Receptor-ligand supplementation via a self-cleaving 2A peptide–based gene therapy promotes CNS axonal transport with functional recovery
| Autor: | Andrew Osborne, Peter S. Widdowson, Ilya Manyakin, Katie Hall, Tasneem Z Khatib, Zara Ali, Keith R Martin, Robert Watt, Wanyi Jia, Sujeong Yang |
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| Přispěvatelé: | Khatib, Tasneem Z [0000-0001-6576-451X], Ali, Zara [0000-0001-8442-1387], Hall, Katie [0000-0002-5612-5369], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
genetic structures
Genetic enhancement Receptor expression Tropomyosin receptor kinase B Ligands Axonal Transport 03 medical and health sciences 0302 clinical medicine Neurotrophic factors medicine Receptor Research Articles 030304 developmental biology Neurons 0303 health sciences Multidisciplinary Chemistry SciAdv r-articles Genetic Therapy medicine.disease Ligand (biochemistry) eye diseases Cell biology Dietary Supplements Axoplasmic transport Tauopathy 030217 neurology & neurosurgery Research Article Neuroscience |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.abd2590 |
| Popis: | From vision impairment to memory loss, neurotrophin and receptor supplementation using gene therapy promotes functional recovery. 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. |
| Databáze: | OpenAIRE |
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