OCTOBER 2023LIFE SCIENCES REVIEW8IN MY OPINIONhe whole world realized the power of RNA when the COVID-19 pandemic brought us the first mRNA-based vaccines. Over the next two decades, it is quite possible that most new drugs approved could be based on some form of RNA, whether it be through its delivery or targeting the molecule itself. It is now more critical than ever to drive research and develop the next generation of RNA therapies, leveraging this molecule as a therapeutic modality with transformational potential. Decoding `junk DNA'The Human Genome Project and subsequent studies discovered that most of our DNA (approximately 98-percent) does not actually code for proteins, with humans having approximately 20,000 to 25,000 protein-coding genes. Surprisingly, the protein-coding portion of our genome is comparable in identity and number with the humble fruit fly or worm.The non-coding DNA has been deemed "junk DNA" or "the dark matter" of the human genome, and has led us to ask, "does the dark genome give humans their unique yet complex traits and behavior?" Many scientists are now discovering that this junk DNA plays an essential role in our biology and the epigenetic processes that respond to the environment to drive disease.It turns out that all the epigenetic programming and interfacing with the environment happens in the dark matter. Through many years of research, we now realize that the dark matter produces a type of RNA molecule, which we now call long non-coding RNA (lncRNA). This information processing portion of the genome and the RNAs produced by it, the lncRNAs, regulates the ability of our biological processes to interface with the environment and change cellular states. For example, fibroblasts are a type of cell whose cell state is heavily affected by environmental cues and, subsequently, the production of lncRNAs. Fibroblasts are found in many tissues, including the heart, and can be altered through environmental responses and associated lncRNA expression changes, eventually turning into activated fibroblasts. These activated fibroblasts produce large amounts of potentially deleterious extra-cellular matrix (ECM) proteins, including collagen.In the context of common and chronic diseases, the progressive build-up of activated fibroblasts and subsequent deposition of ECM proteins leads to organs becoming stiff, resulting in tissue scarring or fibrosis. Ultimately, fibrosis can rapidly progress, resulting in end-stage organ failure, an extremely common feature in diseases affecting the heart, lungs, liver, and kidney. We can now start using a toolbox of lncRNA-targeting therapeutics because the dark genome is associated with lncRNA production, which we now know regulates epigenetic states and is extremely tissue- and cell-specific. By targeting these RNAs, we can block the fibrosis process and prevent disease progression in a highly safe, effective, and accessible manner.Drugging the Dark Genome for Treating Fibrotic DiseasesWhile there are a handful of approved drugs for fibrosis, the disease still accounts for one out of three deaths globally because therapeutic interventions lack efficacy and safety. THE DARK SIDE OF THE GENOME TRANSFORMING RNA THERAPIESBy Samir Ounzain, Co-founder, Chief Executive Officer & Board Director, Regulatory RNAs, HAYA TherapeuticsThe problem is that current approaches target the proteins that control fibroblast activity, which themselves are pleiotropic, expressed in many parts of the body and in multiple cell typesT
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