RARE DISEASE
Cystinosis
Cystinosis
Cystinosis
Synonyms: Protein defect of cystin transport
Synonyms: Protein defect of cystin transport
Synonyms: Protein defect of cystin transport
Drug discovery
12
drugs
With orphan designations
Overview
Cystinosis is an autosomal recessive lysosomal storage disorder caused by CTNS gene mutations, leading to cystine crystal accumulation and multi-organ damage [1][6][12]. Primarily affecting the kidneys, it manifests as Fanconi syndrome in infancy, progressing to end-stage renal disease (ESRD) by adolescence without treatment [3][8][16]. Ocular involvement causes photophobia and corneal ulcers [1][16]. Therapies include cysteamine to reduce intracellular cystine and kidney transplantation, though systemic complications persist [3][8][13].
Burden
Renal: ESRD in 74% by adolescence [4]; transplant survival improves outcomes but systemic progression continues [18]
Multisystem: Myopathy (79%), hypothyroidism (72%), growth failure (56%), and mortality (25.6%) [4][16]
Lifelong impact: Daily cysteamine dosing, corneal transplants, and high treatment costs [3][4][16]
(Word count: 68 words for overview)
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare renal diseases
Research Papers
588 drug discovery papers about Cystinosis, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
588 drug discovery papers about Cystinosis, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-05 | Cystinosis-associated metabolic bone disease: pathogenesis and outcome.
Cystinosis-associated metabolic bone disease (CMBD) is a severe complication in patients with infantile nephropathic cystinosis, which is a rare inherited lysosomal storage disease due to pathogenic variants in the CTNS gene that results in an accumulation of cystine in all organs. The kidneys are the organs primarily affected, resulting in renal Fanconi syndrome at around the age of 6-12 months. Without adequate treatment with the cystine-depleting agent cysteamine, this is followed by progressive chronic kidney disease (CKD) and kidney failure in the second decade of life. Patients usually present with progressive disproportionate short stature, rickets, and bone pain in the first 2 years of life. This may be followed by muscle weakness in childhood, and scoliosis and fractures in adulthood, especially if treatment is inadequate. Early diagnosis and treatment are crucial, and this is facilitated by a positive family history, screening programs and care at specialized centers. Therapeutic measures include physical activity, physiotherapy, adequate calcium and phosphate intake, vitamin D supplements, a combination of phosphate supplements and active vitamin D, correction of metabolic acidosis, and, if necessary, growth hormone therapy and surgical correction of persisting leg deformities. Unfortunately, current treatments cannot always prevent progressive bone loss and related skeletal comorbidity. There is increasing evidence for an underlying intrinsic osteoblast and osteoclast defect in cystinosis. Cystine crystal accumulation in macrophages (e.g., in bone and muscle) may result in an inflammatory state promoting increased osteoclast activity and other alterations in myokines and osteokines. Future interventions may target these factors to improve outcomes in patients with cystinosis.
2026-09-04 | From Cysteamine to Pepstatin A: Targeting Cathepsin D To Improve Bone Health in Cystinosis.
Nephropathic cystinosis is a rare genetic lysosomal storage disorder caused by loss-of-function variants of the CTNS gene encoding for the lysosomal H+/cystine symporter cystinosin. The lack of cystinosin causes cystine accumulation in lysosomes and cell damage. Children with nephropathic cystinosis commonly exhibit skeletal abnormalities, including growth retardation, osteopenia and rickets. The only cystine-depleting drug available is cysteamine. However, several observations suggest that cysteamine, particularly at high doses, may have negative effects on the skeleton. In this study, we characterized the effects of cysteamine on bone cells and we identified Pepstatin A, a Cathepsin D-inhibitor, as a potential new therapeutic treatment to restore physiological bone remodeling in cystinosis. We observed a detrimental effect of cysteamine on bone cells inducing further impairment of osteoblast differentiation/activity and failure of cysteamine intraperitoneal injection to improve the somatic growth of pre-pubertal ctns-/- mice. Moreover, we demonstrated that Pepstatin A treatment increased bone formation in vitro acting on the Fibronectin/Sipa1/STAT3/JunB pathway, and rescued somatic growth and bone mass in pre-pubertal ctns-/- mice. Our results provide evidence that cysteamine negatively affects bone in cystinosis and that Cathepsin D inhibition could represent a new therapeutic approach for rescue of bone remodeling in cystinosis.
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.
2026-01-28 | Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.
2025-12-22 | Molecular Characterization of Tunisian Cystinosis Patients Reveals a High Prevalence of the c.829dup Mutation
Background Cystinosis is a lysosomal storage disease caused by the accumulation of intralysosomal cystine in different tissues and organs including: brain, cornea, kidneys, live and, pancreas. This pathology is due the mutations in the CTNS gene that is encoded by the cystinosin protein. The study aimed to explore the genetic and phenotypic diversity of Tunisian patients with cystinosis in order to identify recurrent variants and their correlation with clinico-pathology features. Methods This study was conducted in collaboration with pediatric departments of Sahloul hospital of Sousse, and Tahar Sfar hospital of Mahdia and Hedi Chaker Hospital of Sfax, Tunisia. The entire coding region of CTNS-cDNA, was screened to identify mutations and polymorphisms in 11 families: 6 unrelated and 5 related families with cystinosis. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene. Results Molecular analysis of the CTNS gene was performed in affected individuals and their relatives, leading to the identification of seven pathogenic variants. Four of them were previously reported: c.829dup (p.Thr277fs; rs752919200), c.971-1G > C (rs2142982540), p.Thr334Asn (rs3375433), c.925G > A (p.Gly309Cys; rs758813679 ), and c.251delA ( p.Asn84fs; rs1057516296 ). A novel frameshift mutation, c.529del (p.Thr177fs), was also detected. The c.829dup variant was present in six homozygous patients (5 related and one unrelated) and one heterozygous patient. In total, 42 SNPs were identified including eight novel variants. The most frequent was rs161400 (p.Thr260Asn), which co-occurred with all variants except with c.829dup; was also observed in heterozygous carriers of c.829dup exhibiting a severe cystinosis phenotype. Conclusions Our findings underscore the potential phenotypic modulatory role of the rs161400 SNP, particularly in individuals carrying rare CTNS variants compared to patients carrying the recurrent c.829dup mutation. This study emphasizes the significance of the broader genetic landscape, including variant–variant interactions, in shaping the phenotypic heterogeneity observed among patients. Moreover, this study highlights the distinct mutational profile of Tunisian patients with cystinosis disease.
cell therapies
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.
2025-04-08 | Native kidney and graft survival in a cohort of Egyptian children with nephropathic cystinosis: national referral center experience.
Nephropathic Cystinosis is a rare autosomal recessive lysosomal storage disorder. In addition to kidney dysfunction, this disorder can also affect other organs, such as the eyes, thyroid, muscles, and central nervous system. The current cross-sectional study included 56 patients with nephropathic cystinosis to evaluate the clinical outcome in nephropathic cystinosis patients cohort with regarding kidney function and the need for kidney replacement therapy. Clinical and laboratory data were collected. Among the 56 patients in our study, 32 (57.1%) were male. Furthermore, 52 (92%) of these patients were offspring of consanguineous marriage. Patients' mean age was 116.96 ± 54.1 months, and the mean onset of nephropathic cystinosis suggestive symptoms was 7.63 ± 3.2 months. In addition, the mean age of confirmed diagnosis was 45.38 ± 35.3 months, and the mean age of end-stage kidney disease (ESKD) was 104 ± 25.7 months. Eighteen patients (32.1%)underwent hemodialysis, whereas 12 patients (21.4%) underwent kidney transplantation. When comparing siblings within the same family, we observed a significant difference in the age at diagnosis. The median age for the first sibling was 60 months, while it was 24 months for the second sibling (p-value = 0.031). Additionally, there were significant differences in weight, chronic kidney disease (CKD) stage, and outcome. Improvement in the awareness and the accessibility to diagnosis over years, early sibling screening, and kidney transplantation have a significant impact on the survival of both patients and kidney in children with nephropathic cystinosis.
2023-12-07 | Investigation on Cross-correction of Cystinosis through Genetically Engineered Cells Secreting Cystinosin
Background: Cystinosis is a rare inherited lysosomal storage disease (LSD), caused by a mutation in the Cystinosin Lysosomal Cystine Transporter (CTNS). Novel therapies and strategies are needed to improve patients' clinical conditions and quality of life. Objectives and Methods: This study assessed whether CTNS can be secreted, and investigated a method to enhance its secretion, by adding a secretion signal to the N-terminus. Human Embry-onic Kidney (HEK) 293 cells were transfected with the resulting construct. The amount of protein secreted was then measured. Uptake by monolayer cultures of cystinotic cells and enzyme activity were also assessed. Results: The recombinant protein could effectively be secreted, and the secretion signal slightly further increased its secretion. The secreted recombinant protein was taken up by cystinotic cells, and, after internalization, still retained its biological activity. Conclusion: Optimization of the proposed method to increase the secretion of CTNS would pro-vide new insights into the production of recombinant proteins for medical and industrial use. Further identification and screening of alternative signalling peptides and cell types can maximise the secretion and production of recombinant CNTS, to be used as a therapeutic agent in human healthcare.
2023-04-03 | Engineering the (vascularized) Proximal Tubule, a Guide Towards Functionality
This thesis focused on the fabrication of kidney proximal tubule models. A coaxial printing system allowed the robust and straightforward fabrication of coiled perfusable microfibers, replicating the kidney proximal convoluted tubules. The formed alginate-gelatin microfibers offer a complex tubular shape in which the cells exhibit mature markers, such as functional transporters and polarized monolayers. Moreover, this model has proven to support both healthy and cystinotic proximal tubule cell lines and allows for mechanistically studying tubulopathies. Though distinctive 3D-printing strategies offer opportunities to mimic the structure of the convoluted proximal tubule, printing resolution remains restricted for soft hydrogel materials. Therefore, a unique method was studied, whereby post-printing treatment induced resolution enhancement of methacrylated hyaluronic acid / gelatin methacryloyl (HAMA/GelMA) based hydrogels. This shrinking technique opens a wide application to create higher resolutions for 3D printing. However, we also found that the polycationic shrinking reagents used were relatively toxic for our cells of interest. Therefore, more research is needed to prevent the direct exposure of cells to the shrinking reagents. Using melt electrowriting, scaffolds were fabricated that are self-supportive, yet small-sized and highly porous. These scaffolds enable direct access to the basolateral and luminal cell sides to facilitate solute exchange with vasculature in immediate proximity, which is critical for functional proximal tubule constructs. The polymer applied, polycaprolactone, is used to prepare biomaterials that generally show good biocompatibility and is compatible with implantation in the future. Kidney proximal tubule cells and glomerular endothelial cells form polarized monolayers in our tubules, form their own extracellular matrix, and show functionality for important kidney transporters. In our preliminary results we showed initial work with induced pluripotent stem cell-derived kidney organoids, which is very promising for the development of implantable proximal tubule grafts. The aim was to develop vascularized kidney tubules for studying the clearance of protein bound uremic toxins, while gaining knowledge for the development of implantable kidney tubules. The developed models allow for studying transepithelial secretion of uremic toxins, an overarching application for these constructs. This will further advance our understanding of the kidney secretion processes and aid in studying interventions to main proximal tubule function in chronic kidney disease conditions in vitro. Furthermore, while fundamental by nature, our research deliverables enhance mechanistic insight in additive manufacturing and kidney development processes. Altogether, our findings will further advance the field of kidney engineering, while working towards kidney replacement therapies.
2022-03-03 | Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype.
Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures.
proteins
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.
2025-05-21 | Untangling Traffic Jams: RAB11FIP4 Orchestrates Cellular Recovery in Cystinosis.
RAB11FIP4 (RAB11 family interacting protein 4), a RAB11A (Ras-related protein Rab-11) effector protein downregulated in cystinosis, plays a crucial role in cellular trafficking. Reconstitution of RAB11FIP4 in cystinotic cells restores multiple cellular functions, including lysosomal trafficking, autophagy, and the endoplasmic reticulum stress response. These findings identify RAB11FIP4 as both a key player in cystinosis pathogenesis and a promising therapeutic target. The purpose of this punctum is to highlight how restoring RAB11FIP4 expression rescues cellular homeostasis in cystinosis through the regulation of trafficking pathways.
2025-02-24 | Cystinosin is involved in Na+/H+ Exchanger 3 trafficking in the proximal tubular cells: new insights in the renal Fanconi syndrome in cystinosis.
Cystinosis is a systemic lysosomal storage disease resulting from a defective CTNS gene, leading to the accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, the renal Fanconi syndrome (FS) is the first manifestation of cystinosis that presents early in life of the patients while other complications appear years later. Additionally, the cystine reduction therapy, cysteamine, does not prevent the FS. While the matter is still unresolved, it is apparent that specific function(s) of cystinosin in the proximal tubular cells (PTCs) beyond cystine transport explain the early tubular defects in cystinosis. Here, we report a novel interaction of cystinosin with the sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes in both yeast and mammalian cells. One isoform of Na+/H+ exchanger, NHE3, is a major absorptive sodium transporter at the apical membrane of the proximal tubules. Cystinosin was found to play a significant role in NHE3 subcellular localization, trafficking, and resulting sodium uptake in PTCs. Interestingly, introduction of CTNS successfully rescued these defects in CTNS-deficient PTCs, whereas CTNS-LKG, the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns -/- mice and cystinosis patient kidney. Interestingly, transplantation of wild-type hematopoietic stem and progenitor cells in Ctns -/- mice restored NHE3 expression at the brush border membrane. This study uncovers a new role of cystinosin in the trafficking of NHE3 in the PTCs that is evolutionary conserved, offering new insights in the pathogenesis of the renal FS in cystinosis and potential new therapeutic avenue for this pathology.
2024-07-27 | Chronic Kidney Disease and Growth Failure in Children.
Chronic kidney disease (CKD) is a significant challenge for pediatric endocrinologists, as children with CKD may present a variety of endocrine complications. Growth failure is common in CKD, and its severity is correlated with the degree of renal insufficiency. Management strategies include addressing reversible comorbidities, optimizing nutrition, and ensuring metabolic control. Kidney replacement therapy, including transplantation, determines a significant improvement in growth. According to a recent Consensus Statement, children with CKD stage 3-or on dialysis older >6 months-are eligible for treatment with recombinant growth hormone (rGH) in the case of persistent growth failure. Treatment with rGH may be considered for those with height between the 3rd and 10th percentile and persistent growth deceleration. In children who received kidney transplantation but continue to experience growth failure, initiation of GH therapy is recommended one year post-transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not an option. In children with CKD, due to nephropathic cystinosis and persistent growth failure, GH therapy should be considered at all stages of CKD. Potential adverse effects and benefits must be regularly assessed during therapy. Treatment with GH is safe in children with CKD. However, its general efficacy is still controversial. All possible problems with a negative impact on growth should be timely addressed and resolved, whenever possible with a personalized approach to the patient. GH therapy may be useful in promoting catch-up growth in children with residual growth potential. Future research should focus on refining effective therapeutic strategies and establishing consensus guidelines to optimize growth outcomes in this population.
2022-10-04 | Structure and mechanism of human cystine exporter cystinosin.
Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.
gene therapies
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.
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.).
2025-11-10 | An Isogenic Human Myoblast Cell Model for Cystinosis Myopathy Reveals Alteration of Key Myogenic Regulatory Proteins.
Cystinosis is a rare multisystem, autosomal recessive disease caused by dysfunction or loss of cystinosin (CTNS), which results in lysosomal cystine accumulation, primarily affecting the kidneys. Advances in renal transplantation, cysteamine treatment and improved medical care have increased life expectancy, revealing additional systemic phenotypes like myopathy later in life. Muscle weakness is a major concern leading to life-threatening events in patients, and yet the aetiology of cystinosis myopathy remains to be elucidated. We generated human muscle cell-based models using CRISPR technology to explore the pathophysiology of cystinosis myopathy with the potential to develop new therapies. We used a 4-day differentiation protocol of myoblasts into myotubes to study the effect of CTNS loss in key regulators of myogenic differentiation using western blot analysis. Afterwards, we used lentiviral (LV)-mediated CTNSWT cDNA addition in CTNS-/- cells to corroborate the CTNS-specific effect. As a next step, we performed multiomic analysis (proteomics, transcriptomics and metabolomics) to gain in-depth knowledge of affected mechanisms. The polyclonal, isogenic human CTNS knock-out (KO; CTNS-/-) myoblasts exhibited unaltered growth characteristics and accumulated cystine. Early-stage differentiation of myoblasts into myotubes showed a mild reduction in the fusion index of CTNS-/- myotubes. Upon examination of several key regulators of myogenic differentiation, we observed significantly decreased myosin heavy chain (MyHC) and ryanodine receptor (RyR) protein levels in CTNS-/- myotubes compared to WT cells. Complementation with CTNSWT cDNA addition in CTNS-/- cells rescued the fusion index, cystine and altered protein levels to WT. In addition, proteomic analysis showed no differences at myoblast level upon the loss of CTNS, but following myotube differentiation, CTNS deletion led to an increase of five protein groups mainly involved in oxidative stress pathways, and a decrease of 18 protein groups biologically connected in myofibril assembly and muscle cell differentiation processes. Importantly, LV-mediated CTNS addback reverted protein levels to WT levels. Moreover, metabolomics revealed a distinct clustering resulting from CTNS loss. Muscle-specific complications are often overlooked in systemic cystinosis treatment. We show that defective CTNS function impairs effective cystine mobilization from lysosomes, thereby affecting the protein levels of myogenic regulators. A deeper understanding of the molecular mechanisms underlying cystinosis myopathy holds promise for the development of targeted, personalized therapies to improve the quality of life for patients living with cystinosis.
2025-11-03 | Cystinosis: Unravelling Molecular Mechanisms, Clinical Challenges, and therapeutic Innovations
A rare autosomal recessive lysosomal storage disorder called cystinosis is caused by mutations in the CTNS gene. It causes cystine to accumulate in various organ systems, which causes progressive damage. This review summarizes the most recent findings regarding the molecular pathophysiology, clinical manifestations, diagnostic developments, and treatment approaches for cystinosis. Together with issues related to long-term care and the transition to adult care, we highlight recent advancements in genetic diagnostics, noninvasive imaging, and cutting-edge treatments such as gene editing. To improve patient outcomes in this intricate multisystem disease, this manuscript presents future directions and offers a thorough framework for understanding cystinosis by combining molecular, clinical, and translational perspectives.
2025-06-05 | Emerging therapeutic strategies for cystinosis.
For over 40 years, oral cysteamine has been the mainstay of therapy for cystinosis. While it has been of great benefit, slowing organ deterioration and prolonging life, cysteamine is not well tolerated and may not rescue all pathogenic mechanisms driving the disease. Of late, research groups around the world have been pursuing various novel therapeutic strategies. Here we select just four of many examples - two that address events downstream of the missing Cystinosin protein and two that aim to address the upstream CTNS mutation. Our aim is to update the cystinosis community on some of the exciting work in progress. We have drawn from preliminary reports and oral presentations at cystinosis meetings. While each approach requires further work and critical analysis, the sheer number and variety of these potential therapies is cause for hope.
other
2024-05-23 | MFSD12 depletion reduces cystine accumulation without improvement in proximal tubular function in experimental models for cystinosis.
Cystinosis is an autosomal recessive lysosomal storage disorder, caused by mutations in the CTNS gene, resulting in an absent or altered cystinosin (CTNS) protein. Cystinosin exports cystine out of the lysosome, with a malfunction resulting in cystine accumulation and a defect in other cystinosin-mediated pathways. Cystinosis is a systemic disease, but the kidneys are the first and most severely affected organs. In the kidney, the disease initially manifests as a generalized dysfunction in the proximal tubules (also called renal Fanconi syndrome). MFSD12 is a lysosomal cysteine importer that directly affects the cystine levels in melanoma cells, HEK293T cells, and cystinosis patient-derived fibroblasts. In this study, we aimed to evaluate MFSD12 mRNA levels in cystinosis patient-derived proximal tubular epithelial cells (ciPTECs) and to study the effect of MFSD12 knockout on cystine levels. We showed similar MFSD12 mRNA expression in patient-derived ciPTECs in comparison with the control cells. CRISPR MFSD12 knockout in a patient-derived ciPTEC (CTNSΔ57kb) resulted in significantly reduced cystine levels. Furthermore, we evaluated proximal tubular reabsorption after injection of mfsd12a translation-blocking morpholino (TB MO) in a ctns-/- zebrafish model. This resulted in decreased cystine levels but caused a concentration-dependent increase in embryo dysmorphism. Furthermore, the mfsd12a TB MO injection did not improve proximal tubular reabsorption or megalin expression. In conclusion, MFSD12 mRNA depletion reduced cystine levels in both tested models without improvement of the proximal tubular function in the ctns-/- zebrafish embryo. In addition, the apparent toxicity of higher mfsd12a TB MO concentrations on the zebrafish development warrants further evaluation.NEW & NOTEWORTHY In this study, we show that MFSD12 depletion with either CRISPR/Cas9-mediated gene editing or a translation-blocking morpholino significantly reduced cystine levels in cystinosis ciPTECs and ctns-/- zebrafish embryos, respectively. However, we observed no improvement in the proximal tubular reabsorption of dextran in the ctns-/- zebrafish embryos injected with mfsd12a translation-blocking morpholino. Furthermore, a negative effect of the mfsd12a morpholino on the zebrafish development warrants further investigation.
2024-01-15 | Neurologic involvement in cystinosis: Focus on brain lesions and new evidence of four-repeat (4R-) Tau immunoreactivity.
Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.
2023-11-28 | Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis
Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns-/- zebrafish embryos. Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine-H+ symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and the most severely affected organs, presenting glomerular and proximal tubular dysfunction, progressing to end-stage kidney failure. The current therapeutic standard cysteamine, reduces cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA can restore lysosomal cystinosin expression following lipofection into CTNS-/- kidney cells and injection into ctns-/- zebrafish. A single CTNS mRNA administration decreases cellular cystine accumulation for up to 14 days in vitro. In the ctns-/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. Therefore, this proof-of-principle study takes the first steps in establishing an mRNA-based therapy to restore cystinosin expression, resulting in cystine reduction in vitro and in the ctns-/- larvae, and restoration of the zebrafish pronephros function.
2023-08-17 | mRNA as a medicine in nephrology: the future is now
ABSTRACT The successful employment of messenger RNA (mRNA) as vaccine therapy for the prevention of COVID-19 infection has spotlighted the attention of scientific community onto the potential clinical application of these molecules as innovative and alternative therapeutic approaches in different fields of medicine. As therapy, mRNAs may be advantageous due to their unique biological properties of targeting almost any genetic component within the cell, many of which may be unreachable using other pharmacological/therapeutic approaches, and encoding any proteins and peptides without the need for their transport into the nuclei of the target cells. Additionally, these molecules may be rapidly designed/produced and clinically tested. Once the chemistry of the RNA and its delivery system are optimized, the cost of developing novel variants of these medications for new selected clinical disorders is significantly reduced. However, although potentially useful as new therapeutic weapons against several kidney diseases, the complex architecture of kidney and the inability of nanoparticles that accommodate oligonucleotides to cross the integral glomerular filtration barrier have largely decreased their potential employment in nephrology. However, in the next few years, the technical improvements in mRNA that increase translational efficiency, modulate innate and adaptive immunogenicity, and increase their delivery at the site of action will overcome these limitations. Therefore, this review has the scope of summarizing the key strengths of these RNA-based therapies and illustrating potential future directions and challenges of this promising technology for widespread therapeutic use in nephrology.
2023-04-29 | CTNSmRNA as a potential treatment for nephropathic cystinosis
Abstract Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to correct the genetic defect in nephropathic cystinosis using synthetic mRNA. Cystinosis is a prototype disorder of proximal tubular dysfunction caused by mutations in the CTNS gene, encoding the lysosomal cystine-H + symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and most severely affected organs, presenting glomerular and proximal tubular dysfunction. Cysteamine is the current therapeutic standard that reduces cellular cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA is safe and effective to reintroduce functional cystinosin using lipofection in CTNS -/- kidney cells and following direct injection in ctns -/- zebrafish larvae. CTNS mRNA therapy results in prompt lysosomal expression of the functional protein and decreases cellular cystine accumulation for up to 14 days. In the ctns -/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. We propose that mRNA-based therapy, if sufficient kidney targeting can be achieved, may be a new approach to treat cystinosis. Translational statement Cystinosis is a systemic lysosomal storage disease caused by mutations in the CTNS (cystinosin) gene. It initially affects the kidneys and leads to kidney failure, if left untreated. The current standard therapy, cysteamine, is not curative and has many side-effects. Here we demonstrate the potential of mRNA-based therapy to swiftly restore cystinosin function and ameliorate the kidney phenotype. Future research will focus on mRNA delivery methods and targeting kidney cells in cystinosis rodent models.
small molecules
2026-09-05 | Cystinosis-associated metabolic bone disease: pathogenesis and outcome.
Cystinosis-associated metabolic bone disease (CMBD) is a severe complication in patients with infantile nephropathic cystinosis, which is a rare inherited lysosomal storage disease due to pathogenic variants in the CTNS gene that results in an accumulation of cystine in all organs. The kidneys are the organs primarily affected, resulting in renal Fanconi syndrome at around the age of 6-12 months. Without adequate treatment with the cystine-depleting agent cysteamine, this is followed by progressive chronic kidney disease (CKD) and kidney failure in the second decade of life. Patients usually present with progressive disproportionate short stature, rickets, and bone pain in the first 2 years of life. This may be followed by muscle weakness in childhood, and scoliosis and fractures in adulthood, especially if treatment is inadequate. Early diagnosis and treatment are crucial, and this is facilitated by a positive family history, screening programs and care at specialized centers. Therapeutic measures include physical activity, physiotherapy, adequate calcium and phosphate intake, vitamin D supplements, a combination of phosphate supplements and active vitamin D, correction of metabolic acidosis, and, if necessary, growth hormone therapy and surgical correction of persisting leg deformities. Unfortunately, current treatments cannot always prevent progressive bone loss and related skeletal comorbidity. There is increasing evidence for an underlying intrinsic osteoblast and osteoclast defect in cystinosis. Cystine crystal accumulation in macrophages (e.g., in bone and muscle) may result in an inflammatory state promoting increased osteoclast activity and other alterations in myokines and osteokines. Future interventions may target these factors to improve outcomes in patients with cystinosis.
2026-09-04 | From Cysteamine to Pepstatin A: Targeting Cathepsin D To Improve Bone Health in Cystinosis.
Nephropathic cystinosis is a rare genetic lysosomal storage disorder caused by loss-of-function variants of the CTNS gene encoding for the lysosomal H+/cystine symporter cystinosin. The lack of cystinosin causes cystine accumulation in lysosomes and cell damage. Children with nephropathic cystinosis commonly exhibit skeletal abnormalities, including growth retardation, osteopenia and rickets. The only cystine-depleting drug available is cysteamine. However, several observations suggest that cysteamine, particularly at high doses, may have negative effects on the skeleton. In this study, we characterized the effects of cysteamine on bone cells and we identified Pepstatin A, a Cathepsin D-inhibitor, as a potential new therapeutic treatment to restore physiological bone remodeling in cystinosis. We observed a detrimental effect of cysteamine on bone cells inducing further impairment of osteoblast differentiation/activity and failure of cysteamine intraperitoneal injection to improve the somatic growth of pre-pubertal ctns-/- mice. Moreover, we demonstrated that Pepstatin A treatment increased bone formation in vitro acting on the Fibronectin/Sipa1/STAT3/JunB pathway, and rescued somatic growth and bone mass in pre-pubertal ctns-/- mice. Our results provide evidence that cysteamine negatively affects bone in cystinosis and that Cathepsin D inhibition could represent a new therapeutic approach for rescue of bone remodeling in cystinosis.
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.
2026-01-28 | Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.
2025-12-22 | Molecular Characterization of Tunisian Cystinosis Patients Reveals a High Prevalence of the c.829dup Mutation
Background Cystinosis is a lysosomal storage disease caused by the accumulation of intralysosomal cystine in different tissues and organs including: brain, cornea, kidneys, live and, pancreas. This pathology is due the mutations in the CTNS gene that is encoded by the cystinosin protein. The study aimed to explore the genetic and phenotypic diversity of Tunisian patients with cystinosis in order to identify recurrent variants and their correlation with clinico-pathology features. Methods This study was conducted in collaboration with pediatric departments of Sahloul hospital of Sousse, and Tahar Sfar hospital of Mahdia and Hedi Chaker Hospital of Sfax, Tunisia. The entire coding region of CTNS-cDNA, was screened to identify mutations and polymorphisms in 11 families: 6 unrelated and 5 related families with cystinosis. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene. Results Molecular analysis of the CTNS gene was performed in affected individuals and their relatives, leading to the identification of seven pathogenic variants. Four of them were previously reported: c.829dup (p.Thr277fs; rs752919200), c.971-1G > C (rs2142982540), p.Thr334Asn (rs3375433), c.925G > A (p.Gly309Cys; rs758813679 ), and c.251delA ( p.Asn84fs; rs1057516296 ). A novel frameshift mutation, c.529del (p.Thr177fs), was also detected. The c.829dup variant was present in six homozygous patients (5 related and one unrelated) and one heterozygous patient. In total, 42 SNPs were identified including eight novel variants. The most frequent was rs161400 (p.Thr260Asn), which co-occurred with all variants except with c.829dup; was also observed in heterozygous carriers of c.829dup exhibiting a severe cystinosis phenotype. Conclusions Our findings underscore the potential phenotypic modulatory role of the rs161400 SNP, particularly in individuals carrying rare CTNS variants compared to patients carrying the recurrent c.829dup mutation. This study emphasizes the significance of the broader genetic landscape, including variant–variant interactions, in shaping the phenotypic heterogeneity observed among patients. Moreover, this study highlights the distinct mutational profile of Tunisian patients with cystinosis disease.
cell therapies
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.
2025-04-08 | Native kidney and graft survival in a cohort of Egyptian children with nephropathic cystinosis: national referral center experience.
Nephropathic Cystinosis is a rare autosomal recessive lysosomal storage disorder. In addition to kidney dysfunction, this disorder can also affect other organs, such as the eyes, thyroid, muscles, and central nervous system. The current cross-sectional study included 56 patients with nephropathic cystinosis to evaluate the clinical outcome in nephropathic cystinosis patients cohort with regarding kidney function and the need for kidney replacement therapy. Clinical and laboratory data were collected. Among the 56 patients in our study, 32 (57.1%) were male. Furthermore, 52 (92%) of these patients were offspring of consanguineous marriage. Patients' mean age was 116.96 ± 54.1 months, and the mean onset of nephropathic cystinosis suggestive symptoms was 7.63 ± 3.2 months. In addition, the mean age of confirmed diagnosis was 45.38 ± 35.3 months, and the mean age of end-stage kidney disease (ESKD) was 104 ± 25.7 months. Eighteen patients (32.1%)underwent hemodialysis, whereas 12 patients (21.4%) underwent kidney transplantation. When comparing siblings within the same family, we observed a significant difference in the age at diagnosis. The median age for the first sibling was 60 months, while it was 24 months for the second sibling (p-value = 0.031). Additionally, there were significant differences in weight, chronic kidney disease (CKD) stage, and outcome. Improvement in the awareness and the accessibility to diagnosis over years, early sibling screening, and kidney transplantation have a significant impact on the survival of both patients and kidney in children with nephropathic cystinosis.
2023-12-07 | Investigation on Cross-correction of Cystinosis through Genetically Engineered Cells Secreting Cystinosin
Background: Cystinosis is a rare inherited lysosomal storage disease (LSD), caused by a mutation in the Cystinosin Lysosomal Cystine Transporter (CTNS). Novel therapies and strategies are needed to improve patients' clinical conditions and quality of life. Objectives and Methods: This study assessed whether CTNS can be secreted, and investigated a method to enhance its secretion, by adding a secretion signal to the N-terminus. Human Embry-onic Kidney (HEK) 293 cells were transfected with the resulting construct. The amount of protein secreted was then measured. Uptake by monolayer cultures of cystinotic cells and enzyme activity were also assessed. Results: The recombinant protein could effectively be secreted, and the secretion signal slightly further increased its secretion. The secreted recombinant protein was taken up by cystinotic cells, and, after internalization, still retained its biological activity. Conclusion: Optimization of the proposed method to increase the secretion of CTNS would pro-vide new insights into the production of recombinant proteins for medical and industrial use. Further identification and screening of alternative signalling peptides and cell types can maximise the secretion and production of recombinant CNTS, to be used as a therapeutic agent in human healthcare.
2023-04-03 | Engineering the (vascularized) Proximal Tubule, a Guide Towards Functionality
This thesis focused on the fabrication of kidney proximal tubule models. A coaxial printing system allowed the robust and straightforward fabrication of coiled perfusable microfibers, replicating the kidney proximal convoluted tubules. The formed alginate-gelatin microfibers offer a complex tubular shape in which the cells exhibit mature markers, such as functional transporters and polarized monolayers. Moreover, this model has proven to support both healthy and cystinotic proximal tubule cell lines and allows for mechanistically studying tubulopathies. Though distinctive 3D-printing strategies offer opportunities to mimic the structure of the convoluted proximal tubule, printing resolution remains restricted for soft hydrogel materials. Therefore, a unique method was studied, whereby post-printing treatment induced resolution enhancement of methacrylated hyaluronic acid / gelatin methacryloyl (HAMA/GelMA) based hydrogels. This shrinking technique opens a wide application to create higher resolutions for 3D printing. However, we also found that the polycationic shrinking reagents used were relatively toxic for our cells of interest. Therefore, more research is needed to prevent the direct exposure of cells to the shrinking reagents. Using melt electrowriting, scaffolds were fabricated that are self-supportive, yet small-sized and highly porous. These scaffolds enable direct access to the basolateral and luminal cell sides to facilitate solute exchange with vasculature in immediate proximity, which is critical for functional proximal tubule constructs. The polymer applied, polycaprolactone, is used to prepare biomaterials that generally show good biocompatibility and is compatible with implantation in the future. Kidney proximal tubule cells and glomerular endothelial cells form polarized monolayers in our tubules, form their own extracellular matrix, and show functionality for important kidney transporters. In our preliminary results we showed initial work with induced pluripotent stem cell-derived kidney organoids, which is very promising for the development of implantable proximal tubule grafts. The aim was to develop vascularized kidney tubules for studying the clearance of protein bound uremic toxins, while gaining knowledge for the development of implantable kidney tubules. The developed models allow for studying transepithelial secretion of uremic toxins, an overarching application for these constructs. This will further advance our understanding of the kidney secretion processes and aid in studying interventions to main proximal tubule function in chronic kidney disease conditions in vitro. Furthermore, while fundamental by nature, our research deliverables enhance mechanistic insight in additive manufacturing and kidney development processes. Altogether, our findings will further advance the field of kidney engineering, while working towards kidney replacement therapies.
2022-03-03 | Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype.
Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures.
proteins
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.
2025-05-21 | Untangling Traffic Jams: RAB11FIP4 Orchestrates Cellular Recovery in Cystinosis.
RAB11FIP4 (RAB11 family interacting protein 4), a RAB11A (Ras-related protein Rab-11) effector protein downregulated in cystinosis, plays a crucial role in cellular trafficking. Reconstitution of RAB11FIP4 in cystinotic cells restores multiple cellular functions, including lysosomal trafficking, autophagy, and the endoplasmic reticulum stress response. These findings identify RAB11FIP4 as both a key player in cystinosis pathogenesis and a promising therapeutic target. The purpose of this punctum is to highlight how restoring RAB11FIP4 expression rescues cellular homeostasis in cystinosis through the regulation of trafficking pathways.
2025-02-24 | Cystinosin is involved in Na+/H+ Exchanger 3 trafficking in the proximal tubular cells: new insights in the renal Fanconi syndrome in cystinosis.
Cystinosis is a systemic lysosomal storage disease resulting from a defective CTNS gene, leading to the accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, the renal Fanconi syndrome (FS) is the first manifestation of cystinosis that presents early in life of the patients while other complications appear years later. Additionally, the cystine reduction therapy, cysteamine, does not prevent the FS. While the matter is still unresolved, it is apparent that specific function(s) of cystinosin in the proximal tubular cells (PTCs) beyond cystine transport explain the early tubular defects in cystinosis. Here, we report a novel interaction of cystinosin with the sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes in both yeast and mammalian cells. One isoform of Na+/H+ exchanger, NHE3, is a major absorptive sodium transporter at the apical membrane of the proximal tubules. Cystinosin was found to play a significant role in NHE3 subcellular localization, trafficking, and resulting sodium uptake in PTCs. Interestingly, introduction of CTNS successfully rescued these defects in CTNS-deficient PTCs, whereas CTNS-LKG, the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns -/- mice and cystinosis patient kidney. Interestingly, transplantation of wild-type hematopoietic stem and progenitor cells in Ctns -/- mice restored NHE3 expression at the brush border membrane. This study uncovers a new role of cystinosin in the trafficking of NHE3 in the PTCs that is evolutionary conserved, offering new insights in the pathogenesis of the renal FS in cystinosis and potential new therapeutic avenue for this pathology.
2024-07-27 | Chronic Kidney Disease and Growth Failure in Children.
Chronic kidney disease (CKD) is a significant challenge for pediatric endocrinologists, as children with CKD may present a variety of endocrine complications. Growth failure is common in CKD, and its severity is correlated with the degree of renal insufficiency. Management strategies include addressing reversible comorbidities, optimizing nutrition, and ensuring metabolic control. Kidney replacement therapy, including transplantation, determines a significant improvement in growth. According to a recent Consensus Statement, children with CKD stage 3-or on dialysis older >6 months-are eligible for treatment with recombinant growth hormone (rGH) in the case of persistent growth failure. Treatment with rGH may be considered for those with height between the 3rd and 10th percentile and persistent growth deceleration. In children who received kidney transplantation but continue to experience growth failure, initiation of GH therapy is recommended one year post-transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not an option. In children with CKD, due to nephropathic cystinosis and persistent growth failure, GH therapy should be considered at all stages of CKD. Potential adverse effects and benefits must be regularly assessed during therapy. Treatment with GH is safe in children with CKD. However, its general efficacy is still controversial. All possible problems with a negative impact on growth should be timely addressed and resolved, whenever possible with a personalized approach to the patient. GH therapy may be useful in promoting catch-up growth in children with residual growth potential. Future research should focus on refining effective therapeutic strategies and establishing consensus guidelines to optimize growth outcomes in this population.
2022-10-04 | Structure and mechanism of human cystine exporter cystinosin.
Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.
gene therapies
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.
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.).
2025-11-10 | An Isogenic Human Myoblast Cell Model for Cystinosis Myopathy Reveals Alteration of Key Myogenic Regulatory Proteins.
Cystinosis is a rare multisystem, autosomal recessive disease caused by dysfunction or loss of cystinosin (CTNS), which results in lysosomal cystine accumulation, primarily affecting the kidneys. Advances in renal transplantation, cysteamine treatment and improved medical care have increased life expectancy, revealing additional systemic phenotypes like myopathy later in life. Muscle weakness is a major concern leading to life-threatening events in patients, and yet the aetiology of cystinosis myopathy remains to be elucidated. We generated human muscle cell-based models using CRISPR technology to explore the pathophysiology of cystinosis myopathy with the potential to develop new therapies. We used a 4-day differentiation protocol of myoblasts into myotubes to study the effect of CTNS loss in key regulators of myogenic differentiation using western blot analysis. Afterwards, we used lentiviral (LV)-mediated CTNSWT cDNA addition in CTNS-/- cells to corroborate the CTNS-specific effect. As a next step, we performed multiomic analysis (proteomics, transcriptomics and metabolomics) to gain in-depth knowledge of affected mechanisms. The polyclonal, isogenic human CTNS knock-out (KO; CTNS-/-) myoblasts exhibited unaltered growth characteristics and accumulated cystine. Early-stage differentiation of myoblasts into myotubes showed a mild reduction in the fusion index of CTNS-/- myotubes. Upon examination of several key regulators of myogenic differentiation, we observed significantly decreased myosin heavy chain (MyHC) and ryanodine receptor (RyR) protein levels in CTNS-/- myotubes compared to WT cells. Complementation with CTNSWT cDNA addition in CTNS-/- cells rescued the fusion index, cystine and altered protein levels to WT. In addition, proteomic analysis showed no differences at myoblast level upon the loss of CTNS, but following myotube differentiation, CTNS deletion led to an increase of five protein groups mainly involved in oxidative stress pathways, and a decrease of 18 protein groups biologically connected in myofibril assembly and muscle cell differentiation processes. Importantly, LV-mediated CTNS addback reverted protein levels to WT levels. Moreover, metabolomics revealed a distinct clustering resulting from CTNS loss. Muscle-specific complications are often overlooked in systemic cystinosis treatment. We show that defective CTNS function impairs effective cystine mobilization from lysosomes, thereby affecting the protein levels of myogenic regulators. A deeper understanding of the molecular mechanisms underlying cystinosis myopathy holds promise for the development of targeted, personalized therapies to improve the quality of life for patients living with cystinosis.
2025-11-03 | Cystinosis: Unravelling Molecular Mechanisms, Clinical Challenges, and therapeutic Innovations
A rare autosomal recessive lysosomal storage disorder called cystinosis is caused by mutations in the CTNS gene. It causes cystine to accumulate in various organ systems, which causes progressive damage. This review summarizes the most recent findings regarding the molecular pathophysiology, clinical manifestations, diagnostic developments, and treatment approaches for cystinosis. Together with issues related to long-term care and the transition to adult care, we highlight recent advancements in genetic diagnostics, noninvasive imaging, and cutting-edge treatments such as gene editing. To improve patient outcomes in this intricate multisystem disease, this manuscript presents future directions and offers a thorough framework for understanding cystinosis by combining molecular, clinical, and translational perspectives.
2025-06-05 | Emerging therapeutic strategies for cystinosis.
For over 40 years, oral cysteamine has been the mainstay of therapy for cystinosis. While it has been of great benefit, slowing organ deterioration and prolonging life, cysteamine is not well tolerated and may not rescue all pathogenic mechanisms driving the disease. Of late, research groups around the world have been pursuing various novel therapeutic strategies. Here we select just four of many examples - two that address events downstream of the missing Cystinosin protein and two that aim to address the upstream CTNS mutation. Our aim is to update the cystinosis community on some of the exciting work in progress. We have drawn from preliminary reports and oral presentations at cystinosis meetings. While each approach requires further work and critical analysis, the sheer number and variety of these potential therapies is cause for hope.
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2024-05-23 | MFSD12 depletion reduces cystine accumulation without improvement in proximal tubular function in experimental models for cystinosis.
Cystinosis is an autosomal recessive lysosomal storage disorder, caused by mutations in the CTNS gene, resulting in an absent or altered cystinosin (CTNS) protein. Cystinosin exports cystine out of the lysosome, with a malfunction resulting in cystine accumulation and a defect in other cystinosin-mediated pathways. Cystinosis is a systemic disease, but the kidneys are the first and most severely affected organs. In the kidney, the disease initially manifests as a generalized dysfunction in the proximal tubules (also called renal Fanconi syndrome). MFSD12 is a lysosomal cysteine importer that directly affects the cystine levels in melanoma cells, HEK293T cells, and cystinosis patient-derived fibroblasts. In this study, we aimed to evaluate MFSD12 mRNA levels in cystinosis patient-derived proximal tubular epithelial cells (ciPTECs) and to study the effect of MFSD12 knockout on cystine levels. We showed similar MFSD12 mRNA expression in patient-derived ciPTECs in comparison with the control cells. CRISPR MFSD12 knockout in a patient-derived ciPTEC (CTNSΔ57kb) resulted in significantly reduced cystine levels. Furthermore, we evaluated proximal tubular reabsorption after injection of mfsd12a translation-blocking morpholino (TB MO) in a ctns-/- zebrafish model. This resulted in decreased cystine levels but caused a concentration-dependent increase in embryo dysmorphism. Furthermore, the mfsd12a TB MO injection did not improve proximal tubular reabsorption or megalin expression. In conclusion, MFSD12 mRNA depletion reduced cystine levels in both tested models without improvement of the proximal tubular function in the ctns-/- zebrafish embryo. In addition, the apparent toxicity of higher mfsd12a TB MO concentrations on the zebrafish development warrants further evaluation.NEW & NOTEWORTHY In this study, we show that MFSD12 depletion with either CRISPR/Cas9-mediated gene editing or a translation-blocking morpholino significantly reduced cystine levels in cystinosis ciPTECs and ctns-/- zebrafish embryos, respectively. However, we observed no improvement in the proximal tubular reabsorption of dextran in the ctns-/- zebrafish embryos injected with mfsd12a translation-blocking morpholino. Furthermore, a negative effect of the mfsd12a morpholino on the zebrafish development warrants further investigation.
2024-01-15 | Neurologic involvement in cystinosis: Focus on brain lesions and new evidence of four-repeat (4R-) Tau immunoreactivity.
Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.
2023-11-28 | Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis
Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns-/- zebrafish embryos. Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine-H+ symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and the most severely affected organs, presenting glomerular and proximal tubular dysfunction, progressing to end-stage kidney failure. The current therapeutic standard cysteamine, reduces cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA can restore lysosomal cystinosin expression following lipofection into CTNS-/- kidney cells and injection into ctns-/- zebrafish. A single CTNS mRNA administration decreases cellular cystine accumulation for up to 14 days in vitro. In the ctns-/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. Therefore, this proof-of-principle study takes the first steps in establishing an mRNA-based therapy to restore cystinosin expression, resulting in cystine reduction in vitro and in the ctns-/- larvae, and restoration of the zebrafish pronephros function.
2023-08-17 | mRNA as a medicine in nephrology: the future is now
ABSTRACT The successful employment of messenger RNA (mRNA) as vaccine therapy for the prevention of COVID-19 infection has spotlighted the attention of scientific community onto the potential clinical application of these molecules as innovative and alternative therapeutic approaches in different fields of medicine. As therapy, mRNAs may be advantageous due to their unique biological properties of targeting almost any genetic component within the cell, many of which may be unreachable using other pharmacological/therapeutic approaches, and encoding any proteins and peptides without the need for their transport into the nuclei of the target cells. Additionally, these molecules may be rapidly designed/produced and clinically tested. Once the chemistry of the RNA and its delivery system are optimized, the cost of developing novel variants of these medications for new selected clinical disorders is significantly reduced. However, although potentially useful as new therapeutic weapons against several kidney diseases, the complex architecture of kidney and the inability of nanoparticles that accommodate oligonucleotides to cross the integral glomerular filtration barrier have largely decreased their potential employment in nephrology. However, in the next few years, the technical improvements in mRNA that increase translational efficiency, modulate innate and adaptive immunogenicity, and increase their delivery at the site of action will overcome these limitations. Therefore, this review has the scope of summarizing the key strengths of these RNA-based therapies and illustrating potential future directions and challenges of this promising technology for widespread therapeutic use in nephrology.
2023-04-29 | CTNSmRNA as a potential treatment for nephropathic cystinosis
Abstract Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to correct the genetic defect in nephropathic cystinosis using synthetic mRNA. Cystinosis is a prototype disorder of proximal tubular dysfunction caused by mutations in the CTNS gene, encoding the lysosomal cystine-H + symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and most severely affected organs, presenting glomerular and proximal tubular dysfunction. Cysteamine is the current therapeutic standard that reduces cellular cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA is safe and effective to reintroduce functional cystinosin using lipofection in CTNS -/- kidney cells and following direct injection in ctns -/- zebrafish larvae. CTNS mRNA therapy results in prompt lysosomal expression of the functional protein and decreases cellular cystine accumulation for up to 14 days. In the ctns -/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. We propose that mRNA-based therapy, if sufficient kidney targeting can be achieved, may be a new approach to treat cystinosis. Translational statement Cystinosis is a systemic lysosomal storage disease caused by mutations in the CTNS (cystinosin) gene. It initially affects the kidneys and leads to kidney failure, if left untreated. The current standard therapy, cysteamine, is not curative and has many side-effects. Here we demonstrate the potential of mRNA-based therapy to swiftly restore cystinosin function and ameliorate the kidney phenotype. Future research will focus on mRNA delivery methods and targeting kidney cells in cystinosis rodent models.
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Drug Discovery Landscape
12 orphan drug designations for Cystinosis, including 4 approved therapies.
12 orphan drug designations for Cystinosis, including 4 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
N-acetylcysteine amide | small molecules | FDA | Nacuity Pharmaceuticals, Inc. | |
Autologous CD34+ cells transduced with a lentiviral RNA vector that results in integrated cDNA encoding for functional cystinosin | cell therapies | EMA | Novartis Europharm Limited | |
autologous CD34+ enriched cells transduced with a lentiviral vector containing RNA resulting in codon-optimized cDNA encoding for functional human cystinosin | cell therapies | FDA | Novartis Pharmaceuticals Corporation | |
6'-(R)-methyl-5-O-(5-amino-5,6-dideoxy-alpha-L-talofuranosyl)-paromamine sulfate | small molecules | FDA | ELOXX Pharmaceuticals, Inc. | |
Cysteamine hydrochloride | small molecules | EMA | Lucane Pharma SA | |
Mercaptamine bitartrate [Procysbi] | small molecules | EMA | Chiesi Farmaceutici S.p.A. | |
Cysteamine hydrochloride [Cystadrops] | small molecules | EMA | Approved | Recordati Rare Diseases |
cysteamine enteric coated [PROCYSBI] | small molecules | FDA | Approved | Horizon Therapeutics USA, Inc. |
Cysteamine hydrochloride [Cystaran] | small molecules | FDA | Approved | Leadiant Biosciences, Inc. |
Cysteamine [Cystagon] | small molecules | FDA | Approved | Mylan Laboratories, Inc. |
Phosphocysteamine | small molecules | FDA | — | Medea Research Laboratories |
Cysteamine | small molecules | FDA | Thoene, Jess G., M.D. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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