Correction of murine mucopolysaccharidosis type IIIA central nervous system pathology by intracerebroventricular lentiviral-mediated gene delivery

Background Mucopolysaccharidoses (MPS) are inborn metabolic disorders caused by a deficiency of glycosaminoglycan degrading enzymes. Although intravenous enzyme replacement therapy is a viable approach for the treatment of non‐neuronopathic forms of MPS, its effectiveness in the central nervous system (CNS) is limited by the blood–brain barrier. Alternatively, enzyme replacement therapies and other therapies that directly target the brain represent approaches that circumvent the blood–brain barrier and, in the case of gene therapies, are intended to negate the need for repetitive dosing. Methods In the present study, gene therapy was targeted to the brains of young adult mice affected by mucopolysaccharidosis type IIIA (MPS IIIA) by bilateral delivery of two different therapeutic lentivirus vectors to the cerebral lateral ventricles. One vector expressed codon optimised murine sulphamidase, whereas the other co‐expressed sulphamidase and sulfatase modifying factor‐1. Results Six months after gene delivery, bladder distension was prevented in all treated animals, and behavioural deficits were improved. Therapeutic enzyme activity from the most efficacious vector, which was also the simpler vector, ranged from 0.5‐ to four‐fold normal within the brains of treated animals, and the average amount of integrated vector ranged from 0.1–1 gene copies per cell. Consequently, levels of ganglioside and lysosomal β‐hexosaminidase, both of which are characteristically elevated in MPS IIIA, were significantly reduced, or were normalised. Conclusions The present study demonstrates the efficacy of the intraventricular injection as a tool to target the brain with therapeutic genes in adult MPS IIIA mice, and provides evidence supporting this approach as a potentially effective means of treating CNS pathology in MPS IIIA patients. Copyright © 2014 John Wiley & Sons, Ltd.