ProQR’s Bart Klein about the Axiomer® platform “A new way of designing medicines”

2017 was a fruitful year for ProQR, in many ways. One particular advancement was that the company established proof of concept for the Axiomer® platform, a novel and proprietary RNA editing platform technology.

A photo of Bart Klein

The potential of this new technology for RNA therapeutics is immense, says Bart Klein, who was at the forefront of the Axiomer® technology development. ProQR’s Sr. Vice President Innovation makes his point about the promise of Axiomer® technology: “This opens up a whole new way of designing medicines for genetic diseases that were previously ‘out of reach’ for existing technologies.”

Before joining ProQR, Bart Klein was a Dutch and European patent attorney with a Master’s degree in Chemical Biology/Molecular Biology. What is Klein’s connection to RNA therapeutics? “At the end of the 80s, I wrote my master’s thesis about differential splicing of RNA, a biological phenomena that was new back then. Over time, these and other biological insights have led to new therapies based on splice switching, a technology underlying ProQR’s programs in genetic eye and skin diseases, for example. After graduating, I pursued a career as an Intellectual Property (IP) Specialist in life sciences and telecommunications. During my career, I have worked for several start-ups and established enterprises, including Crucell, before joining ProQR.”

“An important milestone came when I met ProQR’s founders in 2012 for a consulting assignment; I was to conduct due diligence for an investor and soon thereafter was asked to advise ProQR in the field of IP. I later joined ProQR and since 2016 I lead the company’s Technology Development department. Coming to ProQR felt as if I had ‘come full circle’ with RNA, after all those years. ProQR is developing oligonucleotide-based therapies targeting several genetic diseases, including ‘splicing diseases’. I find the biology of post-transcriptional gene regulation fascinating, more specifically the oligonucleotide-based technologies that make it possible to interfere with such regulation to cure diseases.”

RNA technology has proven to be a viable path for the development of therapies for underserved rare genetic diseases. How did Axiomer® technology come into play?

“Since the discovery of RNA editing, new findings have led to new technologies. The Axiomer® platform is a great example of this. In 2014, the foundation was laid with the idea to hijack the endogenous RNA editing enzyme ‘ADAR’ in our cells and to redirect it to any target of choice, just using a chemically modified oligonucleotide; after the first successes in the lab we knew we were on to something and built it into what it is today: a new approach to treat rare genetic diseases. And that’s only the start, because treating genetic diseases is not the only application of targeted RNA editing. In fact we can now modulate any RNA at will, changing either the expression of a specific RNA or modulating protein function encoded by it, inside a patient’s own cells, by just using an oligonucleotide as drug modality. Moreover, we do so without messing with a patient’s DNA and avoid the related safety concerns. The establishment of the Axiomer® technology opens up the door to treating disease causing mutations that were untreatable thus far.”

“It most certainly offers new possibilities in RNA modulation, both to ProQR and other companies that believe in the potential of RNA technology. Axiomer® platform can help push current borders, I dare say that it could change the entire playing field!”

That is a bold statement. What potential do you see, compared to, for example, CRISPR?

“CRISPR is another promising new development. It is a new research tool that allows for modification of cells on a DNA level. But it is also a very complex tool. Axiomer® technology is considered to be more elegant and less complex, with less risks involved. Its potential for application is wide, for many different therapeutic areas and genetic diseases. It is estimated that Axiomer® technology can be utilized for at least 20,000 genetic mutations, and that is only according to current knowledge. A lot of progress is being made in identifying mutations, in linking these to diseases and, in the end, in finding therapies for patients. As said before, the technology is not limited to application to genetic mutations. In principle, any change in RNA expression or protein function with benefits for patients can be realized, promising to offer treatments for a wide variety of human diseases, such as age related diseases (think about Alzheimer’s or Parkinson’s disease), forms of cancer and ultimately maybe even infectious diseases. With the Axiomer® platform, we are able to change the localization of proteins that play a key part in health – and change their functionality! We can do that in a much more subtle and sophisticated way than before. We are about to modulate the structure of proteins. On an RNA level, we can also change the quantity of protein. Axiomer® platform is a next step that offers precision we did not have before.”

How will ProQR put Axiomer® platform to work?

“We believe that Axiomer® platform forms the basis for a complete new field of medicine. Going forward we will further build out the platform and intend to transform this scientific breakthrough to generate new therapeutics for patients in need.”

“At the same time, we believe we need to open the window to the world. Axiomer® technology is such a powerful platform for science that we should not limit the use to ProQR only. We therefor plan to collaborate with others in strategic partnerships to enable the entire scientific community that focuses on genetic diseases to benefit from our Axiomer® technology. In January 2018 we entered into a first collaboration with Galapagos NV. In this collaboration we are applying the Axiomer® technology EONs to genetic targets that are believed to be involved with fibrosis.”

ProQR’s scientists found ways to design synthetic oligonucleotides that will go in to a cell and attract the ADAR enzymes to a particular site on the RNA that they want to change. They can make that change in a very specific and directed way without affecting the DNA.

Visualisation of the Axiomer technology at work, in a cell

Building on RNA technology

RNA editing was and is still no easy task; the technology still has its secrets and complexities, which can make clinical application difficult. In 2017, a huge milestone for the Axiomer® technology was achieved, showing we can edit a mutated RNA in the liver and brain in living organisms. Bart Klein: “In short, Axiomer® technology offers a way to make single nucleotide changes to RNA in a highly specific and targeted way. The essence of Axiomer® technology is that it enables targeted RNA editing in living organisms, without the need for external enzymes, needing only a synthetic oligonucleotide as drug modality.” Scientifically speaking, Axiomer® technology Editing Oligonucleotides (EONs) recruit endogenous ADAR in a patient’s cells, to make single nucleotide changes to a target RNA to fix a mutation or make a beneficial change at will, in a highly specific and targeted manner. For physicians, the Axiomer® technology holds the promise of offering new treatments for patients suffering from a wide variety of diseases with currently no or limited treatment options.

A new approach

The Axiomer® technology builds early scientific developments that in our view missed the critical characteristics to become therapeutics. Gerard Platenburg, our Chief Innovation Officer, and myself believed we could pull off targeted editing by taking an entirely new approach; an approach based on synthetic oligonucleotides and RNA editing enzymes naturally present in the cell. ProQR provided the opportunity to explore this idea and made resources available to perform the necessary R&D work. This was late 2014. Already in an early stage of the research project we hit success by redirecting the endogenous RNA editing enzymes to a target RNA of our choice. This was still in cell culture, but the principles worked! The foundation for the Axiomer® technology was established. We delivered in vivo proof of concept in a clinically relevant disease model already 2017 – a major milestone! We can now edit RNA in different cell systems and in living organisms. We realized at once, that this is a breakthrough that supports investing in an entirely new technology platform to treat a wide variety of human diseases. Today, we have a platform that is almost ready to start treatments of real diseases in patients, while we are further building out the platform. Establishing clinical proof of concept by treating a real disease in patients is our next goal. After having established that, we will be ready to target many more mutations and treat many more diseases that were previously ‘out of reach’ for existing technologies. Since the applicability of the technology is in principle very wide, we plan to further build out our partnering strategy to capture maximum value from this exciting new proprietary technology and impact as many diseases as possible.”

Source: ProQR’s Annual Magazine 2017

Learn more about the Axiomer technology.