Therapeutic targets hidden in the dark?
The dark genome’s importance remains chronically underestimated, but that’s gradually changing. Around 98% of our genome doesn’t encode proteins. Instead, it contains a rich source of regulatory control mechanisms that fine-tune gene expression to keep us healthy. It includes important stretches of DNA, such as transposable elements, enhancers, and long non-coding RNAs (lncRNAs), which can directly influence the activity of different genes and critical cellular processes. By modulating some of these key segments of the dark genome, it has become increasingly clear that this approach is a powerful way to tackle many of the chronic diseases we face.
In 2016, researchers from the lab of Jean-Christophe Marine at the Center for Human Genetics, KU Leuven, and the Center for the Biology of Disease, VIB, found one of the most compelling pieces of evidence for the role of the dark genome in disease. They found that a lncRNA called SAMMSON was crucial for the survival of melanoma cells, making it one of the most promising new drug targets for treating both primary and metastatic melanomas.
Expression of SAMMSON was detected in over 90% of human malignant melanomas but was absent in benign skin cancers, making it a strong candidate for targeting. When the researchers silenced SAMMSON with a type of RNA-targeting small-molecule called antisense oligonucleotides, melanoma cells died en masse. The researchers suggested that the cancer cells became ‘addicted’ to the lncRNA for vital mitochondrial functions, and when SAMMSON was removed, the growth of cancer cells halted.
This indicated that the lncRNA is a potentially highly effective and tissue-restricted anti-melanoma therapeutic. A follow-up study from researchers from the OncoRNALab at the Center for Medical Genetics (CMGG), Ghent University, found similar results in a genetically diverse panel of uveal melanoma cell lines when the team again inhibited SAMMSON with antisense oligonucleotides. Uveal melanoma is the most common primary eye malignancy in adults.
LncRNAs in a nutshell
LncRNAs are stretches of more than 500 nucleotides that can change our underlying biology through interactions with other RNAs and RNA-binding proteins. Estimates suggest the presence of upwards of 27,000 lncRNAs in the human genome, around 78% of which are only expressed in specific tissues, unlike most mRNAs, which are typically expressed across multiple tissues. This specificity to particular cell types, like SAMMSON in malignant melanoma cells, makes lncRNAs attractive as therapeutics that might avoid any globally toxic effects on healthy cells.
However, as with any novel therapeutic target, researchers should also be cautious. LncRNAs have roles at almost all stages of the cellular life cycle, so targeting them with compounds or antisense oligonucleotides could have unforeseen effects. LncRNAs directly regulate gene transcription and the main transcription machinery; they have roles in regulating the events after transcription, like mRNA splicing and the translation of mRNA into proteins, and they also play crucial roles in epigenetics and cellular aging.
Pharma and investors take note
The pharmaceutical industry is taking note of the potential of lncRNAs. Eli Lilly recently announced a $1 billion, multi-year agreement with Swiss dark genome specialists, HAYA Therapeutics, to discover novel targets for obesity and related metabolic conditions. HAYA Therapeutics has also just raised $65 million Series A funding to deliver precision RNA-guided medicines for chronic and age-related diseases. They will use the funds to focus on their lead lncRNA-targeting candidate HTX-001 in heart failure and to expand their RNA-guided regulatory genome pipeline development engine.
Bayer and Boston-based NextRNA Therapeutics also announced a collaboration of over $500 million to develop small molecules targeting lncRNAs in oncology. NextRNA focuses on small molecules that disrupt the interaction between lncRNAs and RNA-binding proteins to inhibit lncRNA function.
A bright future for the dark genome
In Belgium, Leuven-based Flamingo Therapeutics won a research grant of €1.7 million in 2023 from Flanders Innovation & Entrepreneurship (VLAIO) to advance its RNA-targeting oncology portfolio, such as its antisense oligonucleotide danvatirsen, which selectively targets the protein-coding mRNA of STAT3. The candidate has shown clinical activity in two phase II clinical studies for head and neck squamous cell carcinoma and is one of the most clinically advanced antisense oligonucleotide pipelines of its kind.
Flamingo will also use the funds to support preclinical research on its program targeting the lncRNA, MALAT-1, with its antisense oligonucleotide development candidate, FLM-7523. MALAT-1 is highly expressed in multiple cancer types, such as metastatic breast cancer, and is associated with disease progression in patients, making it a promising target. The candidate is advancing towards phase I clinical trials in solid tumors.
Flamingo Therapeutics was spun out from a collaboration between VIB, UGent, and KU Leuven in Flanders and the University of Michigan in the US. It counts the researchers who discovered the role of SAMMSON lncRNA in melanoma as key collaborators, alongside US giants, Ionis Pharmaceuticals, who licensed precursors to danvatirsen and FLM-7523 to Flamingo Therapeutics in 2021. In 2023, the company merged with antisense oligonucleotide-focused Dynacure, which bolstered Flamingo’s development pipeline and enabled phase II clinical trials.
The future seems bright for therapeutics targeting the dark genome.
