Adenoviral vector encoded antisense oligonucleotides as a new therapeutic strategy for Spinal Muscular Atrophy

• Applicant: Dr. Till Geib
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 24266021

Spinal Muscular Atrophy (SMA) is a motorneuron disease caused by dysfunction of the Survival of Motorneuron (SMN) gene. The human SMN gene is present in two copies, SMN1 and SMN2. SMN1 primarily produces the full-length form of SMN, whereas differential splicing of the SMN2 pre-mRNA predominantly leads to an isoform lacking exon 7 (SMN(7). This is due to a single nucleotide C to T base difference in exon 7, resulting in the production of low levels of functional SMN protein. All individuals with SMA have retained their SMN2 allele. Therefore, therapy directed towards increasing full length protein expression from the SMN2 gene could prove promising in lowering the clinical severity of SMA. We developed an antisense oligonucleotide-based strategy to modulate SMN2 pre-mRNA splicing in favor of exon 7 inclusion. The objective of the present research proposal is to incorporate this technology into viral vectors for efficacy testing in cell clines and in animal models. The central hypothesis tested here proposes that sufficient quantities of viable SMN protein can be generated from the SMN2 locus by the administration of these gene therapy tools.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Dr. Klemens Hertel