What is the potential for 10 FDA-approved super 20 oligonucleotide therapies to be clinically developed?

In this article, we'll combine this article published in Nature with public information to show you the types of oligonucleotide therapy and the main challenges and coping strategies we face today.
small "body", large potential oligonucleotides are a class of short-chain nucleotides containing about 20 bases, including nucleotides in DNA or RNA.
oligonucleotides regulate gene expression through a range of processes, including gene silencing, shear regulation, non-coding RNA suppression, gene activation, gene editing, and more.
, these drugs have the potential to treat a wide range of diseases.
most oligonucleotides interact with the same target molecule through base pairing.
, nucleic acids can interact with proteins by forming three-dimensional secondary structures, a trait that is also used in the development of disease treatment drugs.
, for example, aptamers are structural nucleic acid licits that act as an antagonists or excitants for specific proteins.
same way, wizard RNA molecules containing hairpin structures can bind to the cas9 protein introduced by an exogenet and direct it to specific genomic DNA bits for targeted gene editing.
the emergence of oligonucleotide drugs makes precision and personalized therapy possible because in theory they can selectively target any gene with minimal, or at least predictable, off-target effects.
In addition, they can also target specific gene sequences in patients with rare diseases, specific allegiant genes (e.g. single nucleotide polymorphisms, etc.), pathogenic fusion transcripts, traditional "non-drugable" targets, and viral sequences that are resistant to certain oligonucleotide therapies, and so on.
these advantages and potentials make oligonucleotides the focus of current research.
10 oligonucleotide drugs approved by the FDA as drugs began about three decades ago.
as of January 2020, 10 oligonucleotide drugs have been approved for market by the FDA.
many types of oligonucleotide drugs, including anisotrine oligonucleotides (ASOs), small interfering RNA (siRNA), tiny RNA (miRNA), nucleic acid fittings, and so on.
Table 1: FDA-approved oligonucleotide drug 1, antonymical oligonucleotide antonymical oligonucleotide is a small, synthetic single-stranded nucleic acid polymer with different chemical properties, which can regulate gene expression through a variety of mechanisms.
these drugs can be subdivided into two categories: RNase H-competent and spatial block.
endogenetic RNase H enzyme RNASEH1 identifies RNA-DNA heterogeneic double-stranded substrates, and the cutting of ASO binding points leads to the destruction of the target RNA, thus silences the expression of the target gene.
next-generation RNase h-type ASOs typically follow the "gapmer" pattern, where a DNA-based central "gap" is surrounded by RNA-based flank regions that promote target binding.
note that RNASEH1 is active in both the cytocyte and the nucleus and is therefore able to target nuclear transcripts that may be difficult to obtain by other technologies.
year, three RNase H-dependent ASO drugs have been approved for market, namely fomivirsen, mipomersen and inotersen (see table 1).
space-bit oligonucleotides can be combined with the high affinity of the target transcription book, but due to the lack of RNase H capability, they do not induce target transcription degradation.
most widely used for these oligonucleotides is to regulate variable shears to selectively exclude or retain specific exons.
, however, the same technique can also be used for shearing destruction, i.e. skipping exons to interrupt the translation of the target gene.
addition, spatially blocked oligonucleotides may also be used to promote heterotype conversion, thereby reducing the expression of harmful protein heterotypes and/or promoting the expression of beneficial proteins.
as of January 2020, three shear-converted ASO drugs had been approved by the FDA: eteplirsen, golodirsen and nusinersen (see table 1).
2, small interfering RNA (siRNA) siRNA is a class of double-stranded RNA molecules: one chain becomes a guide chain (also known as an anisotym chain) that complements the target transcript, and the other chain is a chain of justice.
As part of the RNA-induced silence complex (RISC), siRNAs guide the Argonaute 2 protein (AGO2) to complement the target transcript, and under the catalysis of AGO2, the opposite position of the guide chain is cut, which in turn leads to gene silence.
at least two SiRNAs drugs, patisiran and givosiran, have been approved by the FDA.
3, micro-RNA (miRNA) miRNA is a class of non-coding single-stranded RNA molecules encoded by endogenetic genes, produced by single-stranded RNA pregenitors with hairpin structures that are processed by Dicker enzymes.
miRNA has been linked to a variety of physiological and pathological processes, including cancer, cell cycle progression, infectious diseases, immunity, diabetes, metabolism, muscle production and muscular dystrophy, making it an important target for the development of new drugs.
like siRNA, miRNA can initiate gene silencing by directing RNA-induced silent complexes (RISCs) to the target sequence.
, many companies are already developing miRNA drugs.
, for example, Regulus is developing miRNA oligonucleotide drugs targeting miR-21 and miR-17 to treat Alport nephropathy and polycystic kidney disease, respectively.
MiRagen is developing a variety of miRNA candidates: cobomarsen is an oligonucleotide inhibitor targeted at miR-155 to develop a treatment for skin T-cell lymphoma, and remlarsen is a double-stranded simulator that targets miR-29 to develop treatments for scarring (keloids).
4, transcription activates RNA Many genes express long non-coding RNA, which is usually associated with transcription inhibition of near-end protein-coding genes.
Targeting these long non-coding RNAs with ASO or siRNA (called small activated RNA) can reverse this negative regulatory effect, leading to transcriptional activation, which has been shown in many disease-related genes, including BACE1 (Alzheimer's disease), BDNF (Parkinson's disease), UBE3A (Angman syndrome) and SCN1A (Dravet syndrome), among others.
At present, the importance of endogenated small RNA in the nuclei of cells has been paid more and more attention, as a natural medium for transcription gene activation or silence, endogenated small RNA may itself constitute a target for oligonucleotide therapy.
, many companies are already developing small activated RNA.
For example, MiNA Therapeutics is developing MTL-CEBPA, a small activated RNA targeting CEBPA, a key transcription factor involved in liver cell differentiation and tumor suppression, delivered in the form of lipid nanoparticle preparations for the treatment of hepatocellular carcinoma.
, the drug is currently in the process of conducting Phase 1 clinical trials in patients with hepatocellular carcinoma and cirrhosis.
way to activate specific genes is Stoke Therapeutics' TANGO technology platform, which targets unseemly RNA shearing to increase gene expression and address single-gene diseases caused by loss or decrease in gene function.
company's current main drug candidate is STK-001.
STK-001 is an anthropotic oligonucleotide drug intended to be developed to treat Dravet syndrome.
preclinical study, STK-001 improved survival in mice and reduced the frequency of seizures in mouse models with Dravet syndrome.
currently, the drug in the study is in the process of conducting phase 1/2a clinical trials.
Drug Delivery - "Road Rover" for oligonucleotide drug development Although more than a dozen oligonucleotide therapies have been approved worldwide, the widespread use of oligonucleotide therapies still faces a major challenge in how to effectively deliver oligonucleotide drugs to target organs and tissues outside the liver.
to date, most oligonucleotide therapies, including almost all approved nucleic acid drugs, have been given locally, such as the eyes, spinal cord, and liver.
oligonucleotides are usually large hydro-hydropolymerized anions, a trait that means they are not easily passed through the membrane.
delivery to the central nervous system (CNS) is an additional challenge because oligonucleotide-based drugs often fail to cross the blood-brain barrier (BBB).
, scientists are developing many methods and techniques to solve the problem of oligonucleotide drug delivery.
chemical modification is one of the most effective methods to enhance the delivery of oligonucleotide drugs, which can be used to improve the pharmacodynamics, pharmacology and biological distribution of oligonucleotides to improve the delivery capacity of drugs.
bio-coupled is also an effective way to solve the delivery of oligonucleotide drugs.
The delivery potential of
ASOs and siRNA can be enhanced by direct co-priced coupled with different "components" including lipids, peptides, fittings, antibodies, and glycogens that make oligonucleotides more accessible to target cells.
nanotechnology and materials science also offer advantages and potential solutions to the challenges of oligonucleotide drug delivery, especially for trans-biological barriers and trans-membrane cell delivery requirements.
addition, researchers are developing new technologies such as endogenetic vesicles (i.e. exosomes), speral nucleic acids (SNAs), nanotechnology (such as DNA cages), and "smart" materials.
the advent of future oligonucleotide therapy, making it possible to treat many diseases.
many drugs indicate that the delivery of oligonucleotide drugs is now mature and clinically available for multiple indications.
According to the article, globally, there are at least 20 other oligonucleotide therapies in clinical development, with adaptations involving Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), haemophilia, hepatocellular carcinoma, and so on.
We look forward to more research and breakthroughs in oligonucleotide therapy for the benefit of more patients, with the concerted efforts of scientists, pharmaceutical companies, patient organizations and other sectors of society.
: Roberts, T.C., Langer, R. and Wood, M.J.A. (2020). Advances in oligonucleotide drug delivery. Nature Reviews Drug Discovery.[2] Stoke Therapeutics website. Retrieved Aug 26, 2020, from .3, Mao Kaiyun Chen Daming, etc. (2018). Current situation and trends in the development of oligonucleotide drugs worldwide. China Journal of Bioengineering (China Biotechnology), DOI:10.13523/j.cb.20180413 (4) the production plant of the whole pharmaceutical oligonucleotide kg class is officially put into operation. Retrieved Jan 23, 2020, from.