Antisense Oligonucleotide Development for Treatment of Spinal Muscular Atrophy
T2014-166 The SMN2 gene contains sequences that regulate the level of inclusion of SMN exon7 in SMN mRNA, and some of these act in a negative manner. Antisense oligonucleotides to block the negative regulating protein binding to these sites can increase inclusion of SMN exon 7 and thus, the amount of SMN being produced.
Spinal muscular atrophy (SMA) is a genetic disorder that affects the control of muscle movement. It is caused by a loss of motor neurons in the spinal cord and brainstem, leading to weakness and atrophy in the muscles used for walking, crawling, sitting up, and head movement. In severe instances, SMA can affect the muscles used for breathing and swallowing. It affects 1 in 10,000 new births. In SMA, the survival motor neuron 1 gene (SMN1) is lost or mutated and SMN2 is retained. This leads to less SMN protein and the development of SMA. Restoring the protein levels at the correct time has a major impact on the SMA phenotype. Some sites have been developed for the current approved antisense therapies of SMA. However, it is important to have additional targeted sites to allow improved antisense treatment that do not conflict with the current site being used.
Researchers at The Ohio State University have developed a series of antisense oligonucleotide (ASO) to increase SMN levels in SMA. The ASOs disrupt the binding of proteins that inhibit the inclusion of SMN exon 7 into the mature mRNA and thus increase the amount of full length SMN produced by SMN2.
- Antisense Therapy
- Addresses more than one nucleotide region that when targeted with an antisense can increase SMN levels.
- Promising results in mouse model.