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Therapeutic models for Spinal muscular atrophy

School of Biological Sciences

About the Project

Our laboratory works on Gene Therapy in the Central Nervous System and Gene Repair, using novel viral vectors, gene targeting and induced pluripotent stem cells (iPSCs) as core technologies. Standard lentivectors are very efficient tools for gene therapy and gene transfer, but their integration in the host cell genome can lead to insertional mutagenesis and position effect variegation (Gabriel et al., 2009). We have recently developed integration-deficient lentiviral vectors (IDLVs) through the use of mutations in the viral integrase. Failing to integrate in the host cell genome, these vectors are instead converted into episomal circles, which lack replication signals and are diluted out through cell division (Wanisch and Yáñez-Muñoz, 2009). Gene expression from the viral episomes is transient in dividing cells but long-lived in quiescent tissues, including eye, brain, spinal cord and muscle (Yáñez-Muñoz et al., 2006; Peluffo et al., submitted).

We are particularly interested in applying these vectors to relevant models of Spinal muscular atrophy (SMA), a neuromuscular disorder affecting motor neurons. To study molecular mechanisms of disease and assess novel therapies we have produced iPSCs from several members of an SMA family whose symptoms are of varying severity. We are now seeking applicants to develop the iPSC-based models and test the efficacy of novel IDLVs for therapy of SMA. Project available immediately but only suitable to self-funded students or those in receipt of a personal fellowship; in addition, payment of bench fees will be required. For additional information please visit:


Gabriel, R., Eckenberg, R., Paruzynski, A., Bartholomae, C.C., Nowrouzi, A., Arens, A., Howe, S.J., Recchia, A., Cattoglio, C., Wang, W., Faber, K., Schwarzwaelder, K., Kirsten, R., Deichmann, A., Ball, C.R., Balaggan, K.S., Yáñez-Muñoz, R.J., Ali, R.R., Gaspar, H.B., Biasco, L., Aiuti, A., Cesana, D., Montini, E., Naldini, L., Cohen-Haguenauer, O., Mavilio, F., Thrasher, A.J., Glimm, H., von Kalle, C., Saurin, W. and Schmidt, M. (2009) Comprehensive genomic access to vector integration in clinical gene therapy. Nat Med 15, 1431-1436. doi:10.1038/nm.2057.

Peluffo, H., Foster, E., Ahmed, S.G., Lago, N., Hutson, T., Moon, L., Yip, P., Wanisch, K., Caraballo-Miralles, V., Lladó, J., McMahon, S.B. and Yáñez-Muñoz, R.J. (2011) Efficient gene expression from non-integrating lentiviral vectors in the spinal cord. Submitted.

Wanisch, K. and Yáñez-Muñoz, R.J. (2009) Integration-deficient lentiviral vectors: a slow coming of age. Mol Ther 17, 1316-1332. doi:10.1038/mt.2009.122.

Yáñez-Muñoz, R.J., Balaggan, K.S., MacNeil, A., Howe, S., Schmidt, M., Smith, A.J., Buch, P., MacLaren, R.E., Anderson, P.N., Barker, S., Duran, Y., Bartholomae, C., von Kalle, C., Heckenlively, J.R., Kinnon, C., Ali, R.R. and Thrasher, A.J. (2006) Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 12, 348-353. doi:10.1038/nm1365

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