Targeting RNA can produce less toxic new drugs

The development of new drugs, based on targeting so-called long, non-coding RNA (lncRNA), can produce less toxic, and more specific therapies for various cancers and other major diseases. That is the goal of (opens in a new window)Associate Professor Rory Johnson’s laboratory, which is focused, currently on finding new RNA-based drugs to treat lung cancer. 

Prof. Johnson began his career as a physicist before transitioning to consider biological questions following a path trodden by famous names like Erwin Schrodinger, Francis Crick and Louis Pasteur.  

After studying physics in London and switching to do a PhD in neurobiology, Prof Johnson moved into genomics, the study of the human genome and stem cells. Then, he moved onto bioinformatics where he programmed computers to answer biological questions. 

He went next to (opens in a new window)GENCODE, a large international consortium aiming to identify and classify all human and mouse genes, and to release all this information for the benefit of biomedical research. 

RNA Therapy

After GENCODE, Prof Johnson set up a laboratory in Switzerland with the aim of deciphering the role of RNA in diseases. Since returning to his native Dublin and to UCD with a Research Ireland (formerly Science Foundation Ireland) award, he has worked to discover new drug targets from RNA molecules. 

A key technology that has facilitated his lab’s drive to identify new drug targets at UCD Conway Institute is the gene editing tool, CRISPR (Clustered Regularly Interspaced Short Palindromic Sequences). 

“CRISPR is not just one single tool. It’s really the basis of a huge and growing, diverse array of tools and therapies,” said Prof. Johnson. “My lab has been among the pioneers of using CRISPR as a way of identifying new drug targets.” 
Prof. Johnson is screening thousands of genes at the same time with CRISPR to find those genes which would be good to target therapeutically for a particular disease, such as lung cancer. 

The ‘Poor Cousin’ 

Prof. Johnson said he has been interested in RNA for a long time, even though it’s only become a trending research topic since the Covid-19 pandemic. He agreed that it has been widely seen as the ‘poor cousin’ to DNA but said scientists are beginning to accept that it plays a key role in biology, and that all life began as RNA. 

There are important differences between RNA and DNA too. The DNA that resides in every cell in our body is the same, but RNA is different in every cell. This means, for example, that the RNA present in diseased cells is different compared to healthy cells. 

“That gives us an obvious way to develop drugs against disease by targeting those RNAs which are different in the disease cells.” 

DNA might be thought of as the set code for life, while RNA represents how that code is expressed or acted on. “DNA is simply an information molecule”, said Prof Johnson, “while RNA can catalyse reactions, form structures and do other things, all at the same time, making it a more versatile molecule than DNA.” 

Lung cancer 

A big focus of Prof. Johnson’s lab is on lung cancer, which remains the biggest cancer killer with a poor prognosis. There is a great need for new therapies that are less toxic for patients. 

Prof. Johnson’s lab have developed drugs that kill the cancer in a dish and aim to move towards treating patients in the clinic. They are also looking at other cancers, and other major diseases. 

In January 2024, Prof. Johnson set up Linn Therapeutics, a spin-out company to help achieve his goal of pioneering CRISPR-powered lncRNA therapeutics in oncology. 

There are some 100,000 long, non-coding RNAs, or lncRNAs, said Prof. Johnson, that don’t code for proteins but are biologically important as many of them are specifically active in tumour cells. This is something that Prof. Johnson and his team believe they can exploit. 

“If we hit them with a drug, we hope to have much less toxicity in healthy cells. This is in contrast to most of the cancer drugs we have today that cause terrible side-effects and toxicity in the patients because they don’t have specificity for the tumours.” 

The aim is to create many anti-cancer drugs that target lncRNAs, but leave the rest of the body unharmed. The strategy is to target disease-causing genes that produce RNA using small fragments of RNA. The target, in these cases, is a long RNA, and the drug set against it, is a short fragment of RNA. The latter are called oligonucleotides and they will destroy the target.  

As with DNA, if pieces of RNA recognise each other, they stick together, said Prof. Johnson, and that’s why the longer RNA gets neutralised when a shorter RNA strand attaches to it. The aim is to develop new drugs based on these short RNA oligonucleotides. 

“We hope in the next five years or so to start generating large numbers of early-stage targets that could then be commercialised and secure the substantial investment required to test them first in animal models before moving to clinical trials.” said Prof Johnson. 

Conway Fellow, Associate Professor Rory Johnson from UCD School of Biology & Environmental Science was in conversation with journalist, Sean Duke.