ERANET 1 NEURON 2:Tools for long-lasting and safe CNS gene transfer

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.

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.