DNA and RNA research is revolutionizing pharmaceutics: New drugs are being developed faster and at a lower cost, and they are effective against previously incurable diseases. However, words like ‘gene therapy’ are still met with reservations, and they can be misleading. Often not even doctors are aware of how far nucleic acid-based therapies have come since the 1990s. An overview of new developments and therapies already available today.

By Oskar Köppen

If you want to develop a new drug using conventional methods, you need commitment: In their search for drug candidates, pharmaceutical companies test millions of chemical substances. In the end, after clinical trials and authorization procedures, one drug remains. This all takes an average of 12 to 15 years and costs two billion euros.
What if there was a way to speed up this process? To carry it out in small, low-cost laboratories? To not have to start from scratch again and again in other to secure the necessary state authorizations? And to be able to not only alleviate diseases for which there is currently no treatment, but also address their causes? In order to achieve this, new methods and substances are available that treat diseases at their roots: within our cells. There are RNA agents, which do not interfere with the genome, and DNA therapies, which modify it.

Silencing genes

A new class of drugs that utilizes a natural cellular mechanism is particularly promising: RNA interference. In our body cells, RNA molecules have one main task: as messenger RNA (mRNA), they are a copy of the genetic information in our DNA, which then goes to our protein factories. The proteins produced there determine pretty much everything that happens in our bodies: as enzymes they drive reactions, as receptors they transmit signals, they give our tissue structure, protect us from pathogens and keep our metabolism running. However, errors in the genetic material can have a serious impact. They are the cause of many, often fatal, diseases.

But RNA is not just a messenger in our cells: plant, fungal and animal cells use small RNA molecules (siRNAs) that do not transport genetic information, but rather destroy mRNA with specific protein blueprints in their luggage. Researchers are now using this process, known as RNA interference (RNAi), to specifically prevent the production of faulty and disease-causing proteins using artificial siRNA introduced into the cells – effectively silencing individual genes. In this way, they start one step earlier than conventional drugs and tackle diseases at the root that no one has been able to do anything about before.

RNA OR GENE THERAPY – WHAT IS THE DIFFERENCE?
Nucleic acid-based drugs influence protein production at the DNA and RNA level. RNA therapeutics are only temporarily active and are completely degraded in the end. They do not interact with the genetic material, do not integrate into the genome, do not lead to mutations and are not inherited. Gene therapeutics, on the other hand, use gene techniques such as genome editing to intervene in the cell nucleus DNA, i.e., the genetic material of the cell, in order to correct errors. Gene replacement therapies, usually packaged in viruses, introduce intact genes into cells that contain dysfunctional mutated genes and are therefore ‘diseased’. Gene therapies based on the CRISPR/Cas method (the ‘gene scissors’), on the other hand, can directly correct errors in the genetic material of the affected cells.

SiRNA drugs work according to a modular principle. “Until now, we always had to produce a completely new tool for each disease,” said Roman-Ulrich Müller, nephrologist and professor of medicine at the Faculty of Medicine and University Hospital Cologne. “SiRNAs, on the other hand, are like a cordless screwdriver: we only have to change the bit.” The path from one drug to the next is therefore no longer so long; researchers already know the mechanisms and side effects of the relevant class of therapeutics and react to new mutations and resistances by simply adapting the affected RNA sequence, their “screwdriver bit”. For the liver, for example, the body’s metabolic hub, this modular approach is already potentially applicable to every gene and accelerates basic drug research by years.

Personalized therapy within a year

RNAi therapeutics are one of many new classes of nucleic acid-based drugs, i.e., active substances that act at the DNA and RNA level. Other RNA types such as antisense oligonucleotides (ASOs) and aptamers have very similar effects. And mRNA vaccines are familiar to anyone who still remembers the COVID-19 pandemic. Since 1998, the USA and the EU have approved 22 RNA therapeutics – 18 of them in the last eight years alone.

American companies such as Alnylam, Ionis, Sarepta and Moderna as well as the German company Biontech are leading the way. Treatments for hereditary blood and metabolic diseases are available already. For example, the siRNA agents Lumasiran and Nedosiran are designed to prevent people with the metabolic disorder primary hyperoxaluria (type 1) from forming kidney stones and losing their kidney function. Givosiran, meanwhile, alleviates the painful episodes associated with acute hepatic porphyria, also a metabolic disorder.

New RNA drugs are also effective against certain forms of amyotrophic lateral sclerosis (ALS). In 2014, the degenerative disease of the motor nervous system made headlines when thousands of people doused themselves with ice water as part of the so-called Ice Bucket Challenge, and donated to research into the disease.

It is impossible to predict when which disease will become the focus of pharmaceutical companies. Initially, the companies will continue to research rare hereditary diseases “that have received little attention so far and for which no therapy exists yet”, Michal-Ruth Schweiger, human geneticist and professor at the University of Cologne, believes. It is foreseeable that a completely new, customized therapy could be developed within a good year in the future. Broad applications are also realistic: “It may become possible to treat common diseases with RNA drugs,” Müller said. Biontech’s data on combating tumours, for example, looks promising and Alnylam is already conducting RNA studies to develop a new treatment against high blood pressure. A therapeutic agent to treat high cholesterol is also already on the market.

Tricky biology, inflexible authorities

Despite all the optimism, there are still a few hurdles that stand in the way of the triumphant advance of nucleic acid-based drugs. The biggest one on the biological side is the question of drug delivery: How does the drug get to the right places in the body, how does it reach all the relevant cells? How does the therapeutic RNA make it from the tumour periphery to the centre, for example? What can be done if scarred or hardened connective tissue blocks access? Or when diseased organs do not behave the same way as healthy ones? This problem has now been solved for the liver: therapeutic RNA reaches its target safely via certain modifications; they are the lubricant for the “screwdriver’. The kidney, on the other hand, behaves more stubbornly than many researchers had hoped. Elsewhere, as in the example of the central nervous system, this obstacle can be overcome by direct administration on site, i.e., via injections into the spinal canal and cerebrospinal fluid. This could theoretically treat almost any disease located there for which the target gene is known.

The immune system can also cause trouble and reject RNA therapies. Utilizing or overcoming this is a central point of research. In addition, drugs can sometimes cause off-target effects, i.e. they have an effect in unwanted places and can therefore become toxic to the body. “These are two major issues in which huge progress has been made and which have been solved for many applications,” said Müller. Conventional approaches also have these problems: traditional tumour therapies, for example, attack all cells in the hope of killing the fast-growing, malignant ones faster than the rest. Nucleic acids, however, are “per se much more specific than the chemical substances we are familiar with”, Schweiger added.

The two medical researchers urge that regulations should progress at the same speed as the biological possibilities. “State regulatory authorities are still at the stage of how drugs were developed in the past,” Müller explained, “they don’t yet know how to use the ‘screwdriver’ properly”. This means that to date, if a pharmaceutical company simply wants to replace the ‘screwdriver bit’, it has to go through a completely new authorization process, including new large clinical trials.

CMMC SYMPOSIUM
From 18 to 20 September 2023, the Center for Molecular Medicine Cologne hosted the 37th CMMC Symposium in Molecular Medicine (formerly the Ernst Klenk Symposium). Under the title “From Concepts to Clinic: A New Era of Nucleic Acid Therapeutics”, hundreds of international medical researchers, molecular biologists and other scientists came to Cologne to discuss the state of pharmaceutical research on nucleic acid-based drugs and therapies and to plan joint activities. Michal-Ruth Schweiger and Roman-Ulrich Müller organized the Symposium together with Markus Stoffel of ETH Zurich.

Researchers such as the Dutch human geneticist Annemieke Aartsma-Rus are therefore trying to make “n = 1” studies more politically viable – studies that consist of a single test subject. The resulting drugs would not be authorized for the general public, but could help individuals comparatively quickly. Boston Children’s Hospital in the U.S. has already created two ASO drugs in this way, each precisely tailored to one patient.

Widespread scepticism

Why are so many people still unaware of the potential of RNA drugs? “Progress is underestimated,” Schweiger believes. “Many people have not yet realised how far we have already come.” Also, during the past twenty years the decisive advances have come from the pharmaceutical industry rather than academic research. For Schweiger, this is a sign that society and decision makers are missing the boat. In view of the delivery problem, universities are once again needed to develop completely new solutions free from industrial constraints. In the Rhineland – in Cologne, Bonn, Aachen and Düsseldorf – “fantastic experts” are available, said Schweiger. Together with a good twenty regional colleagues, the researchers are currently looking for financial support to realize their ideas.

But it is not always easy for society to keep up with scientific progress. Many will still remember the setbacks of viral gene replacement therapy at the turn of the millennium – for example, the death of the American teenager Jesse Gelsinger after an inflammatory reaction to a gene therapy to treat his liver disease. This can lead to emotional associations: ‘Gene therapy, designer babies, DNA, RNA – and are the corona vaccines really safe...?’ Schweiger senses a lot of scepticism “from a very broad section of the population. The only thing that helps is education, education, education!” Müller added: “Right now, everything sounds like ‘gene therapy’. But you can’t measure everything by the same yardstick.”

Since the COVID-19 pandemic at the latest, it has become clear that no matter how much information and differentiation there is, it cannot always dispel mistrust. However, the potential of the new therapies in the fight against many illnesses is enormous – and after all, it was once even considered controversial that tiny organisms cause diseases such as tetanus, tuberculosis or sepsis. It therefore remains to be seen whether the obvious success the new treatments will ultimately win them widespread acceptance.