Modeling cystic fibrosis disease progression in patients with the rare CFTR mutation P67L

MacKenzie, Isobel E.R.; Paquette, Valerie; Gosse, Frances; George, Sheenagh; Chappe, Frédéric; Chappe, Valérie

doi:10.1016/j.jcf.2017.03.008

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…The milder phenotype in patients with RF mutations has been demonstrated previously in studies of patients carrying specific mutations such as 2789+5G→A and 3849+10kbC>T , D1152H , 3272‐26A>G , and P67L …”

Section: Discussionsupporting

confidence: 64%

Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry

Salvatore

Padoan

Buzzetti

et al. 2018

Pediatric Pulmonology

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Background: CFTR mutations permitting residual function (RF) of the CFTR protein are disease-causing. These mutations are associated with a pneumopathy that is delayed in onset and is slower in progression than are more common forms of cystic fibrosis (CF), although the disease may become severe in some patients. RF mutations are among the most frequent in Italy, thus encouraging investigation of their prevalence and associated phenotypes.Methods: Data from the Italian Registry were used to compare patients with at least one RF mutation with those homozygous for F508del.Results: A total of 806 patients bearing at least one RF mutation were identified among 5204 registered patients (15.5%). The RF patients were older than the F508del homozygotes (median age 26.0 years vs 19.8 years, respectively), with a higher median age at diagnosis (6.3 years vs 0.2 years, respectively) and a lower median sweat chloride value (76.0 mmol/L vs 100.0 mmol/L, respectively). In the RF group, lung infections and comorbidities were less prevalent than those in the F508del homozygotes, while better FEV 1 and nutritional status were observed at all ages. Within the RF group, RF/F508del subjects showed more severe pneumopathy than did patients with RF/other mutations. In particular, the 3849 + 10kbC → T/F508del subjects had worse FEV 1 and a higher prevalence of lung infections than did patients with other genotypes.Conclusions: Patients with RF mutations are numerous in Italy and have a milder disease phenotype than do F508del homozygotes. Inside the RF group, F508del heterozygotes and, in particular, 3849 + 10kbC → T/F508del patients showed more severe pneumopathy.

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Section: Discussionsupporting

confidence: 64%

Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry

Salvatore

Padoan

Buzzetti

et al. 2018

Pediatric Pulmonology

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“…However, a subset of these patients had substantial airflow obstruction (FEV1% predicted <50%) and exhibited a progressive loss of lung function over time ( Figure 3 A). Consistent with the association of the P67L mutation to a milder phenotype [ 46 ], the lung function of the compound heterozygous F508del/P67L patient remained stable (FEV1% predicted >50%) over several years ( Figure 3 B). Due to the pronounced gating defect the S549R mutation is associated to a severe CF phenotype [ 47 ], however the F508del/S549R patient in this study was able to maintain a FEV1% predicted >80% after the onset of ivacaftor therapy at age 18 ( Figure 3 B).…”

Section: Resultssupporting

confidence: 81%

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Veit

Velkov

et al. 2021

JPM

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Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

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“…P67L is generally associated with a mild CF phenotype, which typically presents with a later age of diagnosis, lower incidence of pancreatic insufficiency, better nutritional status, lower incidence of Pseudomonas aeruginosa infections, lower incidence of CF-related diabetes (CFRD), and equivocal sweat chloride levels that often produce negative results in newborn screening tests. However, P67L is not associated with an improved lung function as the rate of FEV 1 /forced vital capacity (FVC) decline in P67L patients is similar to that observed in patients homozygous for F508del-CFTR, a genotype associated with a severe CF phenotype [ (30) and www.cftr2.org].…”

Section: P67lmentioning

confidence: 99%

Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations

Harutyunyan

Huang

Mun

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting ~1 in 3,500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, more than 2,000 CFTR mutations have been identified, which produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality. Research has focused on identifying small molecules, or modulators, that can restore CFTR function. In recent years, two modulators, ivacaftor (Kalydeco) and lumacaftor/ivacaftor (Orkambi), have been approved by the U.S. Food and Drug Administration to treat CF patients with certain CFTR mutations. The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators' efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients.

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Modeling cystic fibrosis disease progression in patients with the rare CFTR mutation P67L

Abstract: The P67L mutation is associated with a mild disease, even when combined with the severe ΔF508 mutation.

Cited by 3 publications

References 16 publications

Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry

Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations

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