Exercise as Medicine in Cystic Fibrosis: A pilot study assessing the impact of a telehealth exercise program on adherence and self-efficacy

Awardee: Stefanie Krick

Institution: The University of Alabama at Birmingham

Grant Amount: $117,655

Funding Period: February 1, 2022 - January 31, 2023

Pharmacological strategies to target nonsense mutations in cystic fibrosis

Awardee: Luis Juan Vicente Galietta

Institution: Fondazione Telethon - TIGEM

Award Amount: $54,718

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Final Report Lay Summary:

Cystic fibrosis (CF), one of most frequent and severe genetic diseases, affects multiple organs but

the consequences to the lungs are the most important ones for morbidity and mortality. The basic

defect in CF is the loss of function of CFTR, a plasma membrane chloride channel expressed in

various epithelial cell types. There are multiple types of CF-causing mutations that impair the

expression, maturation, and/or gating of CFTR protein. Importantly, some types of CFTR mutants

can be treated with drugs named correctors and potentiators. However, nonsense mutations, also

known as premature termination codons (PTCs), which cause the production of a truncated CFTR,

remain without an effective treatment. The overall goal of our project was to develop strategies to

target PTCs. In our experiments, cells expressing mutant CFTR were treated with combinations of

compounds acting at different levels on CFTR biosynthesis and function. We have identified the

most effective treatments for each mutation. In particular, we found that W1282X is the most

sensitive mutation with a large recovery mutant CFTR function, close to 30% of normal CFTR.

Y122X, G542X, and R1162X mutations could be also treated (10% of normal function) using

12 different combinations of compounds. In contrast, R553X mutation was particularly refractory to

pharmacological treatment. The results in our study will pave the way for future clinical trials in

which patients with specific mutations will be treated with the most appropriate compound

combinations.

Publications:

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Airway Cell Therapy for Cystic Fibrosis Nonsense Mutations

Awardee: Nigel Farrow

Institution: University of Adelaide, South Australia, Australia.

Award Amount: $53,668

Funding Period: February 1, 2019 - January 31, 2020

A New Concept for Gene Delivery and Therapy in Cystic Fib

Awardee: Robert Waymouth

Institution: Stanford University

Award Amount: $52,985

Funding Period: January 1, 2018 - December 31, 2018

Gene-edited stem cells for modeling rare mutations in cystic fibrosis (CF)

Awardee: Amy Firth

Institution: University of Southern California

Award Amount: $63,000

Funding Period: January 1, 2017 - December 31, 2017

Gene-edited stem cells for modeling rare mutations in cystic fibrosis (CF)

Awardee: Amy Firth

Institution: University of Southern California

Award Amount: $53,000

Funding Period: January 1, 2017 - December 31, 2017

Rational Design of Effective Therapeutics for Treatment of the 1282X CFTR Disorder

Awardee: Cooperman

Institution: University of Pennsylvania

Award Amount: $53,000

Funding Period: January 1, 2017 - December 31, 2017

Evaluating “exon‐skipping” as a strategy to repair the CFTR nonsense mutation

Awardee: Christine Bear

Institution: SickKids Hospital-Toronto

Award Amount: $51,500

Funding Period: January 1, 2016 - December 31, 2016

An open label N of 1 study to evaluate the safety and efficacy of long-term treatment with Ivacaftor in combination with ATALUREN (PTC124) in Subjects with Nonsense Mutation Cystic Fibrosis

Awardee: Stephen Rowe

Institution: University of Alabama at Birmingham

Award Amount: $51,500

Funding Period: January 1, 2016 - December 31, 2016

Systematic Evaluation of a Cluster of Nonsense Mutations in Exon 22 of CFTR to Inform Treatment

Awardee: Garry Cutting

Institution: Johns Hopkins University School of Medicine

Award Amount: $69,000

Funding Period: January 1, 2016 - December 31, 2016