C3 transferase gene therapy for continuous conditional RhoA inhibition.
Neuroscience
; 339: 308-318, 2016 Dec 17.
Article
em En
| MEDLINE
| ID: mdl-27746349
ABSTRACT
Regrowth inhibitory molecules prevent axon regeneration in the adult mammalian central nervous system (CNS). RhoA, a small GTPase in the Rho family, is a key intracellular switch that mediates the effects of these extracellular regrowth inhibitors. The bacterial enzyme C3-ADP ribosyltransferase (C3) selectively and irreversibly inhibits the activation of RhoA and stimulates axon outgrowth and regeneration. However, effective intracellular delivery of the C3 protein in vivo is limited by poor cell permeability and a short duration of action. To address this, we have developed a gene therapy approach using viral vectors to introduce the C3 gene into neurons or neuronal progenitors. Our vectors deliver C3 in a cell-autonomous (endogenous) or a cell-nonautonomous (secretable/permeable) fashion and promote in vitro process outgrowth on inhibitory chondroitin sulfate proteoglycan substrate. Further conditional control of our vectors was achieved via the addition of a Tet-On system, which allows for transcriptional control with doxycycline administration. These vectors will be crucial tools for promoting continued axonal regeneration after CNS injuries or neurodegenerative diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Axônios
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Toxinas Botulínicas
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Terapia Genética
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ADP Ribose Transferases
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Proteína rhoA de Ligação ao GTP
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Crescimento Neuronal
Tipo de estudo:
Clinical_trials
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article