Sending the Message: mRNA’s Potential to Give the Body Instructions to Restore Health

January 10, 2020

by Ann Barbier, MD, PhD
Chief Medical Officer
Translate Bio

In 2020, we will report some early interim results from our clinical trial in patients with cystic fibrosis (CF) treated with up to 5 doses of MRT5005, our mRNA therapy administered by nebulization to the lung.

This spotlight will take a closer look at how mRNA therapy works and why it may be ideal for treating genetic diseases, such as cystic fibrosis, which are caused by defective or missing proteins.

Critical unmet needs remain for people with CF whose genetic mutations are considered non-amenable to CF modulators.

The goal of messenger RNA (mRNA) therapy is to provide the instructions needed for cells to produce functional proteins through the cells’ own machinery. This is important since protein defects are the underlying cause of genetic diseases. We envision mRNA therapy as a way to harness the body’s innate ability to produce functional proteins by providing it with the right set of instructions.

“What brought me to Translate Bio was how messenger RNA therapy has the potential to help so many patients with so many different diseases. By helping the body produce a protein that might be missing or might be defective, or where the body could use just a little bit more of a protein it is already producing, we are creating science that is teaching the body to heal itself.”

— Ann Barbier, Translate Bio Chief Medical Officer

DNA, RNA and Proteins: When we explain the potential of mRNA therapy and the beauty of creating drug candidates that give the body the right instructions to produce a desired protein, we first need to look at how mRNA works. In fact, what is not always appreciated is the crucial role played by mRNA.

In our bodies, nearly all functions are maintained by proteins. They are the workhorses that build our muscle, maintain our metabolism, transmit light signals from the environment into our eyes, and fulfill thousands of other daily functions. But how does the body produce these important proteins? It all starts with DNA, the genetic material in our chromosomes that contain all the genetic information. DNA consists of long strands of genetic information that, when properly used, lead to the production of healthy proteins. In genetic diseases, there is a mutation in that DNA that causes the instructions to be garbled or incorrect. And that then leads to the production of an incorrect, deficient protein, or sometimes to no protein at all. You can imagine the consequences for the body: If the protein can’t fulfill its function, this leads to signs and symptoms of disease.

What you may not know is that there is a step in between the DNA and the production of proteins in the body. That intermediary step is messenger RNA, which, as the name indicates, is the messenger between the genetic code and the actual proteins. It is messenger RNA that conveys this crucial genetic information, enabling cells to produce functional proteins. This genetic information is conveyed in two steps: transcription and translation.

  • Step 1 – Transcription: The genetic code from the DNA is transcribed into messenger RNA
  • Step 2 – Translation: The code from the messenger RNA is translated into protein

Science Corner

During transcription, a gene that encodes an amino acid sequence for a particular protein is transcribed into a complementary sequence of mRNA. The mRNA then carries these instructions to other areas of the cell where the instructions are translated by ribosomes, which are specialized molecular machines within cells that carry out protein synthesis. During transcription, the ribosomes use the instructions conveyed by mRNA as a template for assembling the amino acids to create the desired protein. The vision is for therapeutic mRNA to provide the body with the correct set of instructions to express fully functional protein, thereby restoring or augmenting protein function to treat or prevent disease.

Gene therapy focuses on the first step in this process – fixing the defect in the DNA – and does that by introducing new DNA sequences or correcting mutated sequences.

Translate Bio’s research and development efforts focus on the second of these two processes. We hope to deliver mRNA that encodes natural, functional proteins that will correct the deficiencies created by the incorrect protein or compensate for the missing protein.

One of the advantages of mRNA therapy is that, in contrast to gene therapy and other emerging genetic modalities, it has more traditional drug-like characteristics that patients and physicians are familiar with such as : the drug can be given repeatedly, the dosage can be increased or decreased as needed. This is one of the ways in which mRNA replacement therapy is different from gene therapy: it just provides the instructions for the correct protein without interfering with the genetic code.

We have applied this approach to cystic fibrosis, or CF. There is no cure for CF, and it is the most common fatal inherited disease in the United States. It is caused by a dysfunctional or missing CFTR protein, and there are numerous different DNA mutations that can lead to a dysfunctional protein. We are driven to pursue mRNA therapeutic development for the treatment of CF because of its potential impact on the thousands of patients in the U.S. who struggle every day with this life-limiting disease.

We have developed the first mRNA therapeutic, MRT5005, designed to deliver mRNA encoding the functional cystic fibrosis transmembrane conductance regulator (CFTR) protein which would address the underlying cause of CF, regardless of the genetic mutation that the patient might have.

Based on the progress we made in 2019 in our CF program, we are focused on building on our lung delivery platform to maximize the potential of our mRNA technology in additional pulmonary diseases including discovery-stage programs in primary ciliary dyskinesia (PCD), pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF).

What makes mRNA therapy so attractive is that, in principle, one could produce messenger RNA to code for any protein that is missing or in some way defective in the human body. In theory, the possibilities are endless. I believe that we are just beginning to scratch the surface of the wonders of mRNA therapy.