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Published on: February 15, 2019
Comparison of ventricular and intravenous lentiviral-mediated gene therapy for murine MPS VII
Julie Bielicki1, Chantelle McIntyre, Donald S Anson
1Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA, 5006, Australia.
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.
Insights
Gene therapy using lentiviral vectors successfully treated Mucopolysaccharidosis type VII (MPS VII) in mice. Both intravenous and ventricular delivery improved symptoms, with ventricular delivery showing promise for central nervous system effects.
Area of Science:
- Lysosomal storage disorders
- Gene therapy
- Neurology
Background:
- Mucopolysaccharidosis type VII (MPS VII) is a rare genetic disorder caused by a deficiency in the lysosomal enzyme β-glucuronidase.
- MPS VII leads to severe symptoms including intellectual impairment, growth retardation, and organ dysfunction, making the MPS VII mouse a key model for gene therapy research.
Purpose of the Study:
- To evaluate the efficacy of lentiviral vector-mediated gene therapy for MPS VII in mice.
- To compare the therapeutic outcomes of intravenous versus intraventricular delivery of a β-glucuronidase-expressing lentiviral vector.
Main Methods:
- Lentiviral vectors encoding murine β-glucuronidase were administered to 6-week-old MPS VII mice via intravenous injection or direct ventricular infusion.
- Therapeutic effects were assessed 7 months post-gene transfer, focusing on biochemical correction, histological changes, and behavioral performance.
Main Results:
- Intravenous delivery normalized liver β-glucuronidase levels, correcting somatic pathology and reducing brain pathology.
- Ventricular delivery resulted in normal biochemical and histological brain regions, significantly improved open-field test performance, and reduced ocular lysosomal storage.
- While systemic delivery showed promise, CNS-specific improvements were more pronounced with ventricular delivery, suggesting its potential for neurological aspects of MPS VII.
Conclusions:
- Lentiviral vector gene therapy is effective in ameliorating MPS VII symptoms in mice, with distinct benefits from different delivery routes.
- Ventricular delivery offers a promising, though technically challenging, approach for targeting CNS pathology in MPS VII.
- Combination therapy, integrating brain-specific vector delivery with systemic gene transfer, may offer the most comprehensive therapeutic outcome for MPS VII.
