Comparison of ventricular and intravenous lentiviral-mediated gene therapy for murine MPS VII

Abstract

Mucopolysaccharidosis type VII (MPS VII) is caused by the deficiency of the lysosomal hydrolase β-glucuronidase. Symptoms include intellectual impairment, growth retardation, visual and hearing deficits and organ malfunction. The MPS VII mouse displays most of the symptoms variously associated with the MPS disorders, and has been widely used as a developmental paradigm for gene therapy. In this study, a lentiviral vector expressing murine β-glucuronidase was delivered to 6-week-old MPS VII affected mice, either by intravenous injection, or by ventricular infusion. Therapeutic outcomes were assessed 7 months after gene transfer. Intravenous vector delivery restored liver β-glucuronidase to normal levels. Consequently, most somatic pathology was corrected, and brain pathology was reduced. In mice that received ventricular vector most brain regions appeared biochemically and histologically normal. These animals showed significantly improved behavioural performance within the open-field test. An additional positive outcome of ventricular vector delivery was the significant reduction of lysosomal storage within the eye. The blood-brain barrier is not completely impervious to lysosomal enzymes, therefore, therapeutic enzyme can be distributed widely throughout the brain via the extensive cerebral vasculature. However, improvements in somatic gene delivery and expression are required for this to be completely successful. Ventricular vector delivery cleared lysosomal storage within the CNS making this a reasonable, albeit more challenging, therapeutic option for the MPS. The best therapeutic outcomes, with possible synergistic effects within the CNS, might be expected to occur when vector delivery to the brain is used in combination with somatic gene transfer.