Cystinosis is an autosomal recessive
metabolic disease characterized by lysosomal accumulation of
cystine in all the cells of the body. Infantile
cystinosis begins in infancy by a
renal Fanconi syndrome and eventually leads to multi-organ failure, including the kidney, eye, thyroid, muscle, and pancreas, eventually causing premature death in early adulthood. The current treatment is the
drug cysteamine that only delays the progression of the disease. We identified the gene involved, CTNS, and showed that the encoded
protein, cystinosin, is a
proton-driven
cystine transporter. We generated a mouse model of
cystinosis, the Ctns-/- mice, that recapitulates the main disease complications. The goal was next to develop a gene
therapy approach for
cystinosis. We used bone marrow stem cells as a vehicle to bring the healthy CTNS gene to tissues, and we showed that wild-type hematopoietic stem and progenitor cell (HSPC)
transplantation led to abundant tissue integration of bone marrow-derived cells, significant decrease of tissue
cystine accumulation and long-term kidney, eye and thyroid preservation. We then developed an
autologous transplantation approach of HSPCs modified ex vivo using a lentiviral vector to introduce a functional CTNS
cDNA, and showed its efficacy in Ctns-/- mice. We conducted the pharmacology/toxicology studies, developed the manufacturing process using human CD34+ cells, and design the clinical trial. We received Food and Drug Administration (FDA)-clearance to start a phase 1/2 clinical trial for
cystinosis in December 2018. Six patients have been treated so far. In this review, we describe the path to go from the gene to a gene
therapy approach for
cystinosis.