2026-05-20 | Which genetic syndromes have a gene or molecular therapy?
Gene and molecular therapies are being actively developed and show promise for genetic syndromes such as cystinosis, Pompe's disease, GM1 gangliosidosis, and hemophilia B, though further research is necessary to confirm their broader efficacy and safety profiles.
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2026-03-25 | Cystinosin regulates Na+/H+ exchanger 3 trafficking and function in kidney proximal tubular cells.
Cystinosis is a systemic lysosomal storage disease resulting from mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin, leading to cystine accumulation in all organs. Despite cystinosin's ubiquitous expression, renal Fanconi syndrome (FS) is the first clinical manifestation of cystinosis, which is not prevented by cystine reduction therapy with cysteamine. Here, we report a novel interaction of cystinosin and sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes of yeast and mammalian cells. NHE3 is a major absorptive sodium transporter at the apical membrane of proximal tubular cells (PTCs). Cystinosin is required for the correct subcellular localization and trafficking of NHE3 and for sodium uptake. Introducing CTNS successfully rescues these defects in CTNS- deficient PTCs, whereas CTNS-LKG, encoding the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns-/- mice and cystinosis patient kidney. Transplantation of wild-type hematopoietic stem and progenitor cells in Ctns-/- mice restores NHE3 expression at the brush border membrane and improves FS-related phenotypes. This study uncovers an evolutionary conserved novel role of cystinosin in NHE3 trafficking, offering insights into FS pathogenesis and potential new therapeutic avenues.
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2026-03-05 | Successful Surgical Sperm Extraction in a Patient With Cystinosis.
Cystinosis is a genetic lysosomal storage disease with an autosomal recessive inheritance pattern. The mutation causing this disease occurs in the CTNS gene, which is located on chromosome 17 and codes for the lysosomal cystine transporter cystinosin. Cystinosis is characterized by intracellular accumulation of cystine in various organs and tissues, which may lead to impairment of organ function. Kidney injury is characterized by a progressive decline in glomerular filtration rate, leading to end-stage kidney disease if not treated. Other manifestations of cystinosis include ocular abnormalities, hepatomegaly, hypothyroidism, muscle weakness, and growth retardation. Male patients with cystinosis typically have azoospermia, and current data regarding the existence of spermatogenesis and the possibility of surgical sperm retrieval in these patients are limited. This article presents a case of a male patient in his thirties with cystinosis and azoospermia who presented for evaluation and treatment of infertility. His serum testosterone was normal, but gonadotropin levels were markedly elevated. Y chromosome micro-deletion assay was negative, and the karyotype was normal. Testicular sperm extraction revealed the presence of viable mature sperm that were successfully harvested and cryopreserved. The patient's spouse conceived through an in vitro fertilization cycle that utilized the patient's surgically retrieved sperm and subsequently delivered a healthy baby boy. This case report provides novel information on post-thaw quality measures of sperm that were surgically retrieved from a patient with cystinosis, as well as on outcomes of in vitro fertilization that utilized such sperm. The post-thaw quality of sperm is associated with its utility for in vitro fertilization and thus adds to the limited data available thus far regarding the feasibility of surgical sperm retrieval in patients with this disease.
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2026-02-18 | Hematopoietic Stem-Cell Gene Therapy for Cystinosis.
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. 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. 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 3.63×106 to 9.59×106 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. 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.).
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2026-02-03 | SGLT2 Inhibitors Rescue Lysosomal mTORC1 Hyperactivity and Proximal Tubulopathy in Preclinical Models of Cystinosis
Abstract The loss of lysosomal cystine transporter cystinosin (CTNS) disrupts kidney proximal tubule (PT) function, causing cystinosis - a prototypical lysosomal storage disorder characterized by cystine accumulation and metabolic dyshomeostasis. Cystine storage disrupts lysosomal nutrient sensing and downstream mTORC1 signalling, driving loss of PT differentiation and proximal tubulopathy. Here, using cross-species disease models, differentiated cellular systems, lysosome-based assays, and transcriptomics profiling, we demonstrate that sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin or dapagliflozin) ameliorate proximal tubulopathy in cystinosis. In CTNS-deficient PT cells, SGLT2 inhibition restores lysosome proteolysis, autophagic flux, metabolic homeostasis, and epithelial differentiation and function, independently of cystine clearance. Mechanistically, SGLT2 inhibition reduces the assembly of the v-ATPase-Ragulator-Rag scaffolding complex at lysosomes, thereby decoupling cystine storage from pathological mTORC1 activation. These effects reprogram PT metabolic trajectories and differentiation states, mitigating proximal tubulopathy across zebrafish and rodent models of cystinosis. Together, these findings define a lysosome-metabolism crosstalk that links glucose handling to mTORC1 regulation and provide a rationale for repurposing SGLT2 inhibitors as a disease-modifying therapy for cystinosis and related lysosome-driven PT disorders.
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