Cystinosis is a metabolic hereditary disease characterized by intracellular accumulation of cystine. Affected individuals typically present with proximal tubulopathy before one year of age and eventually progress to end- stage renal failure. Cystine accumulation also leads to multi-organ dysfunction. Using the mouse model for cystinosis, the Ctns-/- mice, we showed that transplantation of wildtype Sca1+ HSC expressing Ctns resulted in dramatic reductions of tissue cystine content and long-term of kidney preservation. Within the scope of the original R01-DK090058 grant, we optimized a protocol to obtain efficient HSC transduction and showed that ex vivo transduced HSCs using our lentiviral vector construct, pCCL-CTNS, were also capable of decreasing cystine content in all tissues and improved kidney function in Ctns-/- mice. After submitting a pre-Investigator New Drug (IND) application to Food and Drug Administration (FDA), we are now conducting the pharmacology/toxicology studies required for inclusion in an IND for a phase I clinical trial for autologous gene- modified-HSC transplantation for cystinosis. While this work offers new hope for the treatment of cystinosis, we are proposing to investigate two critical questions for the future clinical application of this strategy.
In Specific Aim 1, we will investigate if the second CTNS isoform, CTNSLKG, would improve the actual gene therapy strategy. Cystinosin-LKG is found in the lysosomes and at the plasma membrane but its function is unknown. However, CTNSLKG has been found highly expressed in PTCs and other cell types that depend on vesicular trafficking and that correlate with cystinosis clinical features including the Fanconi syndrome. We also recently showed that vesicular trafficking was impaired in cystinosis cells. Thus, our hypothesis is that cystinosinLKG is involved in vesicular trafficking of transporters at the apical membrane of the PTCs and that introduction of the two CTNS isoforms via stem cell therapy would augment the therapeutic impact especially the kidney function. If so, these data will serve as the basis for modifying subsequent clinical trial strategies submitted to the FDA but may also elucidate the pathogenesis of the Fanconi syndrome in cystinosis that has remained a mystery all these years despite considerable scientific investigation.
In Specific Aim 2, we will investigate if the patients homozygote for the 57-kb deletion, the most common mutation in cystinosis, can be treated with autologous HSC transplantation. Indeed, this large deletion also removes the adjacent Carbohydrate kinase-like (CARKL) gene encoding the sedoheptulokinase (SHPK). While the absence of this gene does not have an obvious consequence on disease phenotype, SHPK has been recently shown to control macrophage differentiation. Since we recently showed that macrophages play a key role in tissue repair in cystinosis after HSC transplantation, it is critical to verify that the absence of CARKL gene will not impact our stem cell treatment strategy. This work s critical for the future clinical trial for cystinosis but alsowill advance the understanding on macrophage-mediated tissue repair and the role of CARKL in this process.

Public Health Relevance

Cystinosis is an hereditary disease characterized by the accumulation of cystine in all the cells of the body leading to cell death and tissue damage to kidneys, liver, eyes, muscle and brain. We showed that healthy hematopoietic stem cells (HSCs), which are naturally available in the body, can rescue this disease in the mouse model of cystinosis and we are currently developing a clinical trial that allows the patients' own stem cells to be isolated, corrected for the genetic defect and reintroduced to the body to stimulate healing. We are now proposing strategies to improve this stem cell-gene therapy approach and to investigate which patients' genetic profile will benefit the most from the future clinical trial

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rasooly, Rebekah S
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University of California San Diego
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Rocca, Celine J; Cherqui, Stephanie (2018) Potential use of stem cells as a therapy for cystinosis. Pediatr Nephrol :
Cherqui, Stephanie; Courtoy, Pierre J (2017) The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol 13:115-131
Zhang, Jinzhong; Johnson, Jennifer L; He, Jing et al. (2017) Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A. J Biol Chem 292:10328-10346
Ariazi, Jennifer; Benowitz, Andrew; De Biasi, Vern et al. (2017) Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions. Front Mol Neurosci 10:333
Rocca, Celine J; Goodman, Spencer M; Dulin, Jennifer N et al. (2017) Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich's ataxia. Sci Transl Med 9:
Gaide Chevronnay, H P; Janssens, V; Van Der Smissen, P et al. (2016) Hematopoietic Stem Cells Transplantation Can Normalize Thyroid Function in a Cystinosis Mouse Model. Endocrinology 157:1363-71
Cheung, Wai W; Cherqui, Stephanie; Ding, Wei et al. (2016) Muscle wasting and adipose tissue browning in infantile nephropathic cystinosis. J Cachexia Sarcopenia Muscle 7:152-64
Napolitano, Gennaro; Johnson, Jennifer L; He, Jing et al. (2015) Impairment of chaperone-mediated autophagy leads to selective lysosomal degradation defects in the lysosomal storage disease cystinosis. EMBO Mol Med 7:158-74
Rocca, Celine J; Kreymerman, Alexander; Ur, Sarah N et al. (2015) Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation. Invest Ophthalmol Vis Sci 56:7214-23
Gaide Chevronnay, H P; Janssens, V; Van Der Smissen, P et al. (2015) A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing. Endocrinology 156:2349-64

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