# Molecular Genetics of Cystic Fibrosis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

Cystic fibrosis (CF) is one of the most common life-limiting autosomal recessive single gene disorders.
Individuals with CF carry loss of function variants in each CF Transmembrane conductance Regulator (CFTR)
gene. CFTR encodes a cAMP-activated chloride channel that ensures proper hydration and ion content of
mucous secretions in the pulmonary airways and pancreatic ducts and maintains the correct concentration of
chloride in sweat. Treatment of CF has taken a major step forward with the development of two classes of
CFTR-targeted drugs. Ivacaftor (VX-770), a compound that potentiates the function of 33 variant forms of
CFTR that are folded but inactive, has shown dramatic and lasting clinical effect. Lumacaftor (VX-809), a
corrector compound, improves the folding of CFTR and demonstrates modest clinical efficacy in individuals
with CF carrying the common disease-causing variant F508del. The success of these drugs indicate that we
should be able to treat the vast majority of individuals with CF by targeting one or both of their CFTR variants.
Several developments indicate that this goal is within reach. First, with near complete ascertainment of
affected individuals by the CFTR2 project, we know that 520 variants account for 98.2% of CF alleles while the
rest are `private', being reported in only one or two individuals worldwide. Second, in a major shift in policy, the
Food and Drug Administration recently allowed expansion of the use of the CFTR-targeted drugs based on
results of testing CFTR mutants expressed heterologously in immortalized cells. Third, we have developed and
optimized a human airway cell line devoid of endogenous CFTR (termed CF8) for the functional assessment
and drug response of heterologously expressed mutant forms of CFTR in a near native context. The overall
goal of this application is to inform precision treatment by annotating every CF allele according to
mechanism of effect, disease-liability and response to targeted drugs. This goal will be achieved by:
1) Determining disease mechanism, clinical consequences and drug response of CFTR variants to achieve
annotation of 98.2% of all CF alleles reported to CFTR2; 2) Ensuring that the correct disease mechanism has
been elucidated for missense variants that may also affect mRNA splicing or occur in cis with other potentially
deleterious variants and 3) developing and testing predictive methods to determine disease liability and drug
response of ~435 private missense variants in CFTR2. Upon completion of these aims, we estimate that
67,500 of the 70,000 individuals with CF worldwide will have mechanistic, clinical and drug response
information for each CFTR variant they carry, 2,474 will have the same information for one variant leaving only
23 individuals with no information about either CFTR variant they carry. These data will be shared with the
medical community and public on the CFTR2.org website. Our efforts to generate and test predictive
approaches to variant annotati...

## Key facts

- **NIH application ID:** 9942402
- **Project number:** 5R01DK044003-30
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Garry R Cutting
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 1991-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942402

## Citation

> US National Institutes of Health, RePORTER application 9942402, Molecular Genetics of Cystic Fibrosis (5R01DK044003-30). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942402. Licensed CC0.

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