Brain-directed gene therapy for lysosomal storage disease: going well beyond the blood- brain barrier.

Abstract

The lysosomal storage diseases (LSDs) are a heterogeneous group of disorders that affect 1/7,000 live-born infants, the majority of which develop central nervous system (CNS) disease. Brooks et al. (1) report exciting results from Davidson's group with brain-directed gene therapy for murine mucopolysaccharidosis (MPS) VII that are likely to have general implications for the treatment of CNS disease in LSD. Each LSD results from a deficiency of a single lysosomal enzyme important for degrading macromolecules that must be turned over in lysosomes. More than 40 LSDs have been described (2). Over the past two decades, dramatic progress has been made in understanding the biogenesis, structure, and function of lysosomes and the processes by which newly synthesized acid hydrolases are assembled, processed, and transported to lysosomes. Understanding the receptors that target enzymes to lysosomes led to the development of successful enzyme replacement therapy. Understanding the receptors that target enzymes to lysosomes, some of which are expressed on the cell surface, led to the development of successful enzyme replacement therapy for one of the LSDs, Gaucher Disease, a disorder of sphingolipid degradation (3). Gaucher Disease results from deficiency of glucocerebrosidase (β-glucosidase), the enzyme involved in the last step of sphingolipid degradation. Storage of glucocerebroside in macrophages produces tremendous enlargement of spleen and liver, disabling bone involvement and occasional pulmonary incapacity. The strategy for treatment involved purification of placental enzyme and later recombinant enzyme from Chinese hamster ovary cell secretions and modification of the native enzyme to expose mannose residues on oligosaccharides. This strategy targets the infused enzyme to the mannose receptors of fixed-tissue macrophages, precisely the cells affected by the storage; receptor-mediated endocytosis delivers enzyme to the lysosomes where the substrate is stored. Over 3,500 Gaucher Disease patients have been treated since the early 1990s, and the treatment is considered a clinical …