General trends in the effects of VX-661 and VX-445 on the plasma membrane expression of clinical CFTR variants

McKee, Andrew G; McDonald, Eli Fritz; Penn, Wesley D.; Kuntz, Charles P.; Noguera, Karen; Chamness, Laura M.; Roushar, Francis J.; Meiler, Jens; Oliver, Kathryn E.; Plate, Lars; Schlebach, Jonathan P.

doi:10.1016/j.chembiol.2023.05.001

Cited by 11 publications

(27 citation statements)

References 45 publications

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“…We split the VX-445 sensitive variants from VX-661 sensitive variants along a diagonal axis best fit by plotting CFTR immune staining intensity for VX-445 versus VX-661 ( Figure 4A ). VX-445 sensitive variants fell above the dotted line and VX-661 variants fell below the dotted line 7 . The variants were then colored by AM pathogenicity score.…”

Section: Resultsmentioning

confidence: 93%

“…Although not directly interfacing with ICL4, residues 512-532 make up helix 4/4b of the α-helical subdomain and are relatively tolerant to variants except for V520 and C524. V520F was among variants characterized recently as non-responsive to clinical available modulators 7 . Residues 533-547 in the structurally diverse region are expectedly tolerant.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations D923N and M952T are predicted to be pathogenic. 7 . Variants that fell below the best fitdotted line are selectively responsive to VX-661 while variants above the dotted line were selectively responsive to VX-445.…”

Section: Discussionmentioning

confidence: 99%

“…Lung function data proved too highly variable for comparison and was not used, but was still included in the Supplemental Table for reference. In vitro modulator response data was downloaded from 15 and Deep Mutational Scanning data downloaded from 7 . The 650 variants from 15 were filtered to 585 missense variants.…”

Section: Methodsmentioning

confidence: 99%

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Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

McDonald,

Oliver,

Schlebach

et al. 2023

Preprint

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Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) result in cystic fibrosis – a lethal genetic disease. Missense mutations that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis mutations. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense mutations based on dual learned protein structure and evolutionary features. We evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from theCFTR2.orgdatabase. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, and pseudomonas infection rate. Correlation was also modest with CFTR trafficking and folding competencyin vitro. By contrast, the AM score correlated well with CFTR functional datain vitro– demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e., theratype. The development of new approaches to differentiate the biochemical and pharmacological properties of CF variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

McDonald,

Oliver,

Schlebach

et al. 2023

Preprint

Self Cite

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“…A recent deep mutational scanning (DMS) study screened the changes in CFTR cell surface expression for >100 CF causing mutations under basal, VX-661, VX-445, and the combination therapy conditions . Interestingly, several rare CFTR mutants without corrector FDA approval (Class II mutations: L138ins, L927P, and nonclass II mutations: G970R, I1234V) responded well in vitro to the combination treatment compared to controls, warranting further studies of these mutants in CF bronchial epithelial cell and organoid models.…”

Section: Implications For Cystic Fibrosis Personalized Medicinementioning

confidence: 99%

CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine

McDonald,

Meiler,

Plate

2023

ACS Chem. Biol.

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Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR). Class-II mutants of CFTR lack intermolecular interactions important for CFTR structural stability and lead to misfolding. Misfolded CFTR is detected by a diverse suite of proteostasis factors that preferentially bind and route mutant CFTR toward premature degradation, resulting in reduced plasma membrane CFTR levels and impaired chloride ion conductance associated with CF. CF treatment has been vastly improved over the past decade by the availability of small molecules called correctors. Correctors directly bind CFTR, stabilize its structure by conferring thermodynamically favorable interactions that compensate for mutations, and thereby lead to downstream folding fidelity. However, each of over 100 Class-II CF causing mutations causes unique structural defects and shows a unique response to drug treatment, described as theratype. Understanding CFTR structural defects, the proteostasis factors evaluating those defects, and the stabilizing effects of CFTR correctors will illuminate a path toward personalized medicine for CF. Here, we review recent advances in our understanding of CFTR folding, focusing on structure, corrector binding sites, the mechanisms of proteostasis factors that evaluate CFTR, and the implications for CF personalized medicine.

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Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases

Kim,

Plate

2024

Israel Journal of Chemistry

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Cystic Fibrosis (CF) is a genetic disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to a faulty CFTR protein. Dysfunctional CFTR causes chloride ion imbalance, resulting in dense mucus accumulation in various organs, particularly the lungs. CF treatments focus on symptom management and addressing CFTR′s functional defects. Notably, development of CFTR modulator therapies has significantly advanced CF treatment. These drugs target CFTR protein structural defects induced by mutations, restoring its function and improving CF symptoms. VX‐770, a CFTR potentiator, and CFTR correctors like VX‐809, VX‐661, and VX‐445, have gained FDA approval and widespread clinical use, greatly enhancing the health and survival of many CF patients. However, some CFTR mutations lack effective targeted therapies, leaving approximately 6 % of CF patients without suitable options. CFTR modulator therapies have proven essential for combating the underlying causes of protein misfolding diseases, serving as a blueprint for similar treatments in other membrane protein misfolding diseases. This review explores current and future CFTR modulator therapies, and applications of established paradigms to membrane protein misfolding diseases. Ongoing research and innovation hold the potential for further improvements in CF management and the treatment of protein misfolding diseases.

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General trends in the effects of VX-661 and VX-445 on the plasma membrane expression of clinical CFTR variants

Cited by 11 publications

References 45 publications

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine

Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases

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