How RNA- could potentially beat the dominance of protein-based therapy | by Agust Siregar | Feb, 2024

Adalimumab, a recombinant monoclonal antibody that is widely used to treat autoimmune conditions under the brand name Humira, held the title of the top-selling biological drug until it was surpassed by Comirnaty, an mRNA vaccine developed by Pfizer/BioNTech to combat SARS-CoV-2 infection. Yes, Adalimumab and recombinant insulin were two notable examples of protein-based therapy, next we call as PBTs. It is known that PBTs have dominated the global biologics market for a long time, particularly after the discovery of recombinant protein technology in 1977. However, the spotlight on this dominance is shifting with the rise of RNA therapeutics. Since the discovery of the first RNA therapy (antisense oligonucleotide; ASO) a year later after the recombinant protein was invented, it has steadily gained ground, finally culminating in the emergence of the COVID-19 pandemic, where the mRNA vaccine, Comirnaty, proven to be a most effective vaccine against COVID-19 compared to other platforms. Therefore, it makes sense to raise a question: can RNA therapy overtake the dominance of protein therapy? if so, how?. Anyway, before delving into a detailed discussion, let’s first gain an understanding of how biological drugs work and what kind of specific molecules they target are?.

Simply put, a disease arises due to an ‘imbalance’ of proteins and/or metabolites in our body, recalling the concept of Central Dogma, where the DNA is transcribed into RNA and the RNA is translated into protein. Furthermore, the interaction of proteins/enzymes through various biochemical pathways can lead to the production of metabolites including lipids, sugars, organic acids, etc., within the cells. In essence, biological drugs work by targeting these molecules, by either modulating or reducing their amount in our body. Have a look at the diagram below.

Figure 1. Biologics work by targeting DNA, RNA, proteins, or metabolites.

PBT at least works by two modes of action. First, blocking the interaction of an unwanted ligand with a target protein receptor which could lead to the promotion of a disease if not prevented. As an example, monoclonal antibodies can bind to the spike protein of SARS-CoV-2, preventing its interaction with the ACE2 receptors in human cells and thus forestalling the infection. Second, by modulating the amount of certain proteins/enzymes through external injections into the human body, so-called enzyme or protein replacement. We can see this in the case of individuals with type 2 diabetes who are unable to self-produce insulin — a hormone that functions to lower the blood sugar level, often due to mutations in the hnf genes, PBT solves this by externally injecting insulin inside the patient’s body.

To some extent, PBTs have become the best option even the most suitable therapy for certain diseases, as proved by its high volume of sales. However, another problem comes when a disease cannot be treated by a common protein-protein interaction approach, which could happen if the target is located in an inaccessible place and has complex biological mechanisms where the drug-target interaction is not possible to occur. This phenomenon is known as an ‘undruggable disease’ such as Parkinson’s, Alzheimer’s, and a few cancers. However, I think that’s the beauty of biology, if we can’t target the protein, why don’t just control its mRNA, as every protein is translated from mRNA, even we can control it further backward by correcting the gene or the DNA level with technology so-called gene therapy. Here’s how the RBT comes to take the role and close that gap.

If targeting the proteins or metabolites is not possible, then control the RNA; if that still doesn’t work, correct the DNA.

Now, It’s interesting to explore more into how the RNA molecule can be repurposed as a therapeutic agent which is known as RNA-based therapy (RBT). Basically, RBT is any therapy that uses or modifies RNA molecules as the therapeutic agent and works mostly by targeting the RNA molecules too. As was previously mentioned, we can regulate the amount of protein generated as long as we have control over the RNA. If the protein is harmful often due to mutations, then destroy the mRNA encoding that protein. Conversely, if the resulting protein is not functioning as usual, which promotes protein deficiency, also typically caused by mutations, an external mRNA supply would be needed. Therefore, based on its function, RBT mode of action at least could be divided into two, lowering the number of RNA targets by promoting degradation (RNA interference/siRNA) or modulating its expression (antisense oligonucleotide and messenger RNA).

Inclisiran is a well-known example of RBT developed by Novartis, it has been used for hypercholesterolemia medication — an excessive level of bad cholesterol in the bloodstream. This cholesterol needs to be absorbed by the cells through the lipoprotein receptor embedded in the cell surface, but an imbalanced expression of PCSK9 protein can reduce the amount of the lipoprotein receptor. Employing Inclisiran, a short interfering RNA designed to target PCSK9, will induce PCSK9 mRNA degradation so the cells can uptake the cholesterol from the bloodstream. Other recent examples but different modes of action are Comirnaty and Spikevax, two mRNA vaccines against COVID-19 developed by Pfizer/BioNTech and Moderna, respectively.

If we go back in time, the first recombinant protein technology was discovered in 1977. A year later, antisense oligonucleotide, or ASO, was invented and tested to treat RSV viral infection. Then, in 1989, eleven years later, the In-vitro transcription (IVT) technology was established. It demonstrates that PBT was founded and established earlier, which likely helps to explain why PBT has dominated the biologics industry for a long time. Research on RBT is moving rapidly, particularly since the development of IVT, which significantly eases RNA synthesis and is reinforced by the success story of two mRNA vaccines against COVID-19. RBT has the potential to eventually overtake the dominance of PBT. Well, here are some rationales why RNA-based therapy will revolutionize the biopharmaceuticals industry:

  1. RBT could treat rare or undruggable diseases because, in the context of the central dogma of biology, it has the capability to target further backward to the RNA level. As long as we know the sequence of the gene target, we can design the RNA therapeutics to degrade or modulate the target.
  2. Concerning bioprocess development, biologics with an RNA platform can be developed more easily, quickly, and with greater versatility. IVT significantly reduces the time needed to synthesize RNA without having to undergo the cell culture process, as is typically done in recombinant protein production. Once the design is established, the RBT can be synthesized rapidly for clinical trial.
  3. Since RBT could be produced by IVT or a cell-free system, it simplifies the downstream process required, as the impurities will not be as complex as those found in products from the cell culture process.
  4. There is a low or almost no risk of genotoxicity, especially when compared to gene therapy, which targets the DNA sequence. RNA will not alter any DNA blueprint sequence.

Finally, of course, RBT is not a flawless technology. Unlike proteins, naked RNA is highly susceptible to degradation, prompting scientists to consistently seek better solutions for that problem. Numerous modifications have been implemented to enhance RNA stability, such as the groundbreaking work of Katalin Kariko, a Nobel Prize winner in medicine in 2023, who introduced a modification transforming uridine base into pseudouridine. This modification not only improves stability but also reduces the risk of triggering unwanted immune responses. Additionally, the delivery system, which currently relies on well-established lipid nanoparticles (LNPs) and is utilized in recent RNA therapy products including mRNA vaccines, has demonstrated stability. Despite these advancements, there remains ample room for further improvement in RNA-based therapy.

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