With all the advances that are occurring in the field of RNA therapeutics, one can say that we are in the midst of a revolution. Only around 20% of the human proteome is considered to be “druggable” by small molecules, but RNA drugs have the potential to access the rest. The recent SARS-CoV-2 vaccines developed by Moderna and BioNTech illustrate the potential of these therapeutics that have been somewhat dormant until now. These RNA-based vaccines were developed in record time, produced at a mass scale, and with stellar safety profiles. They not only saved the day but perhaps set the start of a new age for therapeutics.
RNA and the potential of RNA therapeutics:
Shortly after DNA was discovered, RNA was proposed as an “unstable messenger” that translates DNA into protein. Since then, many eminent scientists with decades of research have led us to a deeper understanding of this molecule and its indispensable role in the physiology of life. With this understanding, we have now come to appreciate the therapeutic advantages it holds in treating human diseases. RNA-based therapeutics, in conjunction with other biologics, have the potential to make “undruggable” targets obsolete.
Although COVID-19 has brought into focus the immense potential of RNA therapeutics, these have existed in the market since 1998, when Fomivirsen was the first approved RNA-based drug for CMV retinitis. Since then, multiple RNA drugs have entered the market, and many more are being researched and are currently in clinical trials.
Principles of RNA therapeutics:
RNA drugs rely broadly on three principles/mechanisms:
- Binding to proteins for functional modulation (e.g., aptamers)
- Binding to nucleic acids to inhibit translation (e.g., antisense oligonucleotides, siRNAs, microRNAs)
- Expressing proteins or antigens (e.g., mRNA)
mRNA drugs work by expressing proteins with the help of messenger RNA. The first clinical trials that sought to use mRNA were reported in 2005, and these trials were carried out to investigate using mRNA vaccines for melanoma. Currently, there are close to 30 trials that are reportedly trying to use mRNA for therapy. The three major areas where mRNA therapies show great promise are:
- Vaccines against infectious diseases
- Cancer vaccines
- In vitro transcribed mRNA for antibody therapy
mRNA vaccines for infectious diseases:
COVID-19 has been a testament to the effective use of mRNA vaccines for infectious diseases. These vaccines have been developed, approved, and utilized in record-breaking time, given the dire situation throughout the world. The mRNA vaccines have an advantage over traditional vaccines in that they can generate a stronger immune response by production of antibodies and immune system killer cells. Traditional vaccines are generated using attenuated virus cells and also make use of chemicals and cells. For example, a flu vaccine is made by injecting fertilized hen’s eggs or animal cells with viruses and incubating them for a few days. Then, the virus is isolated and purified before mixing with the necessary stabilizers or preservatives.
On the other hand, mRNA vaccines are comparatively safer, since they do not make use of infectious organisms nor do they risk being contaminated with animal antigens. Additionally, mRNA vaccines can be designed and produced quickly, which is especially important not only for epidemic outbreaks but also making them suitable for smaller specialized batches.
mRNA cancer vaccines:
Unlike traditional cancer therapy, cancer vaccines immunize the patient by targeting tumor-associated antigens and stimulating immune responses. These vaccines, once fully developed, will have a huge advantage over the existing therapies. They will be able to target cancer cells more selectively, which has been the biggest challenge with chemo and radiotherapy. Moreover, thanks to mRNA, we can potentially make “personalized” vaccines that can target patient-specific antigens identified from the tumor.
The use of mRNA vaccines for cancer has shown promise in multiple clinical trials. When patients with Stage III or IV melanoma were immunized with the mRNA encoding for the specific antigens, 27% of them showed tumor regression. A Phase II clinical trial established the effectiveness of injecting an mRNA formulation that encodes for tumor antigens in patients with metastatic melanoma. Another study has used a similar approach with regard to non-small cell lung cancer (NSCLC) patients and showed an increased immune response in 84% of the patients. Given the promise these trials show, mRNA drugs are now also being tested in conjunction with checkpoint inhibitors for NSCLC.
mRNA therapeutics for antibody production:
Antibody therapy is a potent and useful tool to tackle various diseases. But widespread development of such therapies is restricted, since these drugs are extremely expensive and difficult to manufacture. This has led to a pursuit of producing and delivering antibodies using alternate strategies. While the idea of using mRNA for in vivo antibody production is still in its infancy, there are promising results in multiple preclinical studies.
The Pardi team was the first group to show that mRNA encoding for an antibody against HIV-1 outperformed a monoclonal antibody delivery in a mouse model. Similarly, the Stadler team has preclinical data on the use of mRNA to produce bispecific antibodies that can be more efficient than monotherapy or even a conventional protein-based therapy.
The use of mRNA for protein replacement therapy has also been shown by Zangi et al, where they introduced mRNA encoding for VEGF in a murine model of myocardial infarction. Recently, Moderna has conducted Phase I clinical trials showing the potential of injecting mRNA encoding VEGF as a regenerative therapeutic in human patients. As these trials move along, we will be able to know how injecting mRNA into the heart supports regenerative angiogenesis.
Existing challenges and potential solutions:
While the above applications reinforce the tremendous potential that mRNA holds, there are certain challenges that need to be overcome before we fully realize these therapies in clinical settings.
Historically, the largest obstacle with RNA therapies has been their delivery to the targeted region in the body, as mRNA is larger than conventional small molecule drugs, is electrically charged, and is susceptible to degradation. Finding the right carrier was the obvious answer, and lipid nanoparticles have shown to be a promising one, having been successfully employed by the two mRNA vaccines on the market currently. RNA can also be bound to conjugates that bind specifically to the receptors of the target organ and deliver it to the cells. Additionally, RNA medicines are thermally unstable, requiring a complicated and expensive cold supply chain down to the end user. Moderna has shown that it is possible to circumvent this by freeze-drying their COVID-19 vaccine, with no significant effects on their efficacy.
Another challenge that needs to be solved is at the manufacturing level. Manufacturing, and particularly, purifying RNA drugs, is a sensitive process, with many variables making the scale-up subject to unpredictability and the entire process very complex. Given this fact, the scaling up of the COVID-19 vaccines has been especially impressive. This has also allowed for RNA manufacturing services and contract firms to flourish that can be used in the future for other RNA therapies.
Inevitably, research on RNA drugs and the increasing approval rates will eventually allow for clinical trials on larger scales, and the demand could even lead to improved at-scale manufacturing.
mRNA developers are starting to make news:
Recently, there has been a flurry of moves in the mRNA therapeutics space, since their potential is becoming evident. This year, in a $470M deal, Sanofi acquired the mRNA therapy company Tidal Therapeutics, which works on using mRNA for immuno-oncology and other diseases. Additionally, Merck acquired AmpTec, an mRNA CDMO, to expand its mRNA-producing capability for vaccines and other treatments.
In Europe, the clinical-stage company eTheRNA immunotherapies NV received an award from the EU commission for developing mRNA-based therapies in the treatment of cancer and infectious diseases. Another clinical stage company, Ultragenyx Pharmaceuticals Inc, received FDA clearance for an IND application for an mRNA-based treatment of a glycogen storage disease.
RNA and mRNA therapeutics hold an advantage not just over traditional small molecule drugs but also gene therapy. Unlike small molecules, RNA drugs can be designed very rapidly, and a great example of this is the COVID-19 mRNA vaccine that was famously designed in only two days.
Additionally, in contrast to gene therapy, RNA therapeutics do not make permanent changes to the DNA and are hence less prone to permanent side effects and don’t need to make it into the nucleus, thus being easier to deliver. RNA therapies are already unlocking treatments for rare diseases (e.g., hereditary transthyretin (hATTR) amyloidosis) that were previously unaddressable. As challenges in the delivery and manufacturing of RNA therapeutics are surpassed and more RNA drugs are making it through clinical trials, the time is ripe for RNA therapeutics to take off.
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