In recent years, nucleic acids have emerged as extremely promising drug candidates for the treatment of a wide range of diseases, including pancreatic cancer (PC). Antisense oligonucleotide (ASO) drug is one of many nucleic acid drugs and the first FDA-approved nucleic acid drug. Here, we offer ASO drug development services for PC, mainly including ASO molecular size and sequence design, ASO manufacturing, and ASO chemical modifications.
Overview of ASO drugs
ASOs are short single-stranded RNA/DNA sequences, usually between 16-21 nucleotides in length. Based on Watson-Crick base pair interactions, ASOs with sequences bind specifically to RNA encoding the target gene, forming a DNA/RNA double-stranded structure that regulates gene expression. By targeting the genes for mRNAs (including pre-mRNA or mRNA), ASOs can post-transcriptionally regulate protein synthesis. Specific mechanisms include modification of pre-mRNA processing and splicing, steric blocking of the translation machinery, competitive repression, and degradation of bound target RNAs. The ability to interact with pre-mRNA allows ASO to target the splicing process and significantly increases the number of RNA sequences that can be selected for ASO binding as well as limits off-target effects. After recognition and binding to mature mRNA, ASO not only causes steric site blocking by forming a strong double-stranded structure, but also recruits RNase H1(DNA: RNA duplexes) or Argonaute 2 ( RNA: RNA duplexes) leading to endogenous RNA degradation. In addition to binding to mRNAs, ASOs can also target miRNAs, and these ASOs are often referred to as antimir or antagomir.
Fig. 1 For ASOs, backbone, sugar or nucleobase modifications of approved ASO therapeutics enhance affinity to target RNA, improve nuclease resistance, alter circulation characteristics and modulate immunological properties. (Kulkarni, Jayesh A., et al., 2021)
The service offering at Alfa Cytology
- ASO molecular size and sequence design
ASO-RNA binding is rigorously regulated by the complementarity between the intact ASO molecule and the target RNA, which directly correlates with ASO efficacy and off-target binding toxicities. With our extensive experience and advanced platform, our services enable accurate molecular size and sequence design of ASOs, minimizing the toxicity associated with off-target binding.
- ASO manufacturing
The quality of raw materials is important for the synthesis of consistently high-quality ASO. With our extensive experience in organic synthesis, accumulated years of advanced nucleic acid drug process development, and established and managed reliable supply chain of high-quality raw materials, we are able to provide high-quality ASO.
- ASO chemical modifications
Due to the instability of RNA/DNA, various chemical modifications have been applied to improve pharmacokinetics and pharmacodynamics, maintain target affinity and efficacy, ensuring the applicability of ASO as a nucleic acid drug. Our services provide chemical modifications of ASO nucleosides, nucleobases, and the internucleoside backbone, and common modifications, such as phosphorothioate modification and sugar modification.
- Other modifications
-Alter nucleoside connectivity and restrict ASO stereochemistry
-Change the backbone charge
-Link ASOs to ligands
- Multiple targets to support ASO drug development for PC
- KARS point mutations
- Bcl-2 family
- Vascular endothelial growth factor
- X-linked inhibitor of apoptosis protein
-Heat shock protein
-miRNA-21
Alfa Cytology is an integrated research, development, and manufacturing organization providing scientific services, primarily ranging from early discovery and development to preclinical research. We provide ASO drug development services to our global clients as part of our comprehensive portfolio of nucleic acid drug development for PC. If you are interested in our services, please contact us for more details. We look forward to working with you on your next project.
References
- Yamada, Yoji. "Nucleic Acid Drugs-Current Status, Issues, and Expectations for Exosomes." Cancers 13.19 (2021): 5002.
- Kulkarni, Jayesh A., et al. "The current landscape of nucleic acid therapeutics." Nature Nanotechnology 16.6 (2021): 630-643.