Bianchi (San Raffaele University, Milan, Italy) (13).…”

Preformulation of cysteamine gels for treatment of the ophthalmic complications in cystinosis

“…The accumulation of cystine as crystals in most tissues leads to the progressive impairment and dysfunction of multiple organs, such as the pancreas, eye, brain and thyroid (Syres, et al 2009). Without treatment, this autosomal recessive disease can result in multi-organ failure and death before the onset of puberty (Gahl, 2009).…”