- 134 views
- 109 downloads
Efficacy of Novel Antisense Oligonucleotides for the Treatment of Spinal Muscular Atrophy
-
- Author / Creator
- Touznik, Aleksander
-
Spinal muscular atrophy (SMA) is one of the most common autosomal recessive neuromuscular disorders affecting the motor neurons, which usually has an early onset resulting in a rapid progression of muscle weakness, leading to death at a young age. SMA is caused by a homozygous mutation of survival of motor neuron 1 (SMN1) gene, which is the primary producer of the survival of motor neuron (SMN) protein. An SMN1 paralog, SMN2, is capable of producing approximately 10% functional full-length SMN protein. SMN2 is a duplicate gene of SMN1, however due to a new C-to-T transition, a new silencer is created which promotes the exclusion of the seventh exon in the post-transcriptional mRNA. Antisense therapy technology uses synthetic RNA-like molecules to target splice silencer sites along the SMN2 gene via Watson-Crick complementation. Once the antisense oligonucleotide (ASO) is bound, it represses the silencer function, resulting in an increase of exon 7 inclusion in the final splice form. Increased levels of full length mRNA transcripts lead to a “knock-up” of functional SMN protein. We will evaluate several ASO-based strategies for splicing correction in SMA patient cell lines and investigate ASO efficacy in the phosphorodiamidate morpholino oligomer (PMO), and locked nucleic acid (LNA) chemistries. Novel ASOs identified in this study will potentially offer improvement for the treatment of SMA in the future.
-
- Subjects / Keywords
-
- Graduation date
- Fall 2016
-
- Type of Item
- Thesis
-
- Degree
- Master of Science
-
- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.