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.
2. Novel Therapy for Cystinosis
Masoumeh Mohkam, MD
Professor od Pediatric Nephrology, Shahid Beheshti
University of Medical Sciences, Tehran, Iran.
June 2020
3. 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
6. De Toni –
Debré –
Fanconi
syndrome
characterized by a
severe fluid and
electrolyte
disturbance,
growth
retardation, and
rickets.
7. 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
9. 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.
10. 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
11. • 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
12. 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)
13. 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
14. 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
15. 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
16. 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
17. 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
18. • 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
19. • 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)
20. 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
21.
22. • 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
