 Juan Carlos Lopez |
 Andy Marshall |
On September 11, the Lasker Foundation awarded the 2025 Lasker~DeBakey Clinical Medical Research Award to Michael Welsh, Jesús González and Paul Negulescu for discoveries that led to the development of Trikafta, a triple combination of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors to treat cystic fibrosis. This award recognizes the contribution of Trikafta to improving the quality of life of ~90% of the 40,000 people living with this condition in the United States, reducing infection-related hospitalizations and lung transplants, among other benefits.
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But what about the other 10% of patients who don’t respond to Trikafta, many of whom carry so-called Class I alleles that cannot be rescued by this drug combination? Although a lot of progress has been made, several obstacles lie in the path of effective medicines for people who produce no, or negligible amounts of, CFTR protein.
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It should come as no surprise that the main therapeutic strategies for Class I alleles aim to put missing CFTR back into lung cells. Among these strategies, mRNA delivery is the most advanced. VX-522, an RNA therapeutic program from Vertex and Moderna currently in Phase 2, is an inhaled drug that aims to deliver full-length CFTR mRNA to the lung using lipid nanoparticles (LNPs). Two related, competing mRNA delivery programs are at a similar stage of clinical development: ARCT-032 by Arcturus Therapeutics using their LUNAR LNPs; and RCT-2100 by ReCode Therapeutics, which uses a lung-targeted SORT (selective organ-targeting) LNP.
A key feature of RNA-based therapies is that any therapeutic benefit would likely be transient, requiring periodic administration of the medicine to achieve sustained effects. Gene therapy and gene editing have the potential to be a curative, “one and done” procedure. Thus far, however, only gene therapy programs have advanced far enough to be in human testing.
Of these, 4D Molecular Therapeutics’ 4D-710 and Spirovants’ SP-101 use different AAV subtypes designed to optimize delivery to airway basal epithelial cells of a CFTR minigene that lacks the regulatory domain. Both projects are in Phase 1/2 of clinical development.
As the large size (6.2 kb) of the CFTR transgene exceeds the packaging capacity of AAV vectors, Krystal Biotech and Boehringer Ingelheim have launched Phase 1/2 clinical programs using viral vectors with a greater payload capacity: KB407 is a re-dosable herpes simplex virus (HSV)-1 vector with a cargo capacity >30 kb that delivers two copies of the CFTR gene to lung epithelial cells using a nebulizer. BI 3720931 is Boehringer’s inhaled lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) engineered to deliver a single copy of the CFTR gene. Further behind in the pipeline, Carbon Biosciences’ CGT-001 is a nebulized non-AAV parvovirus-based vector capable of delivering full-length CFTR gene. Thus far, it has been tested in nonhuman primates and in human bronchial cells in culture.
Companies are also pursuing oligonucleotide therapies to modify disease-causing mutations at the RNA level. SPL84 is an inhaled antisense oligonucleotide (ASO) addressing a splicing defect (cryptic exon; class V mutation) in the ~1,600 CF patients who carry the 3849+10kb C→T mutation. SpliSense has advanced the ASO into phase 2 testing, but it also has in preclinical development an exon-skipping ASO against the class I mutant W1282X. By masking the mutant premature termination codon in exon 23, SP23 induces the splicing machinery to skip exon 23 and stitch together exon 22 and exon 24, forming a partially functional CFTRΔex23 protein.
Gene editing is also beginning to appear on the therapeutic horizon. In July, Prime Medicine announced it had received $25 million in funding to advance prime editors, with a lead program focusing on G542X. Last year, Intellia Therapeutics and ReCode Therapeutics also announced a strategic collaboration to combine the CRISPR pioneer’s Cas9 DNA ‘writing’/insertion technology with Recode’s SORT LNPs. Academic groups have now shown that G542X correction is possible using inhaled LNP- or virus–like particle-delivered adenine base editors. And for RNA editing, at this year’s American Society of Gene & Cell Therapy Wave Life Sciences reported their oligo-based ADAR editors could achieve 21% correction (EC50 = 376nM) of CFTR W1282X nonsense mutations. This is likely a sliver of all the therapeutic activity underway; other programs are targeting mucus itself, which is much thicker than in healthy individuals. If we missed any drug-discovery projects in this space, please let us know!
Despite the plethora of programs, developing genetic therapies against cystic fibrosis patients with class I CFTR mutations faces some stiff translational challenges. For starters, targeted delivery of drugs to lung tissue remains a work in progress. The optimal cell type to be targeted by gene therapy/editing remains an open question, especially as the community continues to identify new cell types in the lung; is it enough to target the more prevalent epithelial cells (alveolar type 2 cells), or will it be necessary to target rarer stem cells (alveolar type 1 cells) to see a long-lasting therapeutic effect? What about the contribution of genetic modifiers and other ion channels known to affect airway dysfunction in CF airway epithelial cells? Also, how to figure out the pharmacokinetics and pharmacodynamics of these disease-modifying therapies in lungs and measure delivery in patients? Specifically, establishing protein expression levels after inhaling a DNA- or RNA-based product would likely require a bronchial biopsy, which is impractical particularly in this fragile patient population.
Last, not unlike most pathologies, new animal and in vitro models with predictive value need to be developed. The use of human bronchial epithelium culture is not as predictive of the efficacy of genetic therapies as it has been for small molecules. At present, the ferret is the gold standard disease model. But it is a time-consuming, challenging animal model, which is only supported by a few groups. All of which slows the path to clinical translation.
Six years after the approval of Trikafta, patient foundations like the CF Foundation, Emily’s Entourage, and the Cystic Fibrosis Trust are devoting increasing resources to translational research to push forward treatments for patients with CFTR Class I mutations who do not respond to potentiators and correctors. The Lasker recognition of the science that led to Trikafta will surely inspire researchers working on those projects to overcome the remaining hurdles.
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