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Limitless Potential of mRNA Creates Tremendous Excitement Despite Uncertainties

Limitless Potential of mRNA Creates Tremendous Excitement Despite Uncertainties

Oct 11, 2022PAO-10-022-NI-02

Decades in Development

Messenger RNA (mRNA) was first discovered in the early 1960s,1 synthetic mRNA was first produced in the laboratory in the mid-1980s, and the first mRNA vaccines were developed in the early 1990s. However, issues with stability and immunogenicity delayed their progress through the clinic. The source of the inflammatory reaction and a means for avoiding it were not discovered until 2005 by researchers at the University of Pennsylvania. Meanwhile, a scalable method for producing lipid nanoparticles (LNPs) — comprising four different lipids and used for nucleic acid delivery to cells — was also established by 2005. The first clinical trials of LNP-based mRNA vaccines for infectious diseases were conducted in 2015, and the first mRNA therapeutic (patisiran, ONPATTRO®, Alnylam Pharmaceuticals) received FDA approval in the United States in 2018.

The rapid development and approval of the first mRNA vaccines against COVID-19 were the direct result of all of the prior efforts in the mRNA space. By early 2020, the advances achieved in LNP drug delivery for mRNA, the prior approval of some mRNA therapies, and the experience gained by companies like Moderna and BioNTech during the development of mRNA vaccine candidates meant that the pieces were in place to facilitate the success of the first mRNA vaccines. The unprecedented levels of government funding2 and extensive cross-industry collaboration, both driven by the urgency of the pandemic, accelerated the technology to the point where its commercialization was possible.3

The experience, knowledge, and capabilities that both Moderna and BioNTech (which had licensed the technology developed by the UPenn researchers4) established developing mRNA vaccines against HIV/AIDs, influenza, and other diseases positioned both companies to rapidly develop candidates against the novel coronavirus. They also benefited from tremendous advances in sequencing technology; previous in-depth research on other troubling coronaviruses, including SARS and MERS; and advanced algorithms capable of rapidly identifying optimal stable molecular structures for mRNA vaccines.5

Delivery Technology Crucial to Success

As a large molecule with a significant electric charge, it is difficult for RNA to cross cell membranes.6 Getting mRNA into the right cells or tissues is challenging as well. Complicating these issues is the fact that RNA is degraded by enzymes (RNases) in the bloodstream. LNPs, originally developed by University of British Columbia, Vancouver researcher Peter Cullis,1 overcome these difficulties. Other technologies being explored for RNA delivery include polymer-based solutions and the use of conjugates, such as N-acetylgalactosamine (GalNAc), that bind to specific receptors on the surfaces of cells.6

Limitless Potential

The success of the COVID-19 mRNA vaccines has generated significant excitement in the field, both for other mRNA vaccines and for therapeutics. Vaccines and therapies can be produced with highly specific molecular designs and functionalities, allowing the targeting of a wide range of biologic mechanisms involved in many different diseases.7 

 

Furthermore, because mRNA delivers instructions to cells that drive protein production, it is unlike other existing types of drugs and can be used to target intracellular proteins, which have previously been considered undruggable using traditional small molecule and antibody-based drugs.8 Similarly, mRNA can potentially be used to target most pathogens.8 As a result, mRNA technologies can theoretically be used wherever immune-related responses are required, such as in vaccines for infectious diseases and cancer, but also where missing or altered proteins are the cause of a disease.3

 

The fact that mRNA drugs can address underlying causes of diseases means they may have the potential to achieve greater efficacy than traditional drugs.9 In addition, with the advanced state of genome sequencing, personalized mRNA therapies and vaccines can be developed for specific patients. The rapid degradation of mRNA also reduces concerns about undesired genomic integration.

 

Manufacturing advantages exist as well. Platform approaches are applicable; only the genetic sequence changes, and manufacturing, purification, and LNP formation are generally the same processes.8 As importantly, mRNA is produced using a chemical synthesis process, not a biological cell culture process, making it far easier to scale.9 Beyond that, a strong manufacturing network for mRNA — and much of the necessary regulatory framework — were both largely established as the result of the success of the COVID-19 vaccines.10 

 

Exploding mRNA R&D

Initial mRNA development efforts focused on rare genetic diseases, such as Usher syndrome type 2 and Hurler’s syndrome, but candidates are now undergoing clinical trials for more common conditions, including cancer and cardiovascular disease, as well as vaccines for many different infectious diseases.7 By late summer 2021, there were over 1,800 clinical studies involving mRNA listed on ClinicalTrials.gov, nearly one-quarter of which were in phase II.9 Approximately 60% of the pipeline are oncology therapies for solid tumors, and 30% are vaccines against infectious diseases.3 The remaining candidates cover a wide range of diseases with varying disease mechanisms, including the production of hormones or cytokines. Some specific examples include treatments for colorectal cancer and Lyme disease, cures for autoimmune diseases, and nonviral delivery systems for gene therapies.11

 

Some of the biggest projects are targeting the development of vaccines for infectious diseases that have to date eluded effective vaccine solutions, including malaria, influenza, and HIV/AIDS. The speed of development and the ability to encode for multiple variants in one vaccine are driving this interest.12 Development speed is also crucial for many of the cancer vaccines in the pipeline, for which genetic analysis data for individual patient tumors can be used to produce personalized mRNA vaccines that are administered after surgery to generate an immune response against those tumor cells for years to come.

 

Today, BioNTech and Moderna have extensive clinical pipelines that include both mRNA vaccines and therapeutics. Other companies are developing targeted mRNA candidates by putting the mRNA into viruses or non-viral particles that are only taken up by certain cells or using polymers that are absorbed only by certain tissues.9 Some companies are taking an orthologous approach to RNA metabolism: rather than produce mRNA as therapeutics, they are developing small molecule drugs that regulate mRNA activity.

 

Even so, there is tremendous excitement in the biopharma industry about the arguably limitless potential of mRNA technology to enable the development of vaccines and therapeutics that will address significant unmet medical needs. The market is expected to expand at double-digit growth rates over the next five years.13,14 Estimates for the value of the global mRNA therapeutic and vaccine market differ significantly, however. IMARC Group predicts that it will expand at a CAGR of 10.5% from $9.41 billion in 2021 to $15.49 billion by 2026.13 BCC Research, meanwhile, pegs the value at $46.7 billion in 2021 and rising at a CAGR of 16.8% to $101.3 billion by 2026.14 

Estimates for the value of the global market for all RNA-based therapeutics, including antisense RNA and RNA interference (RNAi) drugs for the treatment of genetic and autoimmune disorders, is estimated to be expanding at a CAGR of approximately 5% to 17.5% to reach $11.4 billion by 202715 and $25.12 billion by 2030.16

Many Possible mRNA Vaccines

While a few vaccines continue to be produced based on live, inactivated, or dead viruses, most current vaccines are based on engineered proteins that represent the portions of viruses that illicit immune responses. Although the development time for the latter is much shorter — 3–4 years versus 8–10 — cell culture or fermentation is still required. However, the simpler and platformable nature of mRNA technology allows for the development of new vaccines in much less time. Once the desired genetic sequence is known, candidates for preclinical and clinical studies can be generated within a few months, allowing more options can be screened and thus increasing the likelihood of creating an optimum vaccine.17

 

There is particular excitement about the potential for mRNA to enable a vaccine against HIV because of its ability to generate broadly neutralizing antibodies.18 Similarly, there is interest in developing an mRNA-based flu vaccine, because the shorter development times would reduce the opportunity for virus mutation, and there is a potential for mRNA vaccines to work against all variants, leading to increased efficacy while also reducing the frequency at which immunization would be required.9 For this application, self-amplifying mRNA (sa-mRNA) vaccines are showing real promise.19 Unlike regular mRNA, sa-mRNA instructs the body to replicate mRNA, amplifying the amount of protein made, thus providing the same response levels at reduced dosage or stronger cellular responses and higher antibody titers at the same dose levels.

Many startups and big pharma companies are developing mRNA vaccines for a wide range of infectious diseases.2 In October 2021, a total of 49 mRNA prophylactic vaccine candidates were in clinical development. The U.S. Defense Advanced Research Projects Agency (DARPA ) and the UK Charity Wellcome Leap are two organizations providing significant funding for mRNA vaccine development and the establishment of standard manufacturing platforms.17 Organizations such as the Bill & Melinda Gates Foundation and the Coalition for Epidemic Preparedness Innovations (CEPI) are also funding research efforts focused on the development of mRNA vaccines for infectious diseases that have not received much interest in recent years, such as dengue and Lassa fever.10 Other important targets include malaria, which has presented challenges owing to the complex and evolving nature of the organism that causes it, rabies, tuberculosis, Nipah, Zika, herpes, and hepatitis.20–22

Many Possible Precision mRNA Cancer Therapies

Cancer vaccines that encode specific genetic mutations within a given patient’s tumor could potentially train immune cells to target tumor cells bearing those mutations. mRNA provides an effective means of antigen delivery in combination with innate immune activation–mediated co-stimulation.23 Approaches include mRNA-based dendritic cell vaccines, mRNA-encoded antigen receptors, mRNA-encoded antibodies, and mRNA-encoded immunomodulators, such as cytokines and stimulatory ligands and receptors. With a platform manufacturing approach, mRNA is making this type of oncology treatment practically possible, even for more common cancers.24 

 

Beyond cancer vaccines, the versatility of mRNA is allowing for the exploration of a wider range of mRNA-based cancer immunotherapies.23 For instance, mRNA is being used to produce CAR-T cells with better safety profiles, and the first mRNA-encoded cytokine therapies are being evaluated in the clinic.

Role for mRNA in Gene Editing

mRNA has been shown to be an attractive vehicle for delivering gene-editing tools into the right cells. In fact, mRNA was used to delivery CRISPR gene-editing technology in the first clinical trial to demonstrate that CRISPR can be used to treat genetic disorders in humans.25 The specific case involved delivery of the gene-editing instructions to the liver, but it is expected that with modifications mRNA could be used to deliver gene-editing solutions for diseases of other tissues, including bone marrow, nervous system, and muscle diseases. Separately, a new mRNA delivery system that harnesses a human retrovirus-like protein was used to deliver CRISPR-Cas9 gene-editing tools that edited a specific location on a chromosome in human cells.26

Another application of mRNA as an alternative to viral vectors for gene editing is the modification of induced pluripotent stem cells (iPSCs). It has been used to directly generate a variety of different therapeutic cells and/or enhance their proliferation, survival, or function.27 mRNA has also been transfected into mesenchymal stromal cells (MSCs), which have numerous attractive properties, including the capabilities to self-renew, to differentiate into different cell lineages, and to migrate to sites of injury and secrete proteins that reduce inflammation and promote tissue repair. While these approaches involve ex vivo modification of cells, researchers are also exploring direct injection of mRNA therapies, such as for cardiac regeneration.

Continuous Improvement

Although the COVID-19 vaccines were developed and commercialized in record time, there are still opportunities for improvement of mRNA therapeutic and vaccine designs and the manufacturing processes used to produce them.10 Researchers at King’s College London are aiming to develop a very small, cartridge-based mRNA manufacturing system that could eliminate cold-chain issues and lower costs by enabling the production of vaccines in hospitals. BioNTech is seeking to develop mRNA that can only enter certain cells, last longer, and generally make delivery more precise and less toxic.

 

Ginkgo Bioworks and partner Aldevron report achieving a “breakthrough” in mRNA manufacturing that increases production yields of the vaccinia capping enzyme (VCE), which helps the body recognize foreign mRNA and thus prevent its degradation, by more than 10-fold.28 GreenLight Biosciences produces mRNA via fermentation rather than chemical synthesis to, according to the company, disrupt manufacturing bottlenecks.29

Significant M&A and Deal Activity

Smaller companies have largely been the firms to establish mRNA expertise (approximately 12 companies other than Moderna and BioNTech30), and big pharma has largely elected to partner with or acquire them. Examples include not only Pfizer with BioNTech, but AstraZeneca with Moderna and GSK with CureVac. Sanofi and Merck acquired Translate Bio31 and AmpTec,32 respectively. Big pharma is also financing smaller firms. mRNA startups, largely in the United States and Europe, raised approximately $4.6 billion in funding in recent months.6

Anticipating Real Proof

Commercialization of the COVID-19 mRNA vaccines took place under unique circumstances that led to unprecedented funding and collaboration. Those conditions are no longer in play, and challenges for mRNA drug products remain. LNPs do not fully address instability and cellular uptake issues. Targeted cell delivery is still an issue for mRNA therapeutics, as are dose optimization and immunogenicity.7 Immunogenicity problems and off-target effects are observed with many mRNA candidates. In general, a better understanding of the biology of mRNA and its specific roles in various diseases is needed.3 Both therapeutics and vaccines face high costs, some of which are due to cold-chain challenges. Regulatory guidelines have advanced somewhat, but some uncertainties remain.

 

Some clinical trials have afforded promising results. mRNA candidates have been in development for many years, yet not one — other than the COVID-19 vaccines — has received regulatory authorization. At this point, it is not known whether the success achieved with the SARS-CoV-2 vaccines will be repeatable for other infectious diseases or whether mRNA immuno-oncology treatments — especially if they require personalized solutions, such as with autologous CAR-T-cell therapies — and other therapeutics will be achievable with practical dosing schedules and no undesired immunogenicity.

 

Many people believe, however, that the challenges still facing mRNA therapeutics and vaccines can and will be overcome. Given its potentially limitless potential, there is real hope that mRNA will indeed be truly transformative, with many of the current vaccine and therapeutic candidates successfully addressing the tremendous unmet medical needs that exist across numerous rare and prevalent diseases.

 

Several Types of RNA Therapeutics
While the COVID-19 pandemic has turned the spotlight on mRNA, there are several different types of RNA with potential for use as therapeutics.6,33 After mRNA, the most well-studied class of RNA drugs is based on antisense RNA (RNAi), which are short oligonucleotides that recognize and hybridize to complementary sequences in endogenous RNA transcripts and alter their processing.33 Other classes include antisense oligonucleotides (ASOs), small interfering RNA (siRNA), micro-RNA, and aptamers.
Antisense oligonucleotides are short, single-stranded oligonucleotides that are complementary to a certain region of a target RNA (such as an mRNA) with high affinity and stability.6,33 They can, for instance, be designed to bind to a virus and interfere with its reproduction. RNase H–dependent ASOs are dependent on the endogenous RNase H enzyme that hydrolyzes the RNA strand of an RNA/DNA duplex and are more common than RNase H–independent ASOs that function basic on steric interactions. As of early 2021, three ASO drugs had received FDA approval.
Small interfering RNAs (siRNAs) are small, non-coding, double-stranded RNAs that are generally complementary to the coding region of a target mRNA, leading to knockdown of a specific target gene.33 Alnylam Pharmaceuticals has two FDA-approved siRNA drugs.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate the expression of multiple mRNAs by blocking translation or promoting degradation of the target mRNAs.33 miRNA mimics are double-stranded RNA molecules that mimic miRNAs, while miRNA inhibitors are single-stranded RNA oligos designed to interfere with miRNAs. No miRNA drug has yet been approved by the FDA, but several are in clinical trials.
RNA aptamers are short, single-stranded nucleic acids that can bind proteins, peptides, carbohydrates, and other molecules as determined by their tertiary structure.33 Just one aptamer has received FDA approval, but several candidates are undergoing clinical trials. There is interest in aptamers as alternatives to monoclonal antibodies because they are easier to produce (chemical synthesis vs. cell culture), less costly, simpler to modify, and have limited immunogenicity issues.

 

References

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