En savoir plus

Abstract

Moderate forms of spinal muscular atrophy (SMA) are a motoneuron (MN) disease affecting neuromuscular system caused by reduced expression of survival motor neuron 1 gene (SMN1) and leading to progressive muscle weakness and death. Intravenous SMN1 gene therapy using adenoassociated virus (AAV) is currently in clinical trial for severe SMA. Systemic AAV delivery allows efficient MNs targeting leading also to transgene expression in peripheral organs, other systems affected in severe forms. Gene transfer restrict to MNs should be more appropriate for moderate SMA treatment. 

In this study, we propose to develop intra-cerebrospinal fluid (intra-CSF) AAV gene therapy for the treatment of moderate forms of SMA.

We firstly compared two routes of delivery based on intra-CSF administration, two ubiquitary and neuron-specific promoters and AAV9 and 10 in order to determine the most adapted route and vector. We demonstrate that lumbar intrathecal delivery of AAV9-neuron specific targets efficiently the MNs.

In the second part, we sought to perform proof of concept of intrathecal gene therapy in the SMNRT mice model of moderate form of SMA. Full pathological and molecular characterization was performed in order to determine the therapeutic window and to confirm the interest of these models for comparative pathology.

PhD supervisor: Marie-Anne Colle

Fundings:

- Région Pays de la Loire

- NeurATRIS

Associated publications:

• Bey K., Ciron C., Dubreil L., Deniaud J., Ledevin M., Cristini J., Blouin V., Aubourg P., Colle M.-A., Efficient CNS targeting in adult mice by intrathecal infusion of single-stranded AAV9-GFP for gene therapy of neurological disorders.Gene Therapy, 2017, 24(5):325-332. DOI: 10.1038/gt.2017.18.