Feel ill? Pop a pill or take an injection. Haven’t we all done this intuitively, without giving a second thought to the kind of artificial chemical concoction we are exposing ourselves to? Now, scientists have unearthed a natural biochemical entity, in our own body, that could soon become a coveted tool in our disease-fighting arsenal.
With the dawn of the genomic era, our fight against major diseases is increasingly getting channelized towards understanding the disease at molecular levels. As a result, we are now in a position to provide metabolic, genetic, biochemical and physiological explanations for common diseases that were, until a few decades back, being treated solely based on the physiological symptoms of the disease. Not surprisingly then, this fresh perspective of disease metabolism is further enabling us to devise newer molecular strategies to combat these diseases. MicroRNA (or miRNA) is one such new kid on the block, which has completely changed our perspective towards designing disease therapeutics.
So, what exactly are microRNAs? As the name suggests, they are tiny RNA molecules, once thought to be a waste product of our protein-producing machinery. They are made of the same building blocks as our DNA, and are found in all our cells. These pygmy RNA molecules lie at the forefront of the cutting edge advances in molecular biology, and might be the answer to curing diseases like cancer, viral infections, diabetes, metabolic disorders, genetics defects, etc.
Every single time a protein needs to be made in our body, an elaborate set of steps need to occur without a hitch. This includes unraveling of the specific stretch of DNA, production of temporary copies of that genetic information in the form of messenger RNAs (mRNAs), processing and exporting these mRNAs from the nucleus into the cytosol, and finally production of proteins using these mRNAs as templates.
This entire chain of events is orchestrated and regulated by distinct sets of proteins. Some of these proteins act as on/off switches to set off these chain reactions and are called 'regulators' that fine-tune the delicate gene expression. Usually, these regulator proteins bind to the genes themselves to regulate the step of mRNA production. However, some years ago, scientists uncovered a different kind of 'switch' that kicks in after the mRNAs have been produced and exported. These new regulators were called microRNAs or miRNAs and are known to target specific mRNA copies to prevent their conversion into proteins, thus blocking that last important step of protein production to take place at all. So, why is the mRNA produced at all in the first place? That is body’s audit mechanism. Such a miRNA-mediated regulation serves as a crucial check and balance mechanism that confers another layer of control over protein production, and also helps prevent the cells from sliding into a diseased state.
Thousands of miRNAs have been discovered so far and have rapidly acquired a lot of prominence. They are ubiquitously found in both plant and animal kingdoms, and are involved in a wide range of gene regulatory processes, including those controlling the development of an embryo. Moreover, a single miRNA can regulate more than one target mRNA, and can thereby influence a large network of genes and proteins.
Not surprisingly, any disruption in the spatio-temporal distribution, density and/or biogenesis of miRNAs could potentially lead to cellular malfunction and eventually a diseased state. The aberrant expressions of many of these miRNAs are known to lead to diseases like cancer, diabetes, heart attack, and neurological diseases like Parkinson’s, Alzheimer’s etc. All of these characteristics of miRNAs make them ideal targets for directing therapeutic interventions for curing major diseases.
Scientists have been coming up with various new strategies for employing miRNAs as a part of gene therapy approaches – a novel mode of clinical therapy wherein the genes responsible for the disease are directly targeted, instead of alleviating the disease symptoms alone. “These microRNAs can completely revolutionize modern gene therapy, because they are the only small therapeutic molecule of cells, which can be introduced and incorporated from outside the cell,” explains Dr. Utpal Bhadra, a senior scientist from the Centre for Cellular and Molecular Biology (CCMB), Hyderabad. In a recently published study, Dr. Bhadra and his team from CCMB collaborated with Dr, Manika Pal –Bhadra’s team at the Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad and have published a review on the range of miRNA-regulated diseases in humans and also providing an insight into the recent progress made in the fields of miRNA-based therapeutic interventions.
Since specific regulatory miRNAs can influence the onset of a disease either positively or negatively, miRNA-based gene therapy can be pre-dominantly segregated into two categories: miRNA mimics and miRNA antagonists. In the former case, if a miRNA involved in preventing a disease is under-represented in the cell for some reason and causes a disease state, then a miRNA mimic can be introduced into the cell to restore the normal cellular state. The latter case is employed if a miRNA upon over-expression causes the disease itself. Here, chemically modified molecules that inhibit miRNAs and suppress its inadvertent function, are introduced.
The miRNA numbers can be fine tuned by regulating miRNA expression in the tissue or the strength with which they bind target mRNAs. Such disease specific miRNA mimics as well as miRNA antagonists can be developed for every disease, which is regulated by miRNAs at some crucial step.
“As compared to the usual practise of using chemically-derived drugs against a disease, miRNA-based therapeutics are more preferable due to their higher efficacy and accuracy. For example, the use of miRNA antagonists for silencing genes can directly cut down the root of several physiological disorders,” explains Dr. Bhadra.
However, despite all these exciting advances, there are still many hurdles to cross before miRNA-based gene therapy becomes a mainstream cure for major diseases. One of them is addressing the off-target effect of these introduced miRNAs, primarily because most miRNAs have multiple mRNA targets. The challenge is to make these introduced miRNA mimics/antagonists specific enough to not cause inadvertent side-effects. Other limitations include toxicity due to immune response, poor intracellular delivery of miRNAs, and insufficient doses of miRNAs in the target tissues due to premature degradation of miRNAs or their slower penetration due to mechanical and biological barriers. Nonetheless, there are enough reasons to believe that these limitations will soon be overcome as both research laboratories, as well as pharmaceutical companies, are already working aggressively in this direction and a few clinical trials are in progress.
In the journey of utilizing miRNAs as a new weapon in our arsenal to fight diseases, we have just begun to scratch the tip of the iceberg. Also, miRNAs hold great promise in revolutionizing other fields of research too, like genetic modification of crops and livestock, as well as development of vaccines against major pathogenic infections. The possibilities with miRNAs are so immense and widespread, that it is hard to imagine where and how these pygmy warriors are going to come to our rescue in the coming future!