AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy

Mol Ther. 2017 Dec 6;25(12):2727-2742. doi: 10.1016/j.ymthe.2017.08.004. Epub 2017 Aug 10.

Abstract

The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of α-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV-PHP.B-GBA1 restored physiological levels of the enzyme, reduced α-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies.

Keywords: AAV; DREADD receptors; Parkinson’s disease; Tsc1; gene therapy; neurodegenerative diseases; synucleinopathy; tuberous sclerosis.

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Electroencephalography
  • Enzyme Activation
  • Gene Expression*
  • Gene Order
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Transduction, Genetic
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism
  • beta-Glucosidase / metabolism*

Substances

  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • alpha-Synuclein
  • beta-Glucosidase