Chapter 14. Lysosomal Storage Disorders

Summary

Lysosomal storage disorders are characterised by the inability of lysosomal hydrolytic enzymes to degrade macromolecules or by the failure to transport the products into the cytosol. There is substantial variation in the age of clinical onset; for gene therapy, the correct defect must be identified before the pathology becomes irreversible. Metachromatic leukodystrophy is due to a sulphatase deficiency and restoration of only 1-5% of the normal enzyme level confers clinical benefit. Enzyme replacement and bone marrow transplantation are current treatment options. Most of the genes concerned have been cloned and the small cDNAs (less than 5 kb) are suitable for use in retroviral vectors. Approaches tested in animals include implantation of ‘neo-organs’ containing transduced fibroblasts and genetic manipulation of primary lymphocytes or autologous bone marrow. Direct targeting of the CNS has been tried with adenovirus and herpes simplex virus and the future use of neural stem cells shows promise.