Gains in tRNAslation: It’s time for investors to realize the potential of European RNA technologies – MedCity News

The original is unfaithful to the translation, Jorge Luis Borges

Investing in new innovative RNA technologies can lead to rapid value creation, and Europe is a fertile ground to hunt for them. The discovery of DNA and the gene underlies much of modern medical therapy, and with the recent advent of successful gene therapies, is undergoing a renaissance. Only in the last couple of decades, however, has the translator of DNARNA, gained appreciation as a potential inroad for new therapies and led to the creation of several multibillion-dollar companies. While the field of RNA therapy has started to blossom recently, it, much like biotechnology companies in Europe, has underappreciated potential.

The main purpose of RNA, known as messenger RNA or mRNA, is to convert (or translate) the genetic information of DNA into proteins. There are many other forms of RNA now recognized, and each a potential target for therapies to combat disease and illness in ways considered undruggable until now. A short list would include the protein synthesis RNAs: messenger RNA (mRNA, Moderna- Covid-19 Vaccine), transfer RNA (tRNA), ribosomal RNA (rRNA), and small nuclear RNAs (snRNA), and regulatory RNAs: micro RNA (miRNA) and short interfering RNA (siRNA). The applications of these RNA species is for therapeutics for various treatment applications, including cancer, cardiovascular disease, kidney disease, infectious disease, metabolic disease and more.

Examples of RNA therapies already approved include: Macugen (approved 2004; Pfizer) for the treatment of AMD, Exondys 51 (approved 2016; Sarepta Therapeutics Inc) for the treatment of Duchenne muscular dystrophy; Spinraza (December 2016; Biogen) approved for the treatment of spinal muscular atrophy in children and adults, and Onpattro (August 2018; Alnylam Pharmaceuticals) approved for the treatment of hATTR in adults.

The major advantages of targeting RNA are specificity and therapeutic leverage. One of the major barriers to developing any new drug is the safety profile and potential side effects. While a given drug may affect the target you want, there is always potential that it will also affect other targets. This is less true for RNA as its made of a specific sequence of 1 of 4 nucleic acids, the longer the matching sequence the lower the chance of targeting the wrong RNAand mathematically, this occurs very rapidly as each nucleic acid is added to the molecule. This is essentially the same technique that another new breakthrough technology such as CRISPR (also an RNA-guided technology) relies on for targeting. Further, as mRNA is upstream of much of the activity of making a protein, one does not need as much material to achieve a large effect.

The major obstacle in the development of these technologies, DNA, RNA, gene therapy, etc., turns out to be getting the oligonucleotide (DNA or RNA) to its intended target cell. The development of oligonucleotide therapeutics is challenging since DNA/RNA is inherently unstable and prone to degradation, immunogenic and rapidly cleared, and requires safe and effective delivery. To date, therefore, the greatest successes have been in easy to reach or target organsspecifically the liver, eye and muscle.

In my recent diligence, I have come across two new RNA technologies, being pioneered for clinical use by European and/or Israeli companies that seek to overcome the above-stated challenges.

The first technology is known as DNAzymeusing sequences of DNA that contain two factors: first, a sequence of oligonucleotides that will match a specific sequence of RNA (specificity) and the second, when this sequence is matched, it activates an internal loop of the DNA that can act to cleave the target RNA, and it can do this repeatedly, like an enzyme (therapeutic leverage). Instead of using oligonucleotides to match a given sequence of RNA, bind to it, and thus turn off its activity, DNAzyme, because it can be used repeatedly to target and cleave the same sequence of RNA has an increased advantage in therapeutic leverage. This allows for smaller amounts needed to achieve an effect, and, therefore, potentially improves the range of delivery technologies available and potential targets.

A second innovative RNA technology that has reached the clinic is short activating RNA. Short interfering RNA has been used by pioneering companies like Alnylam. Essentially, a given short RNA sequence can be used to convince cells to reduce or turn off the production of a protein. It turns out that similar short sequences of RNA can also convince a cell to turn on or produce more of a protein. Thus, short activating RNAs (saRNA) are a new approach being used to turn on targeted proteins enabling an increase in translation, if you will. saRNA opens a whole new landscape of potential therapies by turning on genes and increasing protein production.

European and Israeli companies are pioneering the clinical application of these technologies partly due to the fact that the intellectual property around earlier technologies is already well established and thus there is a need to find new technologies. Regardless, the fact that Israel and Europe are innovating in this area presents an interesting dynamic for investors. On the one hand, these companies often need greater management depth and might require more investor time and effort, on the other hand, the valuations can be lower and there is less capital available for later-stage investing, allowing for greater deployment at better terms.

As companies continue to demonstrate success with RNA therapeutics, especially as Moderna or BioNtech may soon have an approved Covid-19 vaccine using mRNA, I believe that we will see rapid expansion of RNA-targeted therapeutics and value creation. Additionally, as the arsenal of RNA technologies increases, we will see greater ability to target yet-undruggable proteins with these young companies providing a large platform for patient cures and investor returns.

Photo: Abscent84, Getty Images

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Gains in tRNAslation: It's time for investors to realize the potential of European RNA technologies - MedCity News