RNA Interference Drugs Offer Faster, More Effective Alternative to Traditional Drug Discovery

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMAug 28 2024

The process of drug discovery is often laborious and time-consuming, with problems such as lack of efficacy and unintended adverse effects leading to lower success rates. The precise fit between the drug and the target protein increases the efficacy of the drug and lowers the attrition rates.

However, this requires a comprehensive understanding of the protein structure, which is not knowledge that can be transferred to the discovery and development of another drug.

A recent article published in Nature portfolio reported the development of ribonucleic acid (RNA) interference-based drugs by Alnylam Pharmaceuticals, Inc.

These drugs target the RNA transcripts of the target genes instead of the proteins, providing a faster alternative to traditional drug discovery methods and increasing the success of clinical trials.

​​​​​​​Study: How the RNAi therapeutic ‘operating system’ is rewriting drug discovery. Image Credit: luchschenF/Shutterstock.com

RNA Interference

The central dogma in molecular biology dictates that genetic information that is stored in the deoxyribonucleic acid (DNA) is converted or

transcribed into messenger RNA (mRNA), which is then translated by ribosomes into proteins. These proteins are the functional molecules of most biochemical processes, including tissue repair, hormonal and enzymatic activity, and the development of organs.

RNA interference, also known as post-transcriptional gene silencing, is a naturally occurring biological process that regulates gene expression by using double-stranded RNA to target mRNAs and deactivate them.

Therapeutic methods involving RNA interference use synthetic small interfering RNAs or siRNAs that have a complementary sequence to the target mRNA and can bind to this mRNA and silence it. This technology can be used to deactivate any gene that is involved in disease pathways effectively.

RNA Interference Therapeutics

Targeting the mRNA instead of the protein allows RNA interference-based drugs to function upstream of most traditional classes of medicines, including monoclonal antibodies and small molecule drugs, which target the proteins.

Furthermore, siRNAs can be designed to target not only mutated genes involved in disease pathology but also the mRNAs of any other proteins that might not be directly responsible for the disease but are involved in pathways associated with the disease.

This broadens the scope of RNA interference therapeutics to address complex human diseases that are not caused by specific single gene mutations, such as hypertension and hypercholesteremia.

To streamline and accelerate the development of RNA interference therapeutics, Alnylam Pharmaceuticals developed a platform that uses knowledge of the target gene sequence and the target cell or tissue for siRNA delivery to rapidly design new complementary siRNAs and test these drugs on the target tissues or cells.

This platform significantly accelerates the drug discovery process and allows the design knowledge to be transferred to the development of siRNAs for other target genes.

Compared to traditional drug discovery methods, using Alnylam’s RNA interference platform circumvents the need to start the development process from scratch for every new drug.

Benefits and Drug Delivery

Six RNA interference-based drugs have already been approved by the United States (U.S.) Alnylam Pharmaceuticals has developed the Food and Drug Administration (FDA) and five of these.

Furthermore, not only is RNA interference-based therapy well tolerated by patients but it can also be administered infrequently in injection form. This presents a significant advantage over other pill-based medications, which require long-term adherence to medication regimens, especially for chronic conditions.

However, the delivery of RNA interference-based drugs to the appropriate target tissue has been a significant challenge. Compared to small molecule drugs, siRNAs are much larger and negatively charged, which makes it difficult for the siRNA to traverse the cell membrane. Furthermore, it can trigger the host’s immune responses and degrade easily.

The scientists at Alnylam Pharmaceuticals have explored various methods to improve the delivery of siRNAs, including the use of siRNAs encapsulated in lipid nanoparticles and conjugate molecules that attach to the siRNAs and guide them toward the target tissue.

The use of N-acetylgalactosamine or GalNac has improved the delivery of siRNAs to the liver, and the subsequent development of C16 conjugates, consisting of carbon molecule chain attached to the siRNA, have improved the potential for successful drug delivery into the cells of the central nervous system.

One of Alnylam’s candidate RNA interference drugs for Alzheimer’s disease that targets the mRNA in the central nervous system is being tested in phase I clinical trials.

Conclusions

Overall, Alnylam’s RNA interference therapeutics have significant potential advantages over traditional and small molecule drugs since they do not rely on accurate matches between the drug and the target protein structure for efficacy.

Furthermore, the standard chemical and physical properties of siRNAs make them easily adaptable and applicable for various gene targets, substantially reducing the costs and time required for drug discovery.

The scientists at Alnylam believe that this technology can address some of the most challenging and complex human diseases and impact millions of lives.