PROJECT: JTC2008: ProGen

Protecting against neurodegeneration by somatic gene therapy

Abstract

An intervention will be developed to slow down or even prevent neurodegeneration in Alzheimerïs disease through somatic gene-therapy with high therapeutic efficacy and minimal or no side-effects. Neurodegeneration will be prevented by neuron-specific inhibition of cell-cycle re-entry, a critical trigger of neuronal cell death, and will be accomplished by inhibition of CDK4 through ectopic expression of its inhibitor p16INK4A and RNA interference based gene silencing. Proof of principle for this concept has previously been provided by transgenic approaches validating the neuroprotective effects of p16INK4a expression in in vivo models of neurodegeneration. The project follows a translational approach combining preclinical expertise in R&D on viral vectors for gene-silencing in the CNS and on molecular and cellular mechanisms of neuroprotection. Existing risks with delivery of reagents for gene regulation and specific challenges posed by the CNS will be met through the development of new gene therapeutic tools for long lasting and safe transgene delivery and expression based non-integrating lentiviral vectors. Widespread but cell-type-specific targeted distribution of expression will be achieved through combination of convection enhanced delivery with neuron-specific promoters Incorporating regulable expression systems into non-integrating episomal based vectors will allow for tuning expression according to therapeutic requirements and will further enhance therapeutic safety.

Keywords

therapy, gene therapy; viral gene transfer; non-pharamcological treatment; non-amyloid based therapy

Call topic

Neurodegeneration

Proposed runtime

2009 - 2012

Project team

Thomas Arendt (Coordinator)
Germany (BMBF)
James Uney
United Kingdom (MRC)
Barbara Nawrot
Poland (NCBiR)