Junk DNA: How the dark genome is changing RNA therapies

DNA helix

Samir Ounzain, PhD, CEO & Co-Founder of HAYA Therapeutics, looks at how a better understanding of our DNA can lead to increased activity for RNA therapeutics.

The whole world realised 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. Therefore, it is now more critical than ever to advance the science to 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%) does not actually code for proteins, with humans having approximately 20,000 tox 25,000 protein-coding genes. In actuality, the protein-coding portion of our genome is comparable in identity and number with the humble fruit fly or worm.

This 98% of 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 behaviour?” 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 is happening in the dark matter. Through many years of research, we now realise that the dark matter produces a type of RNA molecule, which we now call long non-coding RNAs (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 extracellular 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.

Because the dark genome is associated with lncRNA production, which we know regulates epigenetic states and is extremely tissue-and cell-specific, we can now start using a toolbox of lncRNA-targeting therapeutics. 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 diseases

While 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 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 field

We 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. Just 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, i.e., how we eat and exposure to the environment. Therefore, 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.

DDW Volume 24 – Issue 3, Summer 2023

Samir OunzainAbout the author:

Samir Ounzain, PhD, CEO & Co-Founder of HAYA Therapeutics, is a molecular biologist exploring the dark genome and its role in development and disease. Previously, Ounzain was a Project Leader and Research Fellow at the Lausanne University Hospital (CHUV), where his research directly led to the discovery of novel heart-enriched lncRNAs.

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