The pandemic due to Covid-19 brought RNA into the global discussion. Looking into the future, RNA is set to play a vital role in the development of novel medicines, either by delivering drugs or targeting specific molecules directly. Now, the aim is to elevate RNA science forward to create the next generation of therapies, using it as a potential tool for treatment.
But what about the so-called 'junk' DNA? The Human Genome Project, which cost $2.7 billion, revealed that a significant portion of our DNA (around 98%) does not code for proteins. This non-coding DNA, often called 'dark matter,' has an important role in living organisms. It's involved in processes of interacting with various environmental factors and can result in the development of diseases.
Research has indicated that this non-coding DNA produces long non-coding RNAs (lncRNAs), which are necessary for regulating biological processes. For example, fibroblasts cells respond to their environment by changing lncRNA expression. This can lead to the production of proteins that results in tissue scarring or fibrosis in various organs, and their failure.
Fibrosis, caused by the deposition of certain proteins, stiffens organs and can be fatal in chronic diseases. Targeting the 'dark genome' and the lncRNAs it produces could be a promising way to treat fibrosis, as these RNAs regulate specific cell behaviors. Currently, there are few approved drugs for fibrosis, and they aren't always effective or safe. Most target proteins that control cell activity, but these proteins are also found in other tissues, causing tremendous side effects. In contrast, targeting the dark genome and its related activities offers two key advantages: precision and safety. This approach gets to the root cause of cell activation, and since lncRNA targets are specific to certain tissues and cell states, treatments can be more channelized, reducing side effects.
Advancements in RNA research have been fast, leading to a deeper understanding of how RNA functions at the molecular level. Diseases often involve changes in the 'dark genome' and the lncRNAs it produces. A majority of the dark genome comprises of mobile genetic elements called transposons or jumping genes. Such genes when moved from its original location can lead to the expression of cancer-causing genes (oncogenes) and resulting in the formation of new proteins. With more comprehensive genomic data available, researchers can now identify genetic controllers more quickly, paving the way for quicker discoveries. For example, lncRNA has been proven to express in various types of cancers (breast, gastric and other types of cancers) and various oligonucleotide treatments are on the way to target cancer related lncRNA and control the growth of the cancerous cells.
In the past decade, the field of RNA therapeutics has also evolved significantly. Until a few years ago, treatment methods using modified RNA, synthetic RNA, siRNA, and oligonucleotides were questioned for their safety and efficacy. These various RNA were often isolated (using bioinformatics) from other organisms like fruit flies and bacteria. But now these methods have been proved to be both safe and effective in clinical settings. Neurodegenerative disorders like Parkinsons and Alzheimer’s which is triggered by both environment ad genetic factors, could benefit from RNA-based treatments. Understanding how the 'dark genome' and lncRNAs play a role in neurodegeneration in Parkinsons and Alzheimer’s patients could lead to better treatments.
Looking ahead, it's crucial to expand the RNA map to fully tap into its potential. This means developing RNA as a direct therapeutic agent and finding ways to target RNA molecules more precisely. Also, deepening our understanding of lncRNA biology and how it relates to disease will be essential. With this knowledge, we can develop targeted therapies for common chronic diseases, making a significant impact on the treatment outcomes.
In conclusion, delving into RNA and the 'dark genome' presents endless possibilities for developing innovative treatments for various autoimmune, cancer and neurodegenerative disorders. By harnessing the precision and transformative power of RNA, we could see significant advancements in the treatment of chronic and life-threatening conditions in the future.
References
Erkkinen, M. G., Kim, M.-O. & Geschwind, M. D. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 10, a033118 (2018).
Amini, A, Esmaeili, & Golpich. Possible Role of lncRNAs in amelioration of Parkinson’s disease symptoms by transplantation of dopaminergic cells. Nature 10, a56 (2024).
John S. Mattick, Paulo P. Amaral, Piero Carninci, Susan Carpenter, Howard Y. Chang, Ling-Ling Chen, Runsheng Chen, Caroline Dean, Marcel E. Dinger, Katherine A. Fitzgerald, Thomas R. Gingeras, Mitchell Guttman, Tetsuro Hirose, Maite Huarte, Rory Johnson, Chandrasekhar Kanduri, Philipp Kapranov, Jeanne B. Lawrence, Jeannie T. Lee, Joshua T. Mendell, Timothy R. Mercer, Kathryn J. Moore, Shinichi Nakagawa, John L. Rinn, & Mian Wu. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nature Reviews Molecular Cell Biology volume 24, pages 430–447 (2023).
Zhi, H., Deying, Y., Xiaolan. F.,1,2 Mingwang, Z., Yan, Li., Xiaobin, Gu., and Mingyao, Y. The Roles and Mechanisms of lncRNAs in Liver Fibrosis. Int J Mol Sci. (2020).
Robert Krulwich (2003). Cracking the Code of Life (Television Show). PBS.
Cabili MN, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011; 25:1915–1927.
Comments