P 326. Developments in Stem Cell Transplantation in Lysosomal Storage Diseases—An Update on the Example of Mucopolysaccharidoses
30 October 2018 (online)
Background: Lysosomal storage diseases (LSDs) are a heterogeneous group of disorders and include ∼50 diseases, including mucopolysaccharidoses (MPS) with eight subtypes. A deficiency of lysosomal enzymes or transport and activator proteins in the lysosome leads to a reduced degradation of various substrates, for example, glycosaminoglycans, which accumulate in the lysosome, cause progressive cell damage and consecutively multiorgan diseases of variable severity. The neuronal, skeletal, and cardiac systems are particularly affected. Currently, there are four different therapeutic approaches for the treatment of some LSDs: enzyme replacement therapy (ERT), substrate reduction therapy, chaperone therapy, and stem cell transplantation. While the former are relatively new and gene therapy is being tested as a future therapeutic approach, allogeneic stem cell transplantation (SCTT) has been used since the 1980s.1
Goals/Questions: Based on our statement for the GNP in 2011,2 we provide an update focusing on MPS and the role and possible application of SCCT in LSD in the context of other therapeutic options and current developments.
Methods: Selective literature research in PubMed and print media on LSD with focus on MPS since 2011.
Findings: Allogeneic hematopoietic SCTT were performed in 19 LSD with varying success (for MPS in types I, II, VI, and VII). Larger studies exist for six LSD, otherwise individual case reports. For MPS TypIH, M. Hurler, the largest clinical experience, supported by studies, is available.3 Treating children under 2 years with M.Hurler, SZT is gold standard. The outcome is best with early transplantation but without effect on the musculoskeletal system. Regarding the survival rate, significant progress has recently been made (81% after 8 years/95.2% after 5 years).4 ERT before/during SZT has a positive effect on cardiac and cognitive function.5
Although SZT partially leads to a milder course in MPS II, IV, and VI, ERT is favored here and also in mild MPS I. In MPS II, the SZT has no effect on cognitive deterioration. However, a recent retrospective comparative study questions the superiority of ERT over STZ in MPS II.6 For MPS III, SZT is not recommended due to lack of effect.7
In addition to existing therapies, further therapeutic options are continuously being researched. An example is the transplantation of neuronal and mesenchymal stem cells in preclinical studies, aiming at reaching the nervous system or bradytrophic tissue more specifically than with hematopoietic stem cells. The results are partly promising as well as showing challenges such as the engraftment of the transplanted cells.8 The combination of SZT and gene therapy, in which, for example, autologous stem cells are corrected by gene therapy and then transplanted, is the subject of intensive research and an interesting future therapeutic approach.
Conclusion: All currently existing therapeutic approaches show different advantages and disadvantages. A complete cure cannot yet be achieved, although the continuous development of new and existing therapies gives good reason for hope. Further studies are needed to improve the comparability of the different therapies.
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Siddiqi et al. JHHum Gene Ther 2016