A recent review by researchers in California, USA outlines the mechanisms, successes, and challenges of using RNA therapy to treat human disease.
The treatment of diseases by pharmaceutical agents is fundamentally carried out on a molecular level. Traditionally, research into drug development has centered on the screening of small molecules, which can bind to and interact with proteins in a way that alters a biological process and leads to a beneficial treatment outcome. The development and production of these molecules have formed the basis of the pharmaceutical industry for decades. However, small molecules are not without drawbacks that can limit their suitability as drugs. Two of the most important characteristics of a drug are specificity and affinity.
Drug Specificity and Affinity
Drug specificity refers to how specific the interaction is between drug and target. Drug affinity refers to how tightly a drug binds to its target. Many small molecules show a number of off-target interactions that limit their specificity and are manifested physiologically as side effects, some of which can be so severe that they can lead to the eventual abandonment of the drug development program.
In response to these limitations, research into drug development has pursued alternate avenues in recent years. The focus has been on leveraging naturally occurring biological mechanisms to bind to relevant targets and induce therapeutic effects. One of these includes the use and modification of monoclonal antibodies, which are already naturally produced by the immune system, to bind specific targets and treat a variety of diseases including cancer. Another one of these exciting and cutting-edge initiatives is based on using ribonucleic acids (RNA) as a biological disruptor, effectively creating a type of “RNA therapy.”
What is RNA?
What is RNA and how can it be used in this way? Simply put, RNA is the intermediate molecule between our DNA, our fundamental genetic material, and proteins, which carry out the vast majority of our molecular biology activities.
Our DNA is a code which makes us who we are. Not only does it hold the information that makes us unique, but it encodes the information that allows the basic processes of life to take place. That code takes the form of four “base pairs” which we call A, T, C, and G. DNA is normally found in a double-helix structure, where “A” binds to “T”, and “C” binds to “G.” In order for DNA to become a protein, it must be unwound and one strand decoded into a messenger RNA (mRNA) molecule in a process called transcription. That mRNA molecule can then be translated (decoded a second time) into an amino acid sequence that eventually creates a protein.
So what does this mean for RNA therapy? Since the messenger RNA must undergo translation in order to synthesize a protein, blocking that process can inhibit the expression of specific proteins, and produce a pharmacologically relevant outcome.
In the late 1990s, basic science researchers discovered that specific kinds of RNA could be induced to enter cells and form a complex with enzymes that would find complementary sequences of mRNA and chop them up to effectively stop the translation process. While this discovery opened up a world of possibilities with regards to biological research in the lab, it is not until recently that it has been considered as a medical therapy to inhibit protein expression.
RNA Therapy Today
A recent review by a group of scientists at the University of California San Diego and Ionis Pharmaceuticals details the state-of-the-art in RNA therapy. The article, published in the journal Cell Metabolism, provides an exceptionally detailed review of the different kinds of RNA therapy, the types of diseases treated, the chemistry behind optimizing these molecules as pharmaceutical agents, and the challenges that lie ahead. Currently, most of these programs still reside in some phase of clinical trials, although a few have been approved for use.
Double-Stranded vs. Single-Stranded RNA
Generally, RNA can come in one of two forms, either double-stranded or single-stranded. This simple distinction has many biological implications. For example, double-stranded RNA cannot efficiently pass through cell membranes and is therefore difficult to administer, yet once inside it unwinds and efficiently forms complexes with specific enzymes, travelling to the target mRNA to prevent protein expression. These kinds of therapies show great promise from a mechanistic point of view but have run into challenges because of the need to administer them with specific delivery molecules that mimic the characteristics of membranes, some of which can cause a significant degree of inflammation.
Single-stranded RNA has molecular properties that allow it to travel to multiple tissues and enter cell membranes and therefore is much easier to administer to patients. While the mechanism of action is somewhat more variable, this form has proven promising at treating several diseases, even if the specificity of single-stranded RNA is somewhat lower than its double-stranded counterpart.
Single-stranded RNA has been used to treat spinal muscular atrophy
Perhaps the greatest success story to date of RNA therapy has been the use of single-stranded RNA to treat a severe genetic disorder call spinal muscular atrophy. Prior to this option, there was no treatment for this disease and most infants afflicted by it either died in the first six months of age or suffered severe motor impairment, never being able to walk or even lift their arms as they aged. This particular RNA therapy, called Nusinersen, has produced absolutely stunning effects, allowing these children to progressively gain the ability to walk and engage in normal motor activity. Video evidence of this progression has been documented by parents and shared on social media outlets worldwide.
While many challenges and much research lies ahead in the domain of RNA therapy, successes such as Nusinersen illustrate that this new class of pharmaceuticals is only scratching the surface of its potential.
Written by Adriano Vissa, PhD
Reference: Crooke ST, et al. RNA-Targeted Therapeutics. Cell Metabolism. https://doi.org/10.1016/j.cemt.2018.03.004
