by The Earth formed 4.5 billion years ago and life less than a billion years later. Although life as we know it depends on four major macromolecules (DNA, RNA, proteins and lipids), only one is believed to have been present at the beginning of life: RNA.
Not surprisingly, RNA probably came first. It is the only one of those important macromolecules that can replicate and catalyze chemical reactions, both essential for life. Like DNA, RNA is made up of individual nucleotides linked together into chains. Initially, scientists understood that genetic information flows in one direction: DNA is transcribed into RNA, and RNA is translated into proteins. That principle is called the central dogma of molecular biology. But there are many deviations.
An important example of an exception to the central dogma is that some RNAs are never translated or encoded into proteins. This fascinating departure from central dogma is what led me to dedicate my scientific career to understanding how it works. In fact, RNA research has lagged behind other macromolecules. Although there are multiple classes of so-called non-coding RNAs, researchers like me have begun to focus a lot of attention on short stretches of genetic material called microRNAs and their potential to treat various diseases, including cancer.
MicroRNA and disease
Scientists consider microRNAs to be master regulators of the genome due to their ability to bind and alter the expression of many protein-coding RNAs. In fact, a single microRNA can regulate between 10 and 100 protein-coding RNAs. Instead of translating DNA into proteins, they can bind to protein-coding RNAs to silence genes.
The reason microRNAs can regulate such a diverse set of RNAs is due to their ability to bind target RNAs that do not match perfectly. This means that a single microRNA can often regulate a set of targets that are involved in similar processes in the cell, leading to an enhanced response.
Because a single microRNA can regulate multiple genes, many microRNAs can contribute to disease when they become dysfunctional.
In 2002, researchers first identified the role that dysfunctional microRNAs play in the diseases of patients with a type of blood and bone marrow cancer called chronic lymphocytic leukemia. This cancer results from the loss of two microRNAs that normally participate in blocking the growth of tumor cells. Since then, scientists have identified more than 2,000 microRNAs in people, many of which are altered in various diseases.
This field has also developed a fairly solid understanding of how microRNA dysfunction contributes to disease. Changing one microRNA can change several other genes, resulting in a large number of alterations that can collectively remodel the cell’s physiology. For example, more than half of all cancers have significantly reduced activity in a microRNA called miR-34a. Because miR-34a regulates many genes involved in preventing cancer cell growth and migration, loss of miR-34a may increase the risk of developing cancer.
Researchers are studying the use of microRNA as a therapy for cancer, heart disease, neurodegenerative diseases and others. While results in the lab have been promising, bringing microRNA treatments to the clinic has faced multiple challenges. Many are related to inefficient delivery to target cells and poor stability, which limits their effectiveness.
MicroRNA delivery to cells
One of the reasons it is difficult to deliver microRNA treatments into cells is because microRNA treatments must be delivered specifically to diseased cells while avoiding healthy cells. Unlike COVID-19 mRNA vaccines, which are absorbed by eliminative immune cells whose job is to detect foreign materials, microRNA treatments must trick the body into thinking they are not foreign to avoid immune attack and reach the desired cells.
Scientists are studying various ways to deliver microRNA treatments to their specific target cells. One method that is attracting a lot of attention is based on directly attaching microRNA to a ligand, a type of small molecule that binds to specific proteins on the surface of cells. Compared to healthy cells, diseased cells may have a disproportionate amount of some surface proteins or receptors. Therefore, ligands can help microRNAs home specifically to diseased cells and avoid healthy cells. The first ligand approved by the US Food and Drug Administration to deliver small RNAs such as microRNA, N-acetylgalactosamine or GalNAc, it preferentially delivers RNA to liver cells.
To identify ligands that can transport small RNAs to other cells it is necessary to find receptors expressed at sufficiently high levels on the surface of target cells. Typically, more than one million copies per cell are needed to achieve sufficient drug delivery.
One ligand that stands out is folate, also known as vitamin B9, a small molecule critical during periods of rapid cell growth, such as fetal development. Because some tumor cells have more than a million folate receptors, this ligand provides sufficient opportunities to deliver enough therapeutic RNA to attack different types of cancer. For example, my lab developed a new molecule called FolamiR-34a (folate linked to miR-34a) that reduced the size of breast and lung cancer tumors in mice.
Make microRNAs more stable
One of the other challenges of using small RNAs is their poor stability, which leads to their rapid degradation. As such, RNA-based treatments generally have a short life in the body and require frequent dosing to maintain a therapeutic effect.
To overcome this challenge, researchers are modifying small RNAs in a variety of ways. While each RNA requires a specific modification pattern, successful changes can significantly increase its stability. This reduces the need for frequent dosing, which subsequently decreases the burden and cost of treatment.
For example, modified GalNAc-siRNAs, another form of small RNAs, reduce the dose from every few days to once every six months in non-dividing cells. My team developed modified microRNA-linked folate ligands for cancer treatment that reduced the dosage from once every two days to once a week. For diseases like cancer, where cells divide rapidly and rapidly dilute administered microRNA, this increase in activity is a significant advance in the field. We anticipate that this achievement will facilitate further development of this folate-linked microRNA as a cancer treatment in the coming years.
While there is still much work to be done to overcome the obstacles associated with microRNA treatments, it is clear that RNA shows promise as a therapeutic for many diseases.
This article is republished from The Conversation, an independent, nonprofit news organization bringing you trusted data and analysis to help you understand our complex world. Do you like this article? Subscribe to our weekly newsletter.
It was written by: Andrea Kasinski, Purdue University.
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Andrea Kasinski receives funding from the National Institutes of Health, the Department of Defense, and the American Lung Association. Kasinski is also the inventor of multiple patients associated with her discoveries in the field of RNA therapeutics.
