Antisense oligonucleotides in therapy for neurodegenerative disorders

Abstract

Antisense oligonucleotides are synthetic single stranded strings of nucleic acids that bind to RNA and thereby alter or reduce expression of the target RNA. They can not only reduce expression of mutant proteins by breakdown of the targeted transcript, but also restore protein expression or modify proteins through interference with pre-mRNA splicing. There has been a recent revival of interest in the use of antisense oligonucleotides to treat several neurodegenerative disorders using different approaches to prevent disease onset or halt disease progression and the first clinical trials for spinal muscular atrophy and amyotrophic lateral sclerosis showing promising results. For these trials, intrathecal delivery is being used but direct infusion into the brain ventricles and several methods of passing the blood brain barrier after peripheral administration are also under investigation.

Novel Targeted Therapy for Precursor B-Cell Acute Lymphoblastic Leukemia: Anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate

“…Interestingly, the same phenomenon (early MXD3 protein knockdown without confirmation of mRNA knockdown) was observed with several different MXD3 ASO sequences (data not shown), as well as MXD3 siRNA (47,48), with or without αCD22 Ab as a vehicle. These data suggest that the ASO conjugate may mediate MXD3 translational inhibition and thus would explain the inability to detect a reduction in MXD3 transcript levels (59,60). MXD3 is a transcription factor, with a short half-life of only up to 30 min in Reh cells (unpublished data).…”

Antisense Oligonucleotides as Therapeutics and their Delivery

“…It can also bind to any other region of the target mRNA providing stearic hindrance for the ribosomes. As a result, the ribosomes cannot traverse along the mRNA and hence protein synthesis is altered 5 .…”

“…This enables the As-ODN to be recycled, leading to a long-lasting effect; thus it can be used in micro or nanomolar concentrations 1 . Recognition of As-ODN by RNase H depends on the chemical structure of the oligonucleotide 5 .…”

“…The first major challenge is the action of nuclease enzyme that causes rapid degradation of oligonucleotides and hence reduces their efficacy. A 3-to 5-exonuclease degrades naked As-ODNs within 30 min in serum, while intracellular exonucleases and endonucleases degradade the oligonucleotide even in a shorter time span 5 . The second major challenge is limited cellular uptake.…”

“…As-ODNs can also be used for restoring or modifying proteins by interfering with premRNA splicing 5 . They are also being exploited for the treatment of various diseases where protein synthesis is dysregulated, e.g.…”