CTNS-RD-04, an ex vivo gene therapy for cystinosis, showed reduced white-cell cystine levels and an acceptable safety profile in a small phase 1-2 clinical trial, providing early evidence of its potential therapeutic use in this progressive lysosomal storage disorder. The study was published in The New England Journal of Medicine by Bruce A. and colleagues.Cystinosis is a rare multisystemic disorder resulting from pathogenic variants of the CTNS gene, which encodes cystinosin, a lysosomal transmembrane cystine transporter. Abnormal cystinosin function causes cystine accumulation in lysosomes of various organs, leading to progressive organ dysfunction. Although cysteamine treatment reduces cystine levels and slows disease progression, it fails to prevent complications.This is a phase 1-2, open-label, ongoing clinical trial that assessed the safety and preliminary efficacy of CTNS-RD-04 in patients with cystinosis. The treatment involves autologous CD34+ hematopoietic stem and progenitor cells that are transduced ex vivo with lentiviral vectors containing CTNS complementary DNA. The main endpoints of the study were the safety and tolerability of the treatment, while the secondary endpoints included the efficacy of the treatment, which was measured by the reduction in the level of white-cell cystine and the depletion of cystine storage.Prior to the infusion of CTNS-RD-04, patients discontinued the use of oral cysteamine. The use of cysteamine eyedrops was discontinued one month after the administration of myeloablative conditioning. This was to enable the evaluation of the effect of gene therapy on cystine levels.Key findingsSix individuals aged 20 to 46 years were enrolled and received CTNS-RD-04.Follow-up duration varied from 29 to 63 months. The dose of CD34+ cells administered varied from 3.63×10^6 to 9.59×10^6 cells per kilogram of body weight. The number of vector copies at the time of infusion varied from 0.59 to 2.91 copies per diploid genome, depending on the extent of gene integration that had been accomplished in the transduced cells. At 24 months post-infusion, the number of vector copies varied from 0.51 to 2.67 copies per diploid genome, suggesting that gene marking was maintained over time.All subjects showed stable and highly polyclonal hematopoietic reconstitution, suggesting the absence of dominance by a single clone.A total of 217 adverse events were recorded during the course of the study. The vast majority of the adverse events were mild to moderate in severity and were mostly consistent with the myeloablative conditioning regimen and underlying disease. There was no evidence of monoclonal expansion, which is a significant safety issue with regard to the integration of viral vectors. The levels of cystine in white cells were found to be decreased from the baseline in all patients except one, who was identified to be Patient 4, having the lowest vector copy number. The decrease in cystine levels indicates that CTNS-RD-04 was successful in correcting the function of cystinosin in hematopoietic cells, which in turn aided in the decrease in cystine levels within the body. The stable vector copy numbers and polyclonal reconstitution for the follow-up periods of up to 63 months are also reassuring with regard to the safety of gene integration.In this early phase 1-2 clinical trial, the CTNS-RD-04 gene therapy in six adult patients with cystinosis showed an acceptable safety profile, with 217 mild to moderate adverse events and no monoclonal expansion, while the white-cell cystine levels were reduced in most patients after treatment, suggesting biological efficacy. These results support the idea that ex vivo gene therapy could represent a promising approach for the treatment of cystinosis.Reference:Barshop, B. A., Ball, E. D., Benador, N., Trauner, D., Phillips, S., Dohil, R., Afshari, N. A., Roy, S., Campo Fernandes, B., Kohn, D., Shayan, K., Everett, J. K., Bushman, F. D., Midgley, J., Liang, H., Sawyers, A., Gangoiti, J. A., Panchal, M., Ahmed, I., & Cherqui, S. (2026). Hematopoietic stem-cell gene therapy for cystinosis. The New England Journal of Medicine, 394(8), 753–762. https://doi.org/10.1056/nejmoa2506431