Drugs that act on the CFTR protein only work in patients who produce the protein in the first place. That leaves 6% of patients hanging.
Pictured: a young boy with an oxygen mask/iStock, Anastasia Dobrusina
Vertex’s four FDA-approved cystic fibrosis drugs—once authorized for people of all ages—can potentially treat the underlying cause of disease in up to 94% of patients, according to The Cystic Fibrosis Foundation, a non-profit devoted to curing the disease. This leaves 6% of patients with an unmet need.
A genetic disease, cystic fibrosis (CF), is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in insufficient or defective CFTR protein in cells. People with CF inherit two mutated copies of the CFTR gene, one from each parent. Lack of a well-functioning CFTR chloride channel makes mucus thick and sticky, which can clog airways and lead to infection, inflammation, respiratory failure, and death.
The currently available CF drugs, called CFTR modulators, are designed to bind to and correct aberrant CFTR protein, said Jennifer Taylor-Cousar, who treats cystic fibrosis in adults and children at National Jewish Health in Denver, Colorado and co-authored a 2023 review article on modulator therapies.
One type of CFTR modulator called a corrector, binds to CFTR and improves protein processing, folding and transport to the cell membrane. Another type, potentiators, lengthen the time the CFTR ion channel spends in its open position so that more ions can pass through.
The Cystic Fibrosis Foundation (CFF) estimates that about 6% of CF patients do not produce any CFTR protein, leaving them without an approved treatment.
“[Those patients] do not make any CFTR protein, and so there’s no protein to correct, and there’s no protein to potentiate,” Heather Clark, head of program management at ReCode Therapeutics, told BioSpace.
To treat these remaining patients, companies employ three primary approaches to help cells make CFTR. Jane Davies, professor of Pediatric Respirology & Experimental Medicine at Imperial College London’s National Heart and Lung Institute, told BioSpace.
Some, including Vertex and ReCode, are developing messenger RNA (mRNA) treatments that lung cells can use to make functional CFTR proteins. Others, including 4DMT, are developing gene therapies to introduce working versions of the CFTR gene into cells’ nuclei. ReCode is also working on gene-editing-based treatments.
Gene-editing approaches to treating CF are still in the pre-clinical stages, said Davies, who has advised and led clinical trials of Vertex CFTR modulators and also advised ReCode.
mRNA Therapy
mRNA therapies aim to treat CF by giving cells the mRNA template to produce their own CFTR, ReCode CEO Shehnaaz Suliman told BioSpace. To target the lungs, ReCode’s experimental mRNA therapy is delivered by inhalation and packaged in a lipid nanoparticle (LNP) that includes an additional lipid molecule to direct the LNP to the lungs, Suliman said. ReCode does this with its SORT (selective organ targeting) lipid.
Vertex is also working on an inhaled mRNA treatment for CF, VX-522, developed through a 2016 collaboration with Moderna. Vertex began enrolling adults with CFTR variants who don’t respond to modulators in a Phase I clinical trial in February.
The main distinction between the two approaches is that ReCode’s candidate is packaged in LNPs containing SORT lipids, Suliman said, adding that the primary advantage here lies in the ability to take a traditional four-component LNP—which is the one that’s used in the Vertex-Moderna program—and attach the SORT lipid. Vertex declined to comment on ReCode’s programs.
Gene Therapy and Editing
Gene therapy approaches to CF involve introducing the correct CFTR gene into cells’ nuclei, usually using a viral vector, Taylor-Cousar said. Some gene therapies integrate the functioning gene into the genome, while others do not.
4DMT’s experimental gene therapy, 4D-710, consists of the CFTR gene contained within an adeno-associated virus (AAV) vector. The company used directed evolution in primates to develop a viral capsid that could penetrate the mucus in the lungs to reach target cells, David Kirn, CEO, told BioSpace. He added that the directed evolution of AAV involves generating mutations in the capsid genes to create a library of capsid variants, selecting the variants with desired properties and repeating this process as needed.
After entering the target cell, the capsid delivers the CFTR DNA to the nucleus, which remains as a circular piece of DNA, or episome, outside the host genome. When the cell divides, the episome DNA is not replicated, Kirn said. Because of this, as cells transduced with the therapy divide or die, the transgene will be diluted and eventually lost, according to a 2017 AAV-based gene therapy review. How long such a therapy lasts depends on how quickly cells are replaced.
“In the lung, the turnover is slow. But we don’t know whether we’re going to want to re-dose in two years or three years or five years,” Kirn said. 4D-710 is currently being studied in a Phase I/II clinical trial.
Interim results from the first three patients, presented at the 2022 North American Cystic Fibrosis Conference, revealed that the inhaled gene therapy was expressed in multiple lung cell types, including basal cells, Kirn said, explaining that basal cells are the lung’s stem cells and can differentiate into other lung cell types.
ReCode is also working on a gene-edited therapy for CF. This approach, which the company calls gene correction, could theoretically treat any patient with CF, not just those who make CFTR protein since gene editing can potentially correct any mutation.
“We envision that as a therapy that could impact all patients,” ReCode’s Clark said.
As for which gene editing tool ReCode might use, Suliman named base editing, prime editing, DNA nucleases and CRISPR/Cas9 as potential options.
Best Approach?
Which approach is likely to work best depends partly on how “best” is defined, said Taylor-Cousar, who has received grants and consulting fees from Vertex. “There’s a difference in what will be most effective and what’s most expedient,” she said.
Because of the experience gained during the COVID-19 pandemic, Taylor-Cousar said mRNA therapies will likely reach the market more quickly.
For patients without treatment, time is of the essence, even if all the drug can do is keep them stable while they wait for a better treatment, she said. “If we could stabilize people who aren’t eligible or can’t tolerate modulators, that would be fantastic.”
But mRNA therapies only reach the cells at the surface of the airways, and those cells turn over fairly quickly, as does mRNA itself, Taylor-Cousar said. For those reasons, she said patients will likely need to take inhaled mRNA therapies every day or every other day to have a sustained response.
Gene therapies, in contrast, can reach basal cells, which turn over much more slowly, so their benefits will last longer than mRNA therapies, Taylor-Cousar added. The effects of non-integrating gene therapies, like 4D-710, are still not permanent. Taylor-Cousar has consulted for 4DMT and is the principal investigator of the National Jewish Health site of a clinical trial of 4DMT’s experimental gene therapy.
ReCode’s Suliman said a downside of gene therapies is that they elicit an immune response to the viral vector. After the gene therapy is administered, the immune system produces neutralizing antibodies against the capsid proteins, according to an AAV gene therapy review published in the June edition of Trends in Biotechnology.
This “is a major limitation to repeated dosing,” Imperial College London’s Davies added. Those neutralizing antibodies, created after dose one, are primed to destroy the gene therapy if it is administered a second time, according to the AAV review.
4DMT’s Kirn said that 4D-710 avoided that problem by selecting a vector that would resist the body’s pre-existing antibodies to AAV during the directed evolution process. “When we tested it in primates, it looked safe and didn’t elicit an immune response. And now, in humans, we’ve seen the same thing,” he said, adding that there has been no evidence of an induced immune response.
“Ultimately, I think gene editing will be what will cure CF,” Taylor-Cousar said because it would allow for the possibility of permanently correcting cells’ DNA, whereas other therapies are not permanent. “But that’s a long way away.”
Ashley P. Taylor is a freelance science and health journalist based in New York City.
