Hematopoietic Stem-Cell Gene Therapy for Cystinosis.
Publication Year:
2026
PubMed ID:
41707137
Public Summary:
Cystinosis is a rare genetic disease that affects many organs in the body. It is caused by changes in a gene called CTNS, which normally helps remove a substance called cystine from cells. In people with cystinosis, cystine builds up inside cells and gradually damages organs such as the kidneys and eyes. The current treatment, cysteamine, can slow the disease but does not stop it from progressing.
In this early-phase clinical study, researchers tested a new hematopoietic stem cell gene therapy approach called CTNS-RD-04. This treatment uses the patients’ own blood-forming stem cells, which are modified in the laboratory to carry a healthy copy of the CTNS gene and then returned to the patients. Before receiving the gene therapy, patients stopped taking oral cysteamine.
Six adults with cystinosis received the treatment and were followed for approximately 2 to 5 years. The main goal of the study was to evaluate safety. Most side effects were mild or moderate and were mainly related to the chemotherapy used before the gene-modified stem cell infusion or to the underlying disease. No serious safety concerns, such as abnormal cell growth, were observed. Researchers also looked at whether the therapy reduced cystine levels in white blood cells, a key marker of disease activity. In most patients, cystine levels decreased after treatment.
These early results suggest that CTNS-RD-04 gene therapy appears to be feasible and well tolerated, with encouraging signs that it leads to the reduction of the toxic cystine buildup. Larger and longer-term studies are needed to further evaluate its safety and effectiveness.
Scientific Abstract:
BACKGROUND: Cystinosis is a multisystemic lysosomal storage disorder caused by pathogenic variants in CTNS, the gene encoding cystinosin, a lysosomal transmembrane cystine transporter. In patients with cystinosis, cystine accumulates within lysosomes in all organs. The cystine-depleting agent cysteamine delays but does not prevent disease progression. METHODS: In this phase 1-2, open-label, ongoing clinical study, we performed a preliminary assessment of CTNS-RD-04, which consists of autologous CD34+ cells transduced with lentiviral vectors carrying CTNS complementary DNA, in patients with cystinosis. The primary end points were the safety and the side-effect profiles of CTNS-RD-04. Secondary end points were measures of efficacy, including white-cell cystine levels and cystine storage depletion. Oral cysteamine was withdrawn before CTNS-RD-04 infusion, and cysteamine eyedrops were withdrawn 1 month after myeloablation. RESULTS: Six participants (20 to 46 years of age) received CTNS-RD-04 and were followed for 29 to 63 months. CTNS-RD-04 doses ranged from 3.63x10(6) to 9.59x10(6) CD34+ cells per kilogram of body weight, and vector copy numbers ranged from 0.59 to 2.91 copies per diploid genome. All the patients had sustained and highly polyclonal hematopoietic reconstitution; vector copy numbers at 24 months ranged from 0.51 to 2.67 copies per diploid genome. A total of 217 adverse events occurred, most of which were mild or moderate in severity and largely consistent with the procedures and underlying disease. No evidence of monoclonal expansion was noted. White-cell cystine levels decreased from baseline except in Patient 4, who had the lowest vector copy number. CONCLUSIONS: In this small study, CTNS-RD-04, an ex vivo gene therapy for cystinosis, had adverse effects that were largely consistent with the myeloablative regimen and underlying disease profile. White-cell cystine levels decreased after therapy. (Funded by the California Institute for Regenerative Medicine and others; ClinicalTrials.gov number, NCT03897361.).