Lysosomal storage diseases: Stem cell-based cell- and gene-therapy.

Lysosomal storage diseases (LSDs) are caused by inborn genetic defects and most affected babies show pathology in the CNS. LSDs are caused by a specific inherited enzyme deficiency that results in accumulation of substrates in the lysosomes, distension of the organelles and subsequent cellular malfunction. Currently, no effective treatment is available for most of the LSDs, because the blood?brain barrier bars entry of enzyme preparations into the brain. Treatment for LSDs can be divided into those address symptoms or those address cause. At present, successful treatments for the LSDs are enzyme replacement therapy (ERT) and cell therapy. ERT is most successful in Gaucher disease and has been approved for Fabry disease, and mucopolysaccharidosis I (MPS I). In addition, ERT for Pompe disease, MPS II, MPS VI and MPS VII has been planned and awaiting approval for treatment. Limitations in ERT include need for life-long treatment, development of antibodies, and inability to cross blood brain barrier (BBB) resulting in failure to halt disease progression in the brain. Transplantation of hematopoietic stem cells (HSCs), bone marrow stem cells (BMSCs) and umbilical cord blood-derived stem cells (UCBSCs) offer effective but limited efficacy for patients suffering from Krabbe disease, MPS VII and adrenal leukodystrophy but in other LSDs they are ineffective. Intracranial/intracerebral transplantation of genetically modified stem cells as enzyme delivery system could bypass the BBB effectively and ensure release of therapeutically beneficial amount of enzymes to affected CNS lesion sites. For this reason, stem cell-based gene therapy is the most effective treatment for LSDs. In mouse models of LSDs, genetically modified neural stem cells encoding enzyme genes effectively decreased lysosomal storage, reduced pathology and extended life span of animals. Cell-based gene therapies for LSDs bridge the application of ERT and gene therapy and are important direction to pursue in the future.