The era of CFTR modulators: improvements made and remaining challenges

Cuevas-Ocaña, Sara; Laselva, Onofrio; Avolio, Julie; Nenna, Raffaella

doi:10.1183/20734735.0016-2020

Cited by 24 publications

(24 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, four modulator combinations are approved or being considered for use in Europe, Australia, Canada and the US: KALYDECO ® (ivacaftor); ORKAMBI ® (lumacaftor/ivacaftor); SYMDEKO ® (tezacaftor/ivacaftor); and TRIKAFTA ® /KAFTRIO ® (elexacaftor/tezacaftor/ivacaftor) [ 1 , 2 , 3 , 4 ]. These modulators offer treatment to CF patients with certain variants, leaving those without such variants (i.e., rare or ultra-rare variants) ineligible for CFTR modulator therapy.…”

Section: Introductionmentioning

confidence: 99%

The Equitable Implementation of Cystic Fibrosis Personalized Medicines in Canada

Shemie

Nguyen

Wallenburg

et al. 2021

JPM

View full text Add to dashboard Cite

This article identifies the potential sources of inequity in three stages of integrating cystic fibrosis personalized medicines into the Canadian healthcare system and proposes mitigating strategies: (1) clinical research and diagnostic testing; (2) regulatory oversight and market authorization; and (3) implementation into the healthcare system. There is concern that differential access will cast a dark shadow over personalized medicine by stratifying the care that groups of patients will receive—not only based on their genetic profiles, but also on the basis of their socioeconomic status. Furthermore, there is a need to re-evaluate regulatory and market approval mechanisms to accommodate the unique nature of personalized medicines. Physical and financial accessibility ought to be remedied before personalized medicines can be equitably delivered to patients. This article identifies the socio–ethical and legal challenges at each stage and recommends mitigating policy solutions.

show abstract

Section: Introductionmentioning

confidence: 99%

The Equitable Implementation of Cystic Fibrosis Personalized Medicines in Canada

Shemie

Nguyen

Wallenburg

et al. 2021

JPM

View full text Add to dashboard Cite

show abstract

“…On the other hand, the clinical response size is highly variable even in patients homozygous for F508del [ 7 ]. Therefore, we and others are examining the utility of modulator testing on patient-derived nasal cultures or rectal organoids to predict clinical response size [ 18 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Phenotyping Rare CFTR Mutations Reveal Functional Expression Defects Restored by TRIKAFTATM

Laselva

Ardelean

Bear

2021

JPM

Self Cite

View full text Add to dashboard Cite

The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTATM, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTATM.

show abstract

“…Based on data collected in the CF Patient registry, the next two most common mutations are G542X, a class I mutation in which no functional CFTR is created, and G551D, a class III mutation, characterized by defective protein regulation or gating. G542X and G551D are present in 4.5 and 4.4 percent of people with CF, respectively [ 3 , 4 , 5 ].…”

Section: Cftr Mutations and Cystic Fibrosismentioning

confidence: 99%

The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status

2021

View full text Add to dashboard Cite

Patients with cystic fibrosis (CF) are at increased risk of malnutrition and growth failure due to multiple factors as a result of suboptimal or absent function of the CFTR chloride channel protein. Dysfunctional CFTR contributes to increased energy expenditure, exocrine pancreatic insufficiency causing impaired dietary macronutrient digestion and absorption, intestinal dysbiosis, and impaired bile acid homeostasis. Poor nutritional status as a result of these mechanisms is associated with decreased lung function, worse clinical outcomes, and ultimately, increased mortality. Nutritional interventions addressing these mechanisms, such as pancreatic enzyme-replacement therapy and enteral caloric supplementation, have improved nutritional status and, by association, clinical outcomes. In the last decade, the advent of medications targeting defective CFTR proteins has revolutionized the care of patients with CF by reducing the overall impact of CFTR dysfunction. Below, we summarize the effects of highly effective CFTR modulators on nutritional status overall as well as specific factors including bile acid metabolism, pancreatic function, energy expenditure, and intestinal dysbiosis. The future of CF nutrition care will require a paradigm shift away from focusing on methods addressing CFTR dysfunction such as excess calorie provision and toward an individualized, holistic approach in the context of specific mutations and CFTR-directed therapy.

show abstract

The era of CFTR modulators: improvements made and remaining challenges

Cited by 24 publications

References 58 publications

The Equitable Implementation of Cystic Fibrosis Personalized Medicines in Canada

The Equitable Implementation of Cystic Fibrosis Personalized Medicines in Canada

Phenotyping Rare CFTR Mutations Reveal Functional Expression Defects Restored by TRIKAFTATM

The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status

Contact Info

Product

Resources

About