“RNA” has become a buzzword over the past year, brimming in headlines alongside “vaccines” and “COVID-19.” While this may change as the pandemic slowly comes to an end, it is safe to assume this will not be the last time RNAs come to the rescue. Extensive research into smaller and lesser-known versions of RNA is currently underway, and their potential to improve diagnostics and therapeutics is significant.
Introductory biology classes have familiarized us with the central dogma, illustrating the process of how genetic information flows from DNA to RNA to eventually form functional proteins. More specifically, it is messenger RNA (mRNA) that reflects the sequence of bases in DNA. This code gets translated into proteins, resulting in downstream effects within the cell.
However, there are usually exceptions to rules, and this is no different. Only 2 per cent of the human genome encodes for proteins while the rest is copied into non-coding RNAs (ncRNAs). Previously and mistakenly marked as junk, current evidence shows ncRNAs are not all noise. Many ncRNAs play a pivotal role in regulating the genes involved in various life processes. Their functions are vast and largely unknown.
MicroRNAs (miRNAs) are the most widely studied class of ncRNAs. These molecules are around 22 nucleotides in length and target specific mRNAs to cause degradation or block translation into protein. They are known for their stability, abundance, and high conservation. Furthermore, miRNAs often target multiple mRNAs within one pathway, adding to their potential for achieving a broad and effective response.
Another class of ncRNAs is long ncRNAs (lncRNAs), which are more than 200 nucleotides in length and can fold into relatively large, three-dimensional structures. They work to influence transcription, translation, and the steps in between by interacting with DNA, mRNA, or proteins. Some lncRNAs can even regulate each other or act as miRNA sponges, sequestering them to reduce their regulatory effects on mRNA.
An early step in developing ncRNA-based therapeutics is to identify those that are likely biologically relevant to a given disease. This can involve collecting tissue samples from patients to perform RNA sequencing. As a standard method for quantifying gene expression levels, this advanced technology allows researchers to compare between different conditions and select key ncRNA candidates. These analyses are typically followed by testing disease-specific ncRNAs in cultured cells and animal models.
There is strong evidence that targeting one type of long non-coding RNA could help overcome certain chemo-resistant tumours.
Many online databases contain thousands of experimentally validated lncRNA- or miRNA-target interactions. As new results are generated, they can be added to or matched up with data from existing prediction platforms. This further equips researchers with tools to draw important connections between the transcriptome, genome, and proteome when investigating their ncRNAs of interest.
One widely studied lncRNA is metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), which was initially found to be abundant in patients with non-small cell lung cancer. Many studies since then have revealed its context-dependent functions for regulating various genes and its involvement in other cancers and diseases like diabetes and atherosclerosis. In terms of potential clinical impacts, there is strong evidence that targeting MALAT1 could help with overcoming certain chemo-resistant tumours.
Meanwhile, miRNA-based therapeutics include antagomiRs (miRNA inhibitors) and miRNA mimics, which aim to correct for altered levels of miRNA due to disease. Most patents for miRNA mimics pertain to cancer, metabolic disorders, and inflammatory disorders, with several of them currently being tested in clinical trials.
Two common caveats to overcome when developing RNA therapies surround the molecule’s integrity and its delivery to target cells. As seen with COVID-19 mRNA vaccines, lipid nanoparticles are a safe and effective way of delivering RNA. This technology can also be used for miRNA-targeted therapies such as antagomiRs and miRNA mimics. Given the diverse range of RNA species and the complex nature of RNA-guided regulation, there is no one-size-fits-all solution. Ongoing translational efforts are therefore directed toward optimizing target specificity while minimizing unwanted effects.
With countless instances of miRNA and lncRNA dysregulation in different diseases, ncRNAs make promising biomarkers for diagnosis and targets for treatment. Ongoing studies in molecular medicine continue to discover new ncRNAs and unravel their key roles in gene expression control. This information will likely lead to the development of novel strategies, which may be used alongside standard interventions to enhance care for patients.
It is overall an exciting time to be immersed in this area of research, as the story of ncRNAs and their relevance to medicine is only beginning.