What a Difference a Decade Makes

September 22, 2019

by Michael Heartlein
Founder, MRT Platform
Translate Bio

In 2018, we became the first biotech company to begin testing an mRNA therapy for a genetic disease in patients.

This is quite an accomplishment— we believe it has made us a leader in the field of mRNA.

This didn’t happen overnight however— it took years of dedication, curiosity and effort by a pioneering group of scientists.

But what a difference the decade made…

“The exciting thing about Translate Bio’s approach to mRNA therapy is the potential to give the body the instructions it needs to make a missing or defective protein – to essentially make protein therapies inside cells, something that protein drugs cannot do.”

— Michael Heartlein,
Founder, MRT Platform

There is no doubt that now is an important time for mRNA therapies — but initial proof of concept of using mRNA as a drug was born more than two decades ago.

In the early 1990s, scientists demonstrated the concept of using mRNA for protein replacement, but unfortunately, like many “aha” moments in science, the technology did not exist to advance the discovery into drug development.

Over the last decade, innovations in design, delivery, and manufacturing have made it possible for us to develop mRNA medicines designed to treat diseases that have had few treatment options in the past, such as rare genetic disorders.

For Translate Bio, the path to mRNA drug development started in 2008 when our pioneering group of scientists was established within Shire Pharmaceuticals to work on mRNA design, delivery and manufacturing. Our accomplishments were notable:

  • Established successful in vivo protein production in liver and lung, with delivery to hepatocytes and bronchial epithelial cells
  • Established multiple dosing and efficacy in mice and non-human primates
  • Scaled up and achieved 100g single batch proof of principle production of pure mRNA and a manufacturing process to support preclinical and clinical studies
  • Received patents covering mRNA delivery and use in liver, and mRNA technology itself
    There are now more than 100 patents issued around our MRT platform

Our 10+ years of pioneering mRNA as a therapeutic has solidified our understanding of mRNA therapy and our approach to drug development today.

In late 2016, Translate Bio acquired Shire’s mRNA Therapy (MRT) platform. Because the MRT platform was incubated and supported by Shire for nearly a decade, we have invested significant time and energy to understand and overcome many of the challenges in mRNA drug development. In fact, a number of these challenges have turned into the key pillars of our work and differentiate our platform. For example, messenger RNA is designed by nature to be unstable; within the human body mRNA is produced, it leads to the production of protein, and then it degrades. To administer mRNA that would remain stable in the body, we devised lipid nanoparticles (LNPs) that would encapsulate the messenger RNA and keep it stable while being administered to patients. Furthermore, we developed a delivery method that is nebulized for cystic fibrosis patients, and at-scale manufacturing that retains the same properties that existed in the lab.

Developing mRNA therapies for rare, genetic diseases is a road less traveled.

“Two roads diverged in a wood and I – I took the one less traveled by, and that has made all the difference.”

— Robert Frost, American poet

Many of today’s mRNA companies got their start in vaccines, but from the beginning, we have focused on rare, genetic diseases — many of which are marked by dysfunctional or deficient proteins.

Our focus on cystic fibrosis from the start was unique, but this difference led to the development of a formulation designed to be inhaled and targeted to the lung.

In the case of our lead drug candidate for people with CF, MRT5005:

  • it is inhaled via a handheld nebulizer
  • the mRNA, packaged in an LNP, makes its way to the cells of a patient’s lungs
  • then, the machinery of the lung cells takes over and translates the mRNA into fully functional CFTR protein (the dysfunctional or missing protein in people with CF)

Illustration: CFTR Mutations

Current treatments for people with CF are small molecule modulators that work to enhance dysfunctional protein that already exists. Translate Bio hopes to introduce natural and fully functional proteins that are made by the person’s own cellular machinery — within the cytoplasm specifically. We believe that our mRNA therapy offers a potentially novel approach to treat the underlying cause of the disease.

In our next Spotlight, we’ll provide a deeper dive into the central dogma of mRNA therapy: how it works, which diseases or disorders may be improved by mRNA therapy, and some of its differences from other genetic medicine modalities.

Early History of mRNA Therapeutics

From the beginning of the biotech era, scientists have considered using mRNA as an alternative to DNA-based gene therapy.

While both DNA-based gene therapy and mRNA therapy could produce therapeutic proteins, DNA’s effect is permanent; mRNA offered a temporary, more drug-like effect. Scientists hypothesized that this temporary effect might alleviate some of the long-term safety concerns that existed with gene therapy. Over the next two decades, researchers across the globe would push the field forward in various directions: vaccination, protein replacement therapies, and treatment of genetic diseases.