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RNA-Based Therapies: Are We on the Verge of a Therapeutic Revolution?

Aug. 9, 2021 - Katie McCallum

"The technology is too rushed."

It was a common, uninformed criticism of the COVID-19 mRNA vaccines last January. Dr. John Cooke, medical director of the RNA Therapeutics Program at the Houston Methodist Research Institute, spent weeks — or was it months? — explaining why it was simply a misconception.

He wanted people to understand what he knew to be true: RNA technology wasn't rushed and isn't "new" — it's been studied by RNA experts like him for decades.

"Many of us in the field have recognized the therapeutic potential of RNA for quite some time, so it was thrilling to finally see this technology be approved for use in a vaccine," says Dr. Cooke. "It's taken many brilliant minds and many years of research to solve the several major hurdles of using this fragile molecule in a drug or vaccine, so it feels like an enormous win for the entire RNA field."

Now, Dr. Cooke wants people to know that RNA technology has life-saving implications beyond the COVID-19 vaccines too.

In a review article published in Frontiers in Bioengineering and Biotechnology, Dr. Cooke and his colleagues use the word "limitless" to describe the future of RNA therapeutics.

"We see RNA as biological software that will allow us to treat many diseases that were previously undruggable and untreatable," says Dr. Cooke. "It also has the potential to help us actualize personalized medicine."

Next up: A therapeutic revolution?

Why RNA? Well, conventional drugs come with limitations.

Small molecule drugs are limited by the difficulty of finding a "druggable" active site on a protein contributing to disease pathology, resulting in enormous screening efforts. Recombinant protein drugs overcome this challenge to an extent, but present size and stability issues and are often technically challenging to design and synthesize.

"We've long needed an easier way to target the 'undruggable,' with a therapy that's also cost-effective and relatively easy to manufacture," explains Dr. Cooke. "This is where RNA technology comes in. There are several different ways RNA can be used as a therapeutic, each with its own set of advantages and challenges."

For instance, mRNA-based strategies leverage messenger RNA to help a cell replace a defective protein or produce an immune-stimulating antigen. The latter is how the current COVID-19 mRNA vaccines work.

Antisense RNA strategies, on the other hand, target a cell's endogenous RNA — altering how a transcript is processed, often with the goal of silencing protein production.

"Depending on the specifics of disease pathology, these RNA technologies are being studied in the preclinical and clinical setting for everything from infectious disease to cancer to rejuvenating burn wounds," says Dr. Cooke.

The range of diseases and processes under study include:

  • Cancers, including non-small cell lung cancer (NSLC), advanced melanoma, multiple myeloma, lymphoma, brain and pancreatic
  • Cystic fibrosis
  • Diabetic nephropathy
  • Familial chylomicronemia syndrome (FCS)
  • Ischemic heart disease
  • Macular degeneration
  • Muscular dystrophy
  • Myasthenia gravis
  • Polyneuropathy
  • Spinal muscular atrophy
  • Tissue repair
  • Urea disorder
  • Viral infections, includes rabies, Zika, Chikungunya

RNA technology — just like RNA itself — moves fast

One of the most enticing features of leveraging RNA to treat or prevent disease is how rapidly the technology can be used to produce a new drug or vaccine.

Just look at how quickly the COVID-19 mRNA vaccines were developed.

"Within only months, scientists had already decided which component of the SARS-CoV-2 virus to target, written the code, synthesized the mRNA and generated the vaccine for human testing," says Dr. Cooke. "Speed is a hallmark of RNA technology."

Fortuitously, this rapidity reflects the relatively short lifespan of endogenous RNA itself. For instance, the RNA in the COVID-19 mRNA vaccines hangs around in a person's cell for just a few days — long enough to ensure the amount of antigen needed to stimulate a strong immune response is created, after which point it degrades.

"The short lifespan of RNA, as well as the fact that it's restricted to the cell cytoplasm and doesn't interact with DNA, is yet another reason to feel confident about the overall safety profile of this technology," says Dr. Cooke.

Plus, the ability to rapidly go from concept to drug might just be the difference in making an everyday reality of personalized therapy for some diseases.

"Because RNA is biological software, we can rapidly change the code to tailor it towards the most impactful signatures of a person's particular disease," says Dr. Cooke. "RNA is about the only drug you can use to rapidly create a personalized therapy."

Can hospital-based RNA therapeutics make an even bigger impact?

RNA technology is indeed ready for prime time. In case you still want proof, look no further than the dozens of RNA-based drugs in development across Big Pharma companies.

"But perhaps one of the more innovative concepts of late is democratization of RNA therapeutics — a model in which academic groups and small companies come together to bring an RNA therapy from bench to bedside," explains Dr. Cooke.

At the cornerstone of this model is Dr. Cooke's RNA Therapeutics Program.

"What we have here is very unique," says Dr. Cooke. "It's essentially an assembly line for RNA therapeutics that exists within the most medically-relevant location imaginable — an academic hospital. We have GMP-compliant manufacturing capabilities and quality control methodology, meaning we can take an idea through preclinical development and first-in-human clinical trials all within our hospital walls."

And through a collaboration with VGXI Inc, a local industry partner with large-batch manufacturing capabilities, Houston Methodist can also conduct late-stage RNA-based drug trials as well.

It's a winning model, especially for diseases that may benefit from personalized approaches including hard-to-treat cancers.

"We're situated in an academic hospital," says Dr. Cooke. "So we have access to the patient and the oncologist, we can sample and sequence their tumor, we have the computational biology expertise to design a personalized RNA-based drug specific to it, and we have a manufacturing process to create small, personalized batches of GMP-compliant RNA. In ways like this, our hospital-based approach to RNA therapeutics might be able to offer even greater benefit than the large pharmaceutical companies."

Plus, this isn't all the team is doing. The program has RNA experts at every level. They can also help academic researchers and physician-scientists design RNA constructs, improve the stability and translatability of RNA products and synthesize and validate RNA using GMP protocols.

"We're one of the only, if not the only, academic hospital that has a program dedicated to making clinical grade RNA that can be used in clinical trials," adds Dr. Cooke. "But, as you can see, we can also can do a lot more than that. Our goal is to help make the limitless future of RNA therapeutics a reality through research and drug development."