Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis

Mol Ther. 2013 Feb;21(2):433-44. doi: 10.1038/mt.2012.214. Epub 2012 Oct 23.


Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in all tissues and leads to organ damage including end-stage renal disease. Using the Ctns(-/-) murine model for cystinosis, we tested the use of hematopoietic stem and progenitor cells (HSPC) genetically modified to express a functional CTNS transgene using a self-inactivating-lentiviral vector (SIN-LV). We showed that transduced cells were capable of decreasing cystine content in all tissues and improved kidney function. Transduced HSPC retained their differentiative capabilities, populating all tissue compartments examined and allowing long-term expression of the transgene. Direct correlation between the levels of lentiviral DNA present in the peripheral blood and the levels present in tissues were demonstrated, which could be useful to follow future patients. Using a new model of cystinosis, the DsRed Ctns(-/-) mice, and a LV driving the expression of the fusion protein cystinosin-enhanced green fluorescent protein (eGFP), we showed that cystinosin was transferred from CTNS-expressing cells to Ctns-deficient adjacent cells in vitro and in vivo. This transfer led to cystine decreases in Ctns-deficient cells in vitro. These data suggest that the mechanism of cross-correction is possible in cystinosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Neutral / genetics
  • Amino Acid Transport Systems, Neutral / metabolism
  • Animals
  • Blotting, Western
  • Cystine / analysis
  • Cystine / metabolism
  • Cystinosis / genetics
  • Cystinosis / physiopathology*
  • Cystinosis / therapy*
  • Disease Models, Animal
  • Female
  • Fluorescent Antibody Technique
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / pathology
  • Lentivirus / genetics
  • Luminescent Proteins / metabolism
  • Lysosomes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transduction, Genetic
  • Transgenes


  • Amino Acid Transport Systems, Neutral
  • Luminescent Proteins
  • Recombinant Proteins
  • cystinosin protein, mouse
  • enhanced green fluorescent protein
  • fluorescent protein 583
  • Green Fluorescent Proteins
  • Cystine