Tools for long-lasting and safe CNS gene transfer
Lead Research Organisation:
University of Bristol
Department Name: UNLISTED
Abstract
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Technical Summary
The central nervous system (CNS) poses specific challenges to gene therapy. Here we will provide solutions to meet these specific challenges and overcome existing risks with delivery of reagents for gene regulation. It is the principal aim to develop tools to induce long-lived, safe, cell-type specific and regulated transgene expression in the CNS for application in therapy of neurodegenerative disorders. Integrase-deficient non-integrating lentiviral vectors will be used for gene transfer. Widespread but cell-type-specific targeted distribution of expression will be achieved through combination of convection enhanced delivery (CED) with neuron-specific promoters. Incorporating regulatable expression systems into non-integrating episomal based vectors will allow for tuning expression according to therapeutic requirements and will, thus, further enhance therapeutic safety. Together with subprojects 2 and 3, these tools will be used to target critical molecular switches of cell cycle activation in neurons to prevent or slow down neurodegenera-tion. The modular character of the gene therapeutic tools will allow to adapt the concept in alter-native specifications for the treatment of other neurological disorders which require neuron-specific targeting.
Organisations
People |
ORCID iD |
James Uney (Principal Investigator) |
Publications
Scott H
(2017)
Recognition memory-induced gene expression in the perirhinal cortex: A transcriptomic analysis.
in Behavioural brain research
Howarth JL
(2010)
Using viral vectors as gene transfer tools (Cell Biology and Toxicology Special Issue: ETCS-UK 1 day meeting on genetic manipulation of cells).
in Cell biology and toxicology
Cordero-Llana Ó
(2015)
Enhanced efficacy of the CDNF/MANF family by combined intranigral overexpression in the 6-OHDA rat model of Parkinson's disease.
in Molecular therapy : the journal of the American Society of Gene Therapy
Mastroyiannopoulos NP
(2010)
The application of ribozymes and DNAzymes in muscle and brain.
in Molecules (Basel, Switzerland)
Lee YB
(2009)
Twist-1 regulates the miR-199a/214 cluster during development.
in Nucleic acids research
Scott HL
(2012)
MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex.
in The European journal of neuroscience
Scott H
(2012)
MiR-3120 is a mirror microRNA that targets heat shock cognate protein 70 and auxilin messenger RNAs and regulates clathrin vesicle uncoating.
in The Journal of biological chemistry
Title | viral |
Description | Novel regulatable lentiviral system |
Type Of Material | Technology assay or reagent |
Year Produced | 2009 |
Provided To Others? | Yes |
Impact | This award is part of an EU collaboration (with Thomas Arendt)and we have provided the reagents as agreed in the original grant application |