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RNA-Based Therapies Meet the 21st Century

This post is cross-posted with Berkeley Scientific Journal 

Thousands of medications exist to counteract effects of various proteins and enzymes.
Thousands of medications exist to counteract effects of various proteins and enzymes.

We have all taken aspirin for minor aches, known someone who takes simvastatin to control elevated cholesterol, or are related to someone with hypertension who is prescribed ACE inhibitors for treatment. Most medications and over-the-counter drugs like these target enzymes (specialized proteins) that are directly involved in producing effects such as pain and elevated cholesterol levels.

Targeting RNA

Although most medications rely on targeting appropriate enzymes for specific treatment, a new class of therapy is advancing rapidly from the bench to the bedside. These are RNA-based drugs such as antisense therapy that target an earlier step that prevents the disease-propagating protein or enzyme from being produced in the first place. But what type of diseases can these RNA-based drugs target? It would be detrimental to a cell if a particular enzyme was not produced at all– just imagine how long you would last if you stopped producing the enzyme responsible for making cholesterol (not very long). Even though cholesterol gets a bad rep for its role in heart disease, it plays a critical role in hormone synthesis and the maintenance of cell membranes. However, when the expression (scientist-speak for ‘production of protein’) of a disease-causing protein is highly controlled, it could have great therapeutic value.

The central dogma.
The central dogma. DNA is the hereditary material, RNA relays that information to make protein.

The Central Dogma: Revisited

The central dogma of molecular biology is that DNA makes messenger RNA (mRNA), which in turn makes protein. We all know DNA to be the genetic data storage center of our cell, and mRNA as the intermediate “delivery guy” that relays its information to make protein. Our cells naturally produce another type of RNA called microRNA (miRNA), a newly found class of non-coding small RNAs that regulate expression of mRNAs by physical contact and prevent the mRNA from being translated into a protein. Currently, most pharmaceutical drugs interact with the last step in this process; however, inhibiting microRNA function by an anti-microRNA (anti-miR) drug can effectively control the production of specific enzymes involved in a disease process.

Antisense drugs target mRNA, whereas traditional drugs target protein.

For example, if a particular cancer results from the under-expression of a certain enzyme, a specific anti-miR drug could be developed to inhibit the miRNA that regulates the mRNA corresponding to that enzyme, resulting in increased enzyme production.


21st Century Approach to Medicine

Companies such as Isis PhamaceuticalsRegulus Therapeutics and Alnylam Pharmaceuticals are dedicated to creating RNA-based therapeutics for a wide range of diseases including hypercholesterolemia (high cholesterol), hepatitis C, glioblastoma (brain tumors), kidney fibrosis, and atherosclerosis. In recent years, antisense drugs have made it to the clinic and been approved by the FDA to begin treatment of patients.

Early this year, the FDA approved mipomersen, an antisense drug produced by Isis Pharmaceuticals that targets the mRNA responsible for making apolipoprotein B. The medication has been lauded by families with familial hypercholesterolemia, a genetic disorder responsible for producing unusually high levels of low-density lipoprotein (LDL) cholesterol (commonly referred to as “bad cholesterol”).

In addition, RNA therapeutic technologies have the potential to treat diseases that are globally prevalent. For example, according to the CDC, more than 170 million people are chronically infected with Hepatitis C Virus (HCV) worldwide. Current treatment for HCV requires a combination of peginterferon and ribavirin, which eliminates the virus from over 50% of infected individuals. Administration of these drugs cause major flu-like side effects, making them difficult to take. Additionally, the fact that their efficiency is not very high and that they need to be taken twice daily in some cases calls for alternative treatment options.

For chronic cases, the face of HCV treatment may change with novel antisense/anti-miR drugs that target the RNAs that help replicate hepatitis virus. By targeting an earlier stage in the pathway, these drugs may be more effective in eliminating the virus from replicating on a shorter time scale. A couple anti-miR drugs are being developed and are in clinical and preclinical stages. Santaris Pharma, based in Copenhagen, Denmark has miravirsen in phase 2 clinical trials and more recently, Regulus Therapeutics in La Jolla, CA nominated a clinical candidate, RG-101, for the treatment of HCV. Both of these drugs are aimed at targeting miR-122, the microRNA in the liver that HCV hijacks and allows it to self-replicate. The drugs are still in very early stages, but with other antisense and RNAi drugs gaining fame for their effectiveness against chronic diseases, the development of RNA-based therapies is definitely worth following.


Prashant is a senior undergraduate student studying biochemistry and molecular biology at the University of California, Berkeley. He currently is Editor-in-Chief of Berkeley Scientific Journal, where he became interested in science journalism and its propensity to motivate general audiences.  Read the current issue here. Follow BSJ on Twitter.

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