title: Gene therapy for the neurological manifestations in lysosomal storage disorders.
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.
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA 01701-9322.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000628:therapy*; D014161:Transduction, Genetic
keywords: adeno-associated virus; hematopoietic stem cells; inherited metabolic diseases; lentivirus; neurodegenerative diseases