< Back to previous page

Project

Novel platforms for studying AAV subcellular biology & the design of improved gene therapy vectors

Adeno-associated virus (AAV) gene therapy is currently experiencing a renaissance thanks to a number of successful clinical trials. However, vector doses required to achieve therapeutic effect are high and some tissues remain difficult targets for efficient transduction. In general, gene therapy strategies directed at the brain of patients with inherited neurological or neurodegenerative disorders have shown limited efficacy. One of the main challenges for gene therapy for central nervous system (CNS) diseases is the limited distribution of AAV vectors from the injection site to the target cells. Preliminary studies have shown that mutation of a select number of amino acids (AA) in the AAV2 capsid results in a vector with enhanced transduction and significant spread in the CNS of rodent models. Comparative biodistribution studies demonstrated that this novel vector, AAV-TT, has better distribution abilities than benchmark neurotropic serotypes AAV9 and AAVrh10. Importantly, AAV-TT was the only vector able to correct a mouse model of mucopolyssacharidosis IIIC (MPSIIIC), a CNS disease caused by a lysosomal transmembrane enzyme and therefore reliant on efficient transduction throughout the brain. Here we propose a study that is aimed at delineating which mechanisms contribute to the unparalleled transduction and spread of AAV-TT in the CNS. This will be achieved by comparing the abilities of AAV2 and AAV-TT in biological assays that are designed to measure (1) cellular determinants of transduction i.e. viral attachment, cellular uptake, cytoplasmic escape, nuclear entry and uncoating; (2) interstitial transport within the brain parenchyma; (3) retro- and anterograde axonal transport within the CNS. The experiments proposed here will provide insight into the mechanisms that contribute to the increased bioactivity of AAV-TT in the CNS and will further assist the development of treatments for a group of neurological diseases that are defined by global neuropathy.

Date:1 Oct 2020 →  Today
Keywords:AAV vector, neurological disease, neurotropism
Disciplines:Gene and molecular therapy, Virology, Molecular medicine
Project type:PhD project