Gene therapy that modifies CFTR protein appears to be more effective

Study favors gain-of-function approach with gene therapy for cystic fibrosis

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Gene therapy to deliver a modified and better working version of the CFTR protein may be more effective in treating cystic fibrosis (CF) than a gene therapy aiming to deliver higher levels of the protein, a study shows.

“Gene therapy and gene editing techniques, whilst still in their infancy, hold immense promise as a potential cure for all forms of CF,” the researchers wrote, but “further development and understanding” is needed.

The study, “Gain-of-function CFTR restores essential epithelial function with greater efficacy than wildtype or codon optimized CFTR when expressed in cystic fibrosis airway cells,” was published in Molecular Therapy – Methods and Clinical Development.

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CF is caused by mutations that disrupt the functionality of the CFTR protein. This protein normally sits at the surface of cells, where it acts like a gated channel to help control the flow of chloride ions. The lack of functional CFTR leads to the production of abnormally thick and sticky mucus, which drives most disease symptoms.

Gene therapy is a treatment strategy that aims to deliver a healthy copy of the gene encoding CFTR to a patient’s cells, allowing the cells to make a working version of this protein. However, owing to natural airway barriers, preclinical studies of gene therapies often find that it’s difficult to get enough functional CFTR protein to be made with this approach.

The therapy’s potential, however, remains “immense,” including for people with types of CFTR gene mutations that remain untreatable to this day.

A team of scientists in the U.K. and the U.S. investigated two gene therapy strategies aiming for greater CFTR functionality.

Study into codon optimization vs. gain-of-function therapy approaches

One is called codon optimization, which basically involves modifying the gene so that higher levels of healthy CFTR protein are produced.

The other is called gain-of-function. Rather than trying to make a normal version of the CFTR protein, here the gene is modified to make an alternate version, called K978C-CFTR. This version of the CFTR protein is able to open more easily at the cell surface, so less of the protein is needed in order to get the same effect.

Researchers tested both strategies in a battery of experiments using lung cells derived from people with CF. “The aim of this research was to determine if use of codon optimized or [gain-of-function] forms of CFTR could improve the efficacy of CF gene therapy in a physiologically relevant airway model,” they wrote.

The gain-of-function strategy using K978C-CFTR led to a significant increase in CFTR functionality, results showed. In CF cells with this version of the protein, chloride was able to flow through the protein more easily, and tests suggested improved airway hydration, which is essential to produce wet, slippery mucus, compared with cells harboring the normal version of CFTR.

“K978C-CFTR was much more effective than other forms of CFTR we studied,” the researchers wrote.

Counterintuitively, the codon-optimized version led to less CFTR function compared with the normal version of the gene. The researchers determined that the codon-optimized version did lead to greater CFTR protein production as intended. But the protein ended up getting misplaced inside the cell, rather than going to the cell’s outer edge where it needs to be to work correctly.

“We found that increasing CFTR protein using codon optimisation did not translate to better function … These data provide proof of principle that [gain-of-function] variants may be more effective than codon optimised forms of CFTR for CF gene therapy,” the researchers concluded.