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Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Osborne, Andrew 
Yang, Sujeong 
Jia, Wanyi 

Abstract

Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.

Description

Keywords

Axonal Transport, Dietary Supplements, Genetic Therapy, Ligands, Neurons

Journal Title

Sci Adv

Conference Name

Journal ISSN

2375-2548
2375-2548

Volume Title

7

Publisher

American Association for the Advancement of Science (AAAS)
Sponsorship
Wellcome Trust (104001/Z/14/Z)
Medical Research Council (MC_PC_17230)