# Rare mutations in Cystic Fibrosis: Overcoming barriers to personalized medicine

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $757,115

## Abstract

This project will focus on gaps in knowledge that must be overcome to advance precision, genotype-specific
intervention for cystic fibrosis (CF). First, we will characterize disease-associated alleles, many of which are
extremely rare, and have been assigned to an incorrect or incomplete mechanistic category. Other variants
represent novel defects not evaluated previously. Our goal will be to elucidate limitations of the conventional
diagnostic categories for disease-associated CF alleles, and to address modulator drug responsiveness (i.e.,
‘theratype’) for a number of rare CFTR mutations that have not been previously tested in this manner. We will
also provide examples of ways the recently solved CFTR cryo-EM structure can help define disease-
associated mutations and their effects on CFTR folding (Aim 1). Our studies will provide cell systems for
molecular phenotyping of alleles representing thousands of patients, and should be of value to the scientific
community, clinicians, and patients with the disease. Second, new model systems are needed that predict in
vivo benefit using drugs such as ivacaftor or Orkambi (which contains both ivacaftor and lumacaftor). As a test
of emerging cell systems for this purpose, we will generate iPS lines corresponding to 20 of the CFTR variants
profiled under Aim 1. Experiments such as these will provide a first evaluation of: 1) the extent to which iPS
cells can be used effectively as polarized monolayers according to the best available and innovative protocols
developed by our laboratory and others, 2) whether these model systems exhibit detectable modulator
response in vitro, 3) whether iPS cells are similar in molecular phenotype to widely used (FRT) cell models
encoding the same mutations for this purpose, 4) usefulness of leading edge gene editing technologies in iPS
cells to produce first-line systems, and 5) practical features of iPS technology vis-à-vis personalized
therapeutics, including the extent to which an individual patient sample can be expanded effectively, durability
of CFTR expression, function in vitro, stability of monolayers developed in this manner (Aim 2), etc. Finally, we
will take up the challenge to establish the practical usefulness of our work by facilitating a new intervention in
CF patients carrying the P67L/F508del genotype, a case study emblematic of hundreds of other CFTR
variants. We have a compelling body of data indicating that P67L patients will benefit significantly from a drug
such as Orkambi. Aim 3 will formally pursue this assertion in a clinical setting by directly testing human
subjects with this very rare allele. If successful as predicted, a group of patients who currently have no effective
modulator therapy will directly benefit. Moreover, because we believe it is likely that iPS cells will recapitulate
clinical efficacy, the data is intended to help establish an in vitro surrogate that will improve drug access and
precision therapeutics for a population of CF pat...

## Key facts

- **NIH application ID:** 9923749
- **Project number:** 5R01HL139876-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Brian R. Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $757,115
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923749

## Citation

> US National Institutes of Health, RePORTER application 9923749, Rare mutations in Cystic Fibrosis: Overcoming barriers to personalized medicine (5R01HL139876-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9923749. Licensed CC0.

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