RNA-based Therapies Show Promise in Early Studies, ReCode Reports

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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CF splicing mutation and SPL84-23/Cystic Fibrosis News Today/lab work in cells


RCT223 and RTX0001, ReCode Therapeutics’ experimental RNA-based therapies for cystic fibrosis (CF), safely restored function to CFTR, the faulty protein in CF, in patient-derived lung cells.

Delivered through the company’s non-viral platform — called the selective organ targeting (SORT) lipid nanoparticle (LNP) platform — the therapies were also found to be well-tolerated in lung cells from patients and in mice.

“Our RNA-based approaches and broad LNP platform enable us to tackle CF from multiple angles in order to specifically target the underlying causes of the disease and maximally help patients,” David Lockhart, PhD, ReCode’s CEO and president, said in a press release.

“These data showcase the potential of our differentiated RNA-based molecular therapies to treat cystic fibrosis,” Lockhart said, adding that they are “an important step” as the company advances its CF program closer to studies in people.

ReCode plans to apply to the U.S. Food and Drug Administration in 2022, seeking the agency’s clearance to start clinical trials of these therapies in the U.S.

The preclinical findings were presented by Michael Torres, PhD, the vice president of Recode’s research and development, at the 44th European Cystic Fibrosis Conference held virtually June 9–12.

The oral presentation was titled “Rescue of CFTR function in primary bronchial epithelial cells from patients with cystic fibrosis using lipid nanoparticle delivery of RNA-based therapies.”

In people with CF, mutations in the CFTR gene impair the production of a functional CFTR, a protein channel that controls the flow of water and salts through cells, triggering the mucus in various organs to become thick and sticky.

ReCode’s CF program, supported by a grant from the Cystic Fibrosis Foundation, is focused on treating the 10–13% of CF patients who have nonsense mutations and limited therapeutic options.

Nonsense mutations introduce a premature stop signal in CFTR’s DNA sequence, leading to the production of a shorter, non-functional CFTR protein.

The CF program currently comprises two RNA-based therapies delivered through the company’s SORT LNP platform, which uses tiny non-viral fat (lipid) particles to transport and deliver their cargo to targeted organs.

The company’s lead candidate, RCT223, uses a transfer RNA (tRNA) molecule — which plays a role in the process of protein production — to replace the premature stop signal with a “go” sequence in the CFTR gene, so that the full CFTR protein can be produced.

Newly presented data showed that both single and repeated dosing of RCT223 restored CFTR function in lung cells derived from CF patients and grown in the lab, a gold-standard cell model of CF.

This effect lasted for at least 72 hours (three days) after a single administration, and CFTR functional levels continued to rise with twice-weekly doses.

ReCode’s mRNA replacement agent for CF, RTX0001, is designed to deliver to cells a working version of CFTR’s messenger RNA molecule (mRNA), the intermediate molecule derived from DNA that guides protein production.

As such, RTX0001 is expected to increase the production of a working CFTR protein.

Preclinical data showed that RTX0001, delivered through a commercially available mesh nebulizer, successfully delivered CFTR’s healthy mRNA into patient-derived lung cells and into the lungs of mice.

The delivered mRNA was found to effectively and significantly increase the production of a working CFTR after a single, low dose, and CFTR’s activity was sustained for at least 72 hours after twice-weekly administration.

Both RNA-based therapies were generally well-tolerated in the evaluated preclinical models.

“By leveraging our LNP platform to deliver genomic medicines, we have demonstrated the ability to restore cystic fibrosis transmembrane conductance regulator (CFTR) function through both tRNA and mRNA approaches,” Lockhart said.

The company’s pipeline also includes potential RNA-based therapies for primary ciliary dyskinesia (PCD), a genetic condition that impairs the function of lung cilia — the fingerlike projections in the airways — leading to chronic respiratory infections.

ReCode raised $80 million to support the preclinical development of its CF and PCD programs in April 2020.