CFTR Amplifiers May Be Potent CF Mono or Combo Therapy, Study Says

Amplifiers, a potential new class of therapies that modify CFTR — the protein whose defects cause cystic fibrosis (CF) — do so by stabilizing the template used for its production so the protein works better in cells and there’s more of it, a study into the mechanisms of amplifiers reported.

Specifically, this groups of CFTR modulators work by interacting with a specific protein, PCBP1, that binds to RNA during crucial steps in protein production.

These findings support nesolicaftor (PTI-428), an investigational and small molecule oral amplifier by Proteostasis Therapeutics, to treat CF either alone or in combination with other CFTR (cystic fibrosis transmembrane conductance regulator) therapies, a company press release stated.

The study, “Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA,” was published in the Journal of Cystic Fibrosis.

CFTR, the protein that normally transports water and salts (such as chloride) in and out of cells, is faulty in people with CF due to mutations in the CFTR gene. As a result, the flow of water and salts is hampered, leading to the buildup of a thick, sticky mucus that affects organs like the lungs.

CFTR modulators are specialized therapies designed to correct the defects in the CFTR protein. Currently, two types of these modulators existÚ CFTR potentiators such as Kalydeco, correctors like Orkambi and Symdeko, and the potentiator-corrector combination Trikafta, all by Vertex Pharmaceuticals.

Potentiators are designed to keep the CFTR protein in a stable conformation to aid the transport of water and salts in and out of cells, while correctors help the CFTR protein to fold correctly, ensuring it achieves its normal 3D structure.

Nesolicaftor is a new type of CFTR modulator known as an amplifier, designed to increase production of this protein. It is currently being developed to treat CF patients carrying at least one F508del mutation in the CFTR gene.

Previous early studies on human bronchial epithelial cells found that CFTR amplifiers like nesolicaftor can nearly double the total amount of functional CFTR protein being produced.

A Phase 2 clinical trial (NCT02718495) that ended in 2017 found that patients given nesolicaftor (50 mg once daily) as an add-on to Orkambi showed greater improvements in lung function than those on Orkambi alone, and that treatment led to higher CFTR protein levels.

The 12 researchers in this study — seven of whom work for Proteostasis, and an eighth (a Scripps Research Institute scientist) is a company co-founder — investigated the mechanism of action of these amplifiers.

They found that amplifiers bind to an RNA-binding protein called poly(rC)-binding protein 1 (PCBP1), which regulates the production of the CFTR protein before it is shuffled to its final destination: the cell’s membrane.

Amplifiers work by stabilizing CFTR’s messenger RNA — mRNA, the template cells use to make the CFTR protein — to boost its production. This increase in protein production also contributes to enhance the amount of CFTR delivered to the cell’s membrane.

This means that amplifiers like nesolicaftor may be used alone, or in combination with other CFTR modulators, to increase the amount of CFTR protein being produced and, consequently, the effectiveness of CFTR potentiators and correctors that use CFTR as a substrate.

“These results provide new insight into the cellular regulation of CFTR biosynthesis [production] and further advance the understanding of CF biology for the benefit of the scientific community that is searching for new therapeutic approaches to this serious and life limiting disease,” Jeffery W. Kelly, PhD, the Proteostasis co-founder and study author, said in the release.

Amplifiers “represent a promising new and mechanistically novel class of CFTR therapeutic. They may be useful as a monotherapy or in combination with other CFTR modulators,” the researchers concluded.