ASO Development

Antisense oligonucleotides (ASOs) are a type of single-stranded deoxyribonucleotides, typically 12-30 nucleotides in length, which are designed to bind to the target RNA by Watson-Crick base pairing rules. The length of ASOs determines their specificity to some extent, as oligonucleotides that are 16-20 nucleotides long are capable of uniquely binding to only one target RNA^[1]. Following binding to the targeted RNA, ASOs modulate RNA function by several different mechanisms, resulting in down regulation of target protein expression. ASOs are not only a useful tool for studying loss-of-gene function and target validation, but also have high value as a new therapeutic strategy for the treatment of diseases associated with dysregulated gene expression.

With a comprehensive and state-of-the-art platform, Alfa Chemistry provides therapeutic ASO development services for customers around the world to meet new drug discovery goals.

Mechanism of Action of ASO

Numerous studies have found that the mechanism of action of ASOs can be divided into two types: (1) RNA cleavage and (2) RNA blockage. RNA cleavage includes RNase H1 mediated cleavage (1a) and RNA interference (RNAi) (1b), and RNA blockage includes steric hindrance (2a) and splice modulation (2b) (Figure 1.)^[2]. To be specific, (1a) stands for ASO-mRNA heteroduplex recruits RNase H1 enzyme and this enzyme cleaves the target mRNA; (1b) stands for mRNA degradation by siRNA associated with RNA inducing silencing complex (RISC); (2a) stands for ASO-mRNA complex sterically blocks and prevents the interaction of mRNA with ribosomes for protein translation; and (2b) is an example of splice switching oligonucleotides.

Figure 1. Mechanism of action of ASOs. (Rectangles depict the coding exon regions separated by a curve depicting the non-coding intron region of the pre-mRNA. The red square represents the mutated region of the exon. The dashed line represents the splicing pattern of pre-mRNA).

Applications of ASOs

It has been proved that ASOs are not only of great value in gene functionalization and target validation, but also a new strategy for the treatment of many diseases. The diseases they can treat are mainly as follows:

Neurodegenerative diseases

There are already several therapeutic ASOs that have been approved by the food and drug administration for muscular dystrophy diseases or neurodegenerative, such as Nusinersen for spinal muscular atrophy (SMA), Eteplirsen for Duchenne muscular dystrophy (DMD), and Inotersen for familial amyloid polyneuropathy (FAP)^[3]. And a handful of other therapeutic ASOs are in clinical trials or in preclinical development.

Amyloidosis

ASOs specific for human transthyretin (TTR) inhibit hepatic synthesis of transthyretin mRNA levels and serum transthyretin levels by as much as 80% in transgenic mouse model carrying the human TTR Ile84Ser mutation. Therefore, ASOs may provide a medical means for the treatment of systemic transthyretin amyloidosis.

Cancers

The high specificity of ASOs to bind to target mRNAs allows them to be used as therapeutic agents for the treatment of human cancers. They can be used to modulate the expression of selected genes, and to suppress malignant behavior in cancer cells.

Our Development Process

Alfa Chemistry provides therapeutic ASO development services, and the following is our main development process. No matter which stage of ASO development you encounter challenges, we will provide you with timely help.

• Target selection.
• Sequence design of ASOs.
• Synthesis and chemical modification of ASOs.
• Purification and analysis of ASOs.
• Delivery system selection or development of ASOs.
• Nonclinical evaluation of ASOs.
• Scale-up of ASOs.

Our products and services are for research use only and cannot be used for any clinical purposes.

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