The concept of oligonucleotide therapeutics has constantly been evolving, and currently is mainly comprised of small interfering RNA (siRNA), antisense oligonucleotide (ASO), microRNA (miRNA), activation RNA(RNAa), and aptamer, with siRNA and ASO being the two major categories of oligonucleotide therapeutics. By recognizing and inhibiting target mRNA through complementary base pairing, siRNA and ASO can regulate the expression of corresponding proteins and thereby treat related diseases. Built upon very strong technology foundation and uniquely positioned global strategy, Ribo's development pipeline of oligonucleotide therapeutics has included siRNA, ASO, and aptamer, with siRNA drugs as the major focus.
Efficient and specific delivery of siRNA has been the bottleneck for the therapeutic application of siRNA. The delivery systems based on the uptake of siRNA via interaction of conjugated N-acetylgalactosamine (GalNAc) with its receptor has tremendously accelerated the siRNA drug development for the treatment of diseases associated with any gene expression in hepatocytes. GalNAc-siRNA conjugates specifically bind to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes, and trigger fast endocytosis of the siRNA. This can result in highly specific and highly durable enrichment of the siRNA in hepatocytes. Based on similar principles, additional delivery technologies are under various stages of exploration at Ribo with the strong hope for enabling robust and versatile development of siRNA drugs for diseases related to gene expression in other organs and tissues.
Ribo has independently developed a computer software to design oligonucleotide drug sequences. Taking into consideration of sequence conservation, homology, immunogenicity and potential off-target etc., this software performs a comprehensive sequence analysis against more than 50 parameters for inter-species sequence comparison and homology assessment to rapidly select high-quality siRNA sequences with desired specificity and potential activity. Ribo has also established a platform for the high-throughput screening of oligonucleotide compounds, which are able to rapidly generate lead compounds.
Naked or unmodified oligonucleotides are highly susceptible to degradation, which associates with different degrees of their off-target effects and/or immunogenicity. Chemical modifications may affect oligonucleotide activities to various extent. Ribo scientists have systematically studied the mechanisms for siRNA degradation and correlated their potency with off-target effects. Empirical rules have been established for the chemical modifications that can significantly enhance the stability of siRNA, and lower or eliminate their off-target effects, as well as potential immunogenicity. The overall properties of our drug molecules can be greatly improved through this technology.
Based on the unique characteristics of oligonucleotides and tailored for the specific needs of drug development of oligonucleotides as new therapeutics, Ribo has established a comprehensive platform for the CMC development of oligonucleotides and GMP manufacturing capabilities to enable the development of various types of oligonucleotide therapeutics across all developmental stages. Taking a holistic approach, Ribo has developed manufacturing process and studied quality of oligonucleotide drug substance and product in a systematic manner, meeting the pharmaceutical needs for discovery, preclinical study, clinical trial application and clinical study.