Thematic Review Series: Recent Advances in the Treatment of Lysosomal Storage Diseases: Gene therapy for the neurological manifestations in lysosomal storage disorders |
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Authors: | Seng H Cheng |
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Institution: | Genzyme, a Sanofi Company, Framingham, MA, 01701-9322 |
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Abstract: | Over the past several years, considerable progress has been made in the development of gene therapy as a therapeutic strategy for a variety of inherited metabolic diseases, including neuropathic lysosomal storage disorders (LSDs). The premise of gene therapy for this group of diseases is borne of findings that genetic modification of a subset of cells can provide a more global benefit by virtue of the ability of the secreted lysosomal enzymes to effect cross-correction of adjacent and distal cells. Preclinical studies in small and large animal models of these disorders support the application of either a direct in vivo approach using recombinant adeno-associated viral vectors or an ex vivo strategy using lentiviral vector-modified hematopoietic stem cells to correct the neurological component of these diseases. Early clinical studies utilizing both approaches have begun or are in late-stage planning for a small number of neuropathic LSDs. Although initial indications from these studies are encouraging, it is evident that second-generation vectors that exhibit a greater safety profile and transduction activity may be required before this optimism can be fully realized. Here, I review recent progress and the remaining challenges to treat the neurological aspects of various LSDs using this therapeutic paradigm. |
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Keywords: | neurodegenerative diseases adeno-associated virus lentivirus hematopoietic stem cells inherited metabolic diseases |
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