Lysosomal Storage Diseases: Perspectives and Principles

Published on 04/03/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

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Chapter 20 Lysosomal Storage Diseases

Perspectives and Principles

Edward H. Schuchman, Melissa P. Wasserstein

Table 20-1 Examples of Lysosomal Storage Diseases

Treatment of Lysosomal Storage Diseases

The principle underlying the treatment of most LSDs is replacement of the missing or defective protein. This can be accomplished by stem cell transplantation, protein replacement therapy, or gene therapy. In some cases, treatments also have been developed that are either aimed at slowing the accumulation of undegraded materials (substrate reduction therapy) or enhancement of the mutant protein function (chaperone therapy). BMT has been undertaken in more than 1000 LSD patients with varying results. The premise of this approach is that stem cells in the bone marrow will repopulate in the transplanted individual and provide a source of secreted and normal lysosomal proteins that can be taken up by neighboring cells for metabolic correction (cross-correction). This approach is most effective for soluble lysosomal proteins and diseases in which cells of the monocyte–macrophage system are primary sites of pathology. However, despite the availability of cord blood registries, such cell transplantation is still limited by a high morbidity and the lack of suitable donors. Enzyme replacement therapy is also available for six LSDs and under development for several others. This approach, although effective, requires lifelong weekly or biweekly infusions of the recombinant proteins, and the costs are very high. Gene therapy approaches have been evaluated in numerous LSD animal models but are not yet available for patients. This approach, however, has also proven very effective in some disease models and could be evaluated in the clinic during the upcoming years. In general, the efficacy of any of these approaches is dependent on the cellular and tissue sites of pathology and the ability of the therapeutic proteins, stem cells, or gene therapy vectors to access these sites.

Figure 20-1 A, Typical histopathology (hematoxylin and eosin E staining) of a liver section from a patient with type B Niemann-Pick disease (NPD). Note the lipid-filled macrophages (Niemann-Pick cells) that are characteristic of this disorder. B, Micrograph of the bone marrow from the same patient with type B NPD showing the presence of an NPD cell, as well as a sea-blue histocyte. Both cells may be characteristically found in the bone marrow of these patients. C, Bruising that may be seen in type B NPD and is associated with thrombocytopenia. D, Chest radiograph of a patient with type B NPD showing the diffuse reticulonodular interstitial changes in this disorder.

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