Adeno -associated virus vector mediated correction of a neurogenetic disease: Influence of the vector capsid on dispersal of a therapeutic gene within the central nervous system

Genetic disorders of the brain can be debilitating, causing both cognitive and motor impairments, and often resulting in premature death. Despite this, there are very few effective treatments for neurogenetic diseases. Most systemic therapies are unable to reach the brain, due to the occluding blood-brain barrier. Therapies that directly target the central nervous system (CNS) will be the most beneficial, with direct brain injections probably required to treat many of these diseases. The use of adeno-associated virus (AAV) vectors to deliver therapeutic genes to the CNS allows long-term expression without extensive inflammation or immune response. However, the number of direct brain injections of AAV vectors that are currently estimated to be needed for widespread gene dispersal in the brain is too great for this to be accepted as a suitable treatment method in the clinic. Our goal in this study was to better understand the properties of AAV vectors that can be used to result in a more widespread distribution of a therapeutic gene or protein from a limited number of injections. The amino acid sequence encoding the capsid proteins on the surface of the AAV virion is the main determinant of transduction capabilities. The capsid determines the types and numbers of cells transduced, as well as the patterns of transduction. We tested novel AAV serotypes in the mouse brain, and found that some AAV vectors have the ability to undergo vector transport along neuronal projections, which also appears to depend on the capsid proteins present. We hypothesized that injecting a transportable vector into a region with numerous projections would result in transport of the vector along those projections and thereby result in widespread dispersal of the vector with a single injection. The ventral tegmental area (VTA) is a region with widespread projections and a single small (1μL) injection of the transportable serotype AAV-9 into the VTA of mice with the neurogenetic disease mucopolysaccharidosis type VII (MPS VII) resulted in complete correction of lysosomal storage throughout the brains of these mice. An injection of AAV was also able to reverse circuit abnormalities found in the hippocampi of adult MPS VII mice, further expanding our knowledge about the extent to which an AAV vector is able to reverse disease phenotypes