MRT5005 is a first-in-class mRNA-based therapy developed by Translate Bio for the treatment of cystic fibrosis (CF) — a genetic disease caused by mutations in the CFTR gene, which encodes for an essential ion channel protein called cystic fibrosis transmembrane conductance regulator (CFTR) protein.

MRT5005 — a messenger RNA (mRNA) molecule which provides instructions for the production of proteins in the body — is designed to boost the production of the CFTR protein, which is defective or absent in CF. Thus, it addresses the underlying cause of CF and is a potential therapy for all CF patients irrespective of the type of mutation they carry.

MRT5005 was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in 2015.

How MRT5005 works

MRT5005 works by delivering the mRNA molecule that provides instructions to produce the functional version of the CFTR protein to cells in the body. It is administered by inhalation with a nebulizer so that the therapeutic mRNA can directly reach the airways. Upon inhalation, the mRNA molecule enters the cells that line the inside of the lungs called bronchial epithelial cells, where it uses the cells’ own protein-making machinery to produce fully functional CFTR protein. The functional CFTR protein can then restore the salt-water transport across the lung surface, preventing the build-up of the thick and sticky mucus that’s characteristic of CF.

MRT5005 in clinical trials

Preclinical studies, conducted by the company, in rodents and non-human primates showed that nebulized MRT5005 was efficiently delivered to the lungs of the animals and resulted in the production of functional CFTR protein. Nebulized MRT5005 was also able to reach the lungs and restore functional CFTR production in an animal model that mimicked increased mucus accumulation as seen in CF patients.

A randomized, double-blind, placebo-controlled Phase 1/2 clinical trial (NCT03375047), called RESTORE-CF, is currently recruiting an estimated 32 adult patients with CF in the U.S. to evaluate the safety and tolerability of inhaled MRT5005. The study consists of two parts: single ascending dose and multiple ascending dose. It aims to assess the delivery of mRNA to the bronchial epithelial cells after the fifth dose. Lung function will also be assessed using forced expiratory volume in one second scores.

The trial has advanced to its multiple ascending dose part while the single ascending dose part is still ongoing. Interim data from the trial is expected in the second half of 2019. The trial is conducted in collaboration with the Cystic Fibrosis Foundation Therapeutics Development Network and is expected to be completed in February 2021.

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