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As we know, there are three major categories of medicines according to their sources, including natural medicines, chemically synthesized drugs, and biological therapeutics.

Among them, biological therapeutics (aka. biologics) are drugs developed and manufactured through biotechnology, such genetic engineering, cell engineering, and protein engineering. Two major categories of biopharmaceuticals have been small molecule- and protein/antibody-based biologics.

Recently, fueled by the global use of mRNA-based COVID-19 vaccines and nucleic acid-based testing for the SARS-CoV-2 virus, the new wave of nucleic acid-based medicine development and production has started taking off (pdf). Furthermore, the increasing number of nucleic acid drugs approved by the U.S. Food and Drug Administration (FDA) demonstrates the potential to treat diseases by targeting the genes responsible for them.

What Are Nucleic Acid Therapeutics?

Nucleic acid therapeutics are based on nucleic acids or closely related chemical compounds, and they are completely different from small molecule drugs and antibody drugs.

Instead of targeting protein causes of diseases, they target disease on a genetic level.

Nucleic acid drugs are currently classified into four categories, including medicines based on antisense oligonucleotides (ASOs), small interfering nucleic acids (siRNAs), microRNAs (miRNAs), and nucleic acid aptamers (aptamers).

siRNA and miRNA drugs are called RNA interference (RNAi) medicines.

ASO and siRNA drugs have been approved, and both mainly act on cytoplasmic messenger RNAs (mRNA) to achieve regulation of protein expression through base complementary recognition and inhibition of target mRNAs for the purpose of treating unmet medical needs.

How Do Nucleic Acid Therapeutics Work?

According to the central dogma of molecular biology, DNA is transcribed into RNA, which is then translated into proteins. In some specific cases, RNA can be reverse transcribed into DNA. So, we can see that RNA is critical, because it determines what proteins can be expressed.

Therefore, scientists are trying to see if the process of gene expression can be regulated. That is, instead of interfering at the DNA level, scientists try to regulate the RNA, which is produced in the nucleus and then moves to the cytoplasm. The production of proteins is also carried out in the cytoplasm. If drugs can be absorbed by cells, enter the cytoplasm, and influence the process of translating RNA into proteins, then these drugs can also treat related diseases.

Nucleic acid drugs are designed around this rationale to interfere with the synthesis of disease-causing proteins to treat certain diseases.

ASO is a single-stranded oligonucleotide molecule that enters the cell and binds to the target mRNA through sequence complementation. Then, under the action of ribonuclease H1 (RNase H1), this piece of RNA will be degraded and the expression of the disease-causing proteins will be inhibited consequently.

Both siRNA and miRNA treat diseases through RNA interference, but their molecules have different properties.

siRNAs are encoded by transposons, viruses, and heterochromatin; whereas miRNAs are encoded by their own genes.

miRNAs can regulate different genes, while siRNAs are called the “silencing RNAs,” as they mediate the silencing of the same or similar genes from which they originate.

miRNAs are single RNAs and have an imperfect stem-loop secondary structure.

siRNA is a class of double-stranded short RNA molecules that bind to specific Dicer enzymes to degrade one strand. Then the other strand will bind to other enzymes including Argonaute Proteins (AGO) to assemble into a RNA-induced silencing complex (RISC).

In the RISC, the single strand RNA will bind to a target mRNA through the principle of base complementary pairing. Subsequently, the target mRNA will be degraded in the RISC complex, thus blocking the expression of the target protein for the purpose of treating a disease.

This mechanism of inhibiting protein expression via siRNA is called RNA interference. The scientists that had discovered RNA interference—gene silencing by double-stranded RNA—were awarded the Nobel Prize in Physiology or Medicine in 2006.

ASO Drugs

In terms of therapeutic areas, ASO drugs are mostly developed to cure cancers, infections, as well as neurological, musculoskeletal, ocular, and endocrine diseases.

For instance, fomivirsen, manufactured by Ionis/Novartis, was the first FDA-approved ASO drug, and it is currently used as a second-line treatment for cytomegalovirus (CMV) retinitis. Second-line treatment is used after the first-line (initial) treatment for a disease or condition fails or has intolerable side effects.

Several ASO drugs are also used for treatment of certain rare diseases, including Kynamro (phosphorothioate oligonucleotide drug for the treatment of the rare disease of Homozygous familial hypercholesterolaemia [HoFH]), Exondys 51 (for the treatment of a rare disease called Duchenne muscular dystrophy [DMD]), and Spinraza (for the treatment of spinal muscular atrophy [SMA], a rare inherited disease).

Prior to the development of these medicines, these rare diseases didn’t have any effective drugs for treatment.

siRNA Drugs

siRNA drugs’ therapeutic areas include cancers, infections, as well as neurological, ocular, endocrine, gastrointestinal, cardiovascular, dermatologic, and respiratory diseases.

For instance, patisiran, produced by Alnylam/Genzyme, is the first siRNA drug, and it is used for the treatment of polyneuropathy caused by hereditary transthyretin amyloidosis (haTTR). And the world’s second siRNA drug, Givlaari, produced also by Alnylam, was designed and developed for the treatment of acute hepatic porphyria (AHP), which is a family of ultra-rare disease in adults.

The main manufacturer of ASO drugs is the California-based Ionis Pharmaceuticals. The other major ones include ProQR, Sarepta, WAVELife Sciences, Biogen, and Exicure.

The largest manufacturer of siRNA drugs is Alnylam, a Massachusetts-based biopharmaceutical company specializing in the development and manufacturing of RNA interference therapeutics. The other major producers of these medicines include Dicerna, Quark, and Arrowhead.

Very New Drugs

In terms of the current status of ASO drug development, most of the therapeutics are in the preclinical stage, with their therapeutic areas mainly focused on oncological, neurological, and muscular diseases. The second largest group of ASO drugs are still in their discovery stage, during which medicines are being designed and undergoing preliminary experiments.

The situation with siRNA drugs (pdf) is similar to that of ASO medicines, with the largest group of medicines being in the preclinical stage, and the second largest group in the discovery stage. Currently, five siRNA drugs have been approved, including patisiran, givosiran, inclisiran, lumasiran, and vutrisiran. In addition, around a dozen other drugs are in late stages of phase III clinical trials.

Therefore, in both categories, only a small percentage of drugs have already been launched.

The Advantages of Nucleic Acid Drugs Over Conventional Medicines

Nucleic acid drugs are considered novel therapeutic modalities, as they have great potential to treat diseases that cannot be treated effectively in the past, such as certain cancers, and some rare diseases for which no small molecule or protein/antibody-based biologics were developed.

In comparison with small molecule drugs and antibody-based biologics, nucleic acid-based therapeutics have high specificity towards RNAs.

Furthermore, they have simple designs and rapid and cost-effective development cycles (which would later translate into lower costs for patients), as their preclinical research and development starts with gene sequence determination and reasonable designs for disease genes, the genes can be targeted and silenced, thus avoiding unnecessary development and greatly saving research and development time.

They can also quickly alter the sequence of the mRNA construct for personalized treatments or to adapt to an evolving pathogen. In addition, they have abundant targets, so they can potentially make a breakthrough for some special targets that were previously “undruggable,” to treat certain genetic diseases. And the RNA interference technology has already matured in terms of target selection and small RNA segment synthesis.

Commonly Used Nucleic Acid Drug Delivery Systems

However, getting the small RNA segment generated is only the initial step of drug development. In order for nucleic acid drugs to be applied clinically, the next important issue is delivering the nucleic acids to target tissues and cells. Since nucleic acids are highly hydrophilic and polyvalent anionic, it is not easy for cell uptake.

The selection of different delivery mechanisms of genes or RNA agents can impact the increase or decrease the expression of proteins in a cell.

The commonly used (pdf) nucleic acid drug delivery systems include drug conjugates (such as antibody-siRNA conjugates and cholesterol-siRNA conjugates), lipid-based nanocarriers (such as stealth liposomes and lipid nanoparticles), polymeric nanocarriers (such as nanoparticles base on degradable or non-degradable polymers and dendrimers), inorganic nanocarriers (such as silica nanoparticles and metal nanoparticles), carbon-based nanoparticles, quantum dots, and natural extracellular vesicles (ECVs).

ADRs and Potential Risks of Nucleic Acid Therapeutics

Just like almost all drugs, nucleic acid therapeutics also have side effects and risks, some of which stem from their delivery methods.

The common adverse drug reactions (ADRs) of FDA-approved ASO drugs include injection site reactions (e.g. swelling), headache, pyrexia, fever, respiratory infection, cough, vomiting, and nausea (pdf). Individual ASO drugs have their own respective side effects. For instance, fomivirsen can potentially increase intraocular pressure and ocular infection. Pegaptanib can cause conjunctival hemorrhage, corneal edema, visual disturbance, and vitreous floaters. The ADRs of mipomersen (Kynamro) resemble flu symptoms. Nusinersen can cause fatigue and thrombocytopenia. And inotersen can also cause contact dermatitis.

Users of ASO drugs should also be aware of hepatotoxicity, kidney toxicity, and hypersensitive reactions (pdf).

Inotersen (Tegsedi) even carries black box warnings, which are required by the FDA for medications that carry serious safety risks, against its severe side effects, including thrombocytopenia, glomerulonephritis, and renal toxicity. Furthermore, users of inotersen are warned against possible reduced serum vitamin A, stroke, and cervicocephalic arterial dissection.

Side effects of siRNA drugs are similar to those of ASO drugs, including nausea, injection site reactions, heart block, vertigo, blurred vision, liver failure, kidney dysfunction, muscle spasms, fatigue, abdominal pain, and the potentially life-threatening anaphylaxis.

Specifically, during clinical trials of givosiran, one siRNA drug, 15 percent of subjects reported alanine aminotransferase (ALT) elevations three times above the normal range, and 15 percent reported elevated serum creatinine levels and reductions in estimated Glomerular Filtration Rate (eGFR), both signs of poor kidney function. Therefore, liver and kidney toxicity was reported during these clinical trials.

The use of siRNA drugs by pregnant mothers may entail risks for their unborn children. So far, although data on using givosiran, patisiran, and lumasiran have not been reported, certain ADRs of these drugs can serve as warning signs for use during pregnancy. For instance, patients using patisiran (Onpattro) will experience a reduction in their vitamin A levels. Vitamin A is essential for the unborn baby’s developing organs such as eyes and bones, as well as its circulatory, respiratory, and central nervous systems. Also, givosiran is shown to cause unfavorable developmental effects on animals. Furthermore, inclisiran therapy is not recommended for pregnant mothers, as it may harm the fetus.

Challenges of Nucleic Acid Drugs

In order for nucleic acid drugs to be effective, their design and development need to overcome a number of challenges, such as nuclease degradation, short half-life, immune recognition in circulation, accumulation in target tissues, transmembrane transport, and endosomal escape. Although nuclease stability and avoidance of immune recognition can be greatly reduced by combining chemical modifications, other problems remain to be solved.

Since carrier systems can greatly solve the problems that cannot be solved by chemical modifications and enhance the effectiveness and safety of nucleic acid drug therapeutics, these carrier systems are considered by many as the most important for development and overcoming the aforementioned challenges.

Currently, siRNA drug development faces several challenges (pdf), such as efficacy in siRNA delivery, safety, biocompatibility/biodegradability, and issues of their production, standardization, and approval as multi-component systems.

For example, in the case of lipid nanoparticles (LNPs; one type of lipid-based nanocarriers), only 1 to 2 percent of the internalized siRNAs are released into the cytoplasm. Therefore, research should be focusing on making nanoparticles capable of increasing the release of siRNAs.

However, it should also be noted that the safety, biodistribution, biokinetics, clearance or accumulation of LNPs in different tissues and organs are not well characterized for different types of LNPs.  Therefore, the side effects or adverse reactions triggered by this delivery system should also be carefully studied.

The unprecedented global usage of mRNA vaccines under the context of pandemic has given a very unusual momentum to drive more RNA-based therapeutic development.  However, clear and calm minds are still needed to see the challenges and explore the safety and risks issues comprehensively and longitudinally for any newly designed RNA-based therapeutic drugs.


source: The Epoch Times

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