OCTOBER 2023LIFE SCIENCES REVIEW9The 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 types. As a result, small molecule or protein-based approaches used to drug these proteins may have an anti-fibrotic effect at the intended tissue target, but typically have an off-target effect in other tissues where the protein is expressed. This leads to potentially severe, debilitating, and unbearable toxicities for patients. Targeting the dark genome and the related epigenetic activity is ideally suited to block this fibrosis process for two reasons. First, this method renders the therapy highly effective because it targets the interface between the environment and DNA, which is the root-cause for fibroblast activation. Second, this approach is safer than other currently available treatment options because dark genome lncRNA targets are highly specific to tissues and cell states. The result is a potentially significant anti-fibrotic effect coupled with a reduction in toxicity in off-target tissues and onset of side effects.Exponential Acceleration in the RNA fieldWe have made significant advances in understanding the underlying molecular mechanisms in RNA biology. Studies have demonstrated that the epigenetic and genetic variation that causes disease processes are happening at the level of the dark genome and the lncRNAs produced by it. Furthermore, in the past, discovering the genetic switches of the dark genome would take years to identify. With diverse and integrated genomic datasets now at our fingertips, we can scale up our efforts and make genetic discoveries within days. Additionally, there is now widespread adoption of RNA therapeutics, like modified RNA, synthetic RNA, siRNA and oligonucleotides targeting RNAs. These modalities are proven to be safe and effective in the clinical setting. Five years ago, these approaches were not clinically validated and considered high risk. This landscape is rapidly changing.Heart failure is one of the diseases that lends itself to RNA-based intervention because the condition is primarily caused by lifestyle choices and environmental cues. More specifically, we have discovered the organ's dysfunction in relation to the activity in the dark genome and production of lncRNAs. Many diseases that impact us as a society are driven by our lifestyle-- how we eat and exposure to the environment. Therapeutic strategies that incorporate RNA-guided approaches that target the dark genome could be the most viable option for a multitude of indications.We need to continue to focus our efforts on expanding our RNA toolkit, either by using it as a therapeutic directly or targeting the molecule itself. In addition, we need to increase our fundamental understanding of lncRNA biology, epigenetic programming and disease-driving cell states that causes the common, chronic diseases that plague society. Samir Ounzain
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