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Treatment in cystinosis

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Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). 

Cystinosis is a monogenic hereditary disease caused by mutations or deletions in the ubiquitous gene CTNS, encoding the lysosomal transmembrane cystine transporter, cystinosin.

This gene encodes a seven-transmembrane lysosomal protein, which is a proton-driven cystine transporter.

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Treatment in cystinosis

  1. 1. Novel Therapy for Cystinosis Masoumeh Mohkam, MD Professor od Pediatric Nephrology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. June 2020
  2. 2. Physiopathology of cystinosis • Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). • Cystinosis is a monogenic hereditary disease caused by mutations or deletions in the ubiquitous gene CTNS, encoding the lysosomal transmembrane cystine transporter, cystinosin. • This gene encodes a seven-transmembrane lysosomal protein, which is a proton-driven cystine transporter. Kalatzis V. EMBO J 2001;20: 5940-5949
  3. 3. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate. seven-transmembrane lysosomal protein
  4. 4. De Toni – Debré – Fanconi syndrome characterized by a severe fluid and electrolyte disturbance, growth retardation, and rickets.
  5. 5. Treatment of cystinosis With early and diligent therapy, cystinosis patients can prevent or delay most of the non-renal complications and extend their lives into a fourth or fifth decade, live independently and even have children Cysteamine Gahl WA. Pediatric Nephrology. 2009;6:1019-1038 Dohil R. The Journal of Pediatrics. 2010;156(1:)71-75
  6. 6. Cysteamine deplets intra-cellular cystine accumulation
  7. 7. Cysteamine • Cysteamine improves the outcome and complications of cystinosis but does not prevent them. • Cysteamine does not prevent the Fanconi syndrome even if started very early in life. Stephanie Cherqui, Kidney International 2012 January Gahl WA. Ann Intern Med 2007;147:242-250. Nesterova G. Pediatr Nephrol 2008;23:863-878.
  8. 8. Treatment of renal fanconi syndrome • Avoid dehydration • Nutritional support (calorie intake100-130% RDI) • Supplementation of electrolyte losses: (Na) K citrate 2-10 mmol/kg/day QID Na bicarbonate 2-15 mmol/kg/day QID K chloride 2-10 mmol/kg/day QID Salty food, Na chloride is rarely required • Treatment & prevention of rickets: (Na) K phosphate 0.2-2 mmol P/kg/day QID Alphacalcidol 0.2-2 µg/day QD • Copper deficiency: copper 1-10 mg/day BID • Severe polyuria: indomethacin 0.5-3mg/kg/day TID • Carnitine • In patients with adequate metabolic control, but persistent poor growth: rhGH treatment 0.045 mg/kg/day QD Sex hormones Veys et al. Curr Opin Pediatr 2017
  9. 9. • It was performed on 100 individuals with nephropathic cystinosis, examined between 1985 and 2006. • Their study showed a decrease in the frequency of symptoms with increased time on cysteamine. 92% had received a kidney transplant 75% had hypothyroidism 69% had pulmonary dysfunction 60% had a swallowing abnormality 50% had myopathy. Gahl WA. Ann Intern Med 2007;147:242-250. A comprehensive study on the long-term impact of cysteamine
  10. 10. ESRD • ESRD was delayed in some patients who started cysteamine before 5 years of age. • But majority of these patients still developed ESRD before the age of 15 years. • The mean age at the start of ESRD being 13.4 ± 4.8 Years. Brodin Sartorius A. Kidney Int 2012;81;179-189. • Use of ACE inhibitor decrease risk of CKD in cystinosis Creco et al, Pediatr Nephrology 2010 • Kidney transplantation, Graft survival is excellent Gahl WA. Clinical Journal of the American Society of Nephrology 2006 Levtchenko E, ERKNet April 2019 (The European Rare Kidney Dis. Reference network)
  11. 11. Undesirable side effects of cysteamine • Stomach irritations, with 97% of patients reporting gastrointestinal symptoms (gastric ulcers) • Frequent doses (oral every 6 h plus eye drops once an hour) • Malodorous metabolites (persistent odor and halitosis) • Multiple drugs administration in addition to cysteamine • Lesions on the elbows and knees similar to EhlersDanlos syndrome have been reported, as well as bone lesions • Teratogenicity BUCHAN, B. E.,. Formulation studies on cysteamine for the treatment of nephropathic cystinosis. 2011http://openair.rgu.ac.uk Kleta R. Expert Opinion on Pharmacotherapy 2004;5(11:)2255-2262. Dohil R. The Journal of Pediatrics. 2010;156(1:)71-75
  12. 12. Novel Therapies • Delayed Release Cysteamine (This new formulation needs to be taken twice daily) • Suppository form of Cysteamine for infants and young children and patients with gastric intolerance • Luteolin • The other prodrugs • mTOR inhibitors • Hematopoietic stem cell transplantation • Gene therapy (readthrough agent) BUCHAN B. E. Formulation studies on cysteamine.2011 http://openair.rgu.ac.uk
  13. 13. Hematopoietic stem cell (HSC) transplantation in cystinosis • Bone marrow cell transplantation has recently been investigated for cystinosis. Mechanism of action • Engraftment of HSC in interstitium of organs → differentiation into tissue macrophages → clearance of cystine crystals • Lysosomal cross correction via tunneling nanotubes between macrophages derived from HSC and epithelial cells of recipient
  14. 14. Mechanism of in vitro lysosomal cross-correction via tunneling nanotubes. Ctns−/− fibroblasts virally transduced to express the fusion protein Lamp2-DsRed are co-cultured with macrophages expressing cystinosin-GFP. The macrophages extend tunneling nanotubes (TNTs) toward the fibroblasts and establish an intercellular connection leading to a bidirectional exchange of lysosomes between both cell types. Fibroblasts are then rescued by the presence of healthy lysosomes carrying the functional cystinosin, while macrophages help discarding cystine-loaded lysosomes Rocca CJ. Pediatr Nephrol. 2019;34:965
  15. 15. Rocca CJ. Pediatr Nephrol. 2019;34:965 Mechanism of in vivo lysosomal cross-correction via tunneling nanotubes. The rescue of PTCs requires that macrophages extend tunneling nanotubes (TNTs) crossing the TBM to deliver functional cystinosin-bearing lysosomes and may be take away the endogenous cystine-loaded lysosomes from the PTCs
  16. 16. • Post-transplant, the cystine content in the kidneys was reduced by 70%, with improved renal function and normal serum urea and creatinine levels. • The transplanted cells were also found in other tissues, including eye, brain, thyroid and liver, and in all organs the cystine content was reduced. Decrease of cystine accumulation in different tissues. Hematopoietic stem cell (HSC) transplantation in cystinosis (Syres et al. 2009, Yeagy et al. 2011, Harisson et al. 2013) (Gaide Chevronnat et al. 2016
  17. 17. • HSPC transplantation can preserve near-normal kidney, thyroid and eye architecture in cystinosis via a TNT-based transfer of functional protein. Hematopoietic Stem and Progenitor Cells (HSPCs) transplantation in cystinosis Goodman s. Molecular therapy 2016;24(1) Lobry T. Molecular therapy 2016;24(1) • Chevronnay study evaluated the benefit of HSPC transplantation in the thyroid of Ctns−/− mice. • Abundant engraftment of bone marrow-derived cells in Ctns−/− thyroid correlated with drastic decreased of cystine content, normalization of TSH level and correction of the structure of a large fraction of thyrocytes. Chevronnay HP. Molecular therapy 2016;24(1)
  18. 18. Gene therapy • Some reports raise the possibility that individuals with cystinosis who have a nonsense mutation that is transcribed into a premature termination codon (PTC) can have functional cystinosin by taking a medication that allows translation of the complete CTNS gene. • This complete translation, rather than termination of translation due to the PTC, permits readthrough (RT) of the mutated allele. • Treatment with an RT agent could not only correct the lysosomal accumulation of cysteine but also correct other defects due to cystinosis. • PTC suppression therapy allowing translational RT has the potential to treat disease due to in-frame nonsense mutations. Brasell EJ. Pediatr Nephrol. 2018 Sansanwal PJ Inherit Metab Dis 2010;33:775–786
  19. 19. • Combination therapy with a cystine-depleting drug such as cysteamine and an mTOR pathway inhibitor such as everolimus has potential to improve treatment of cystinosis. • They found that treatment with everolimus, an inhibitor of the mTOR pathway, reduces the number of large lysosomes, decreases apoptosis, and activates autophagy in cystinosis patients. May 2020, 31 (5) 962-982
  20. 20. Take home massage

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