Ex vivo gene therapy for cystinosis had acceptable safety and improved disease biomarkers

1. In this phase 1–2 open-label study, autologous lentiviral hematopoietic stem-cell gene therapy for cystinosis was associated with sustained engraftment and reduced white-cell cystine levels.

2. Adverse events were largely consistent with myeloablative conditioning and preexisting disease, with no evidence of clonal expansion or leukoproliferative complications.

Evidence Rating Level: 2 (Good)

Study Rundown: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in CTNS, leading to systemic cystine accumulation and progressive multi-organ dysfunction. Despite early and continuous treatment with cysteamine, most patients experience chronic kidney disease and extra-renal complications, underscoring the need for disease-modifying therapies. In this first-in-human study, investigators evaluated the effects of autologous CD34+ hematopoietic stem and progenitor cells transduced ex vivo with a lentiviral vector encoding CTNS. Adults who were treated with this therapy demonstrated durable hematopoietic engraftment and sustained transgene expression in peripheral blood. White-cell and granulocyte cystine levels were found to decline from baseline in most participants, with parallel reductions in tissue cystine crystals in several patients. Clinical parameters, including neurologic, endocrine, and transplant kidney function, were generally stable during follow-up. Safety findings were consistent with conditioning-related toxicities and underlying disease rather than vector-related effects, and no clonal dominance was observed. Strengths of the study included extended follow-up and extensive biomarker and clinical assessments. However, the study was limited by the small sample size, absence of a control group, and dependence on surrogate endpoints. Overall, these results suggested that autologous gene-modified stem-cell therapy may offer a promising disease-modifying strategy for cystinosis.

Click to read the study in NEJM

Relevant Reading: Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis

In-Depth [prospective cohort]: This phase 1–2, open-label, single-center study evaluated the safety and preliminary efficacy of CTNS-RD-04, an autologous hematopoietic stem-cell gene therapy, in six adults with infantile nephropathic cystinosis. Participants underwent mobilization and leukapheresis to collect CD34+ hematopoietic stem and progenitor cells, which were transduced ex vivo with a self-inactivating lentiviral vector encoding CTNS and reinfused following busulfan conditioning. The median follow-up was 36 months (range, 29–63), with one patient followed beyond 5 years. A total of 217 adverse events were reported; most events were mild to moderate, but five severe or serious adverse events occurred in two patients. All adverse events were considered to be related to the underlying disease or other preexisting conditions rather than the treatment regimen, and integration-site analysis showed no monoclonal expansion. Regarding efficacy, all patients achieved neutrophil and platelet engraftment at a median of 13 and 19.5 days, respectively. Sustained hematopoietic reconstitution was observed, with peripheral-blood vector copy numbers at 24 months ranging from 0.51 to 2.67 copies per diploid genome. CTNS expression increased 11- to 49-fold over baseline at 24 months. White-cell cystine levels decreased by 25% to 86% from baseline, and granulocyte cystine levels declined by 22% to 81% in five of six patients. Reductions in cystine crystal burden were also observed in rectal and skin biopsy specimens in several participants. Overall, these findings supported the safety and feasibility of this ex vivo gene therapy for cystinosis.

Image: PD

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