Experimental CFTR correctors for the treatment of Cystic fibrosis.

Rationale: Effective drugs for the treatment of Cystic Fibrosis (CF) patients
with trafficking mutations are not yet available, and associated lung and liver
pathologies remain untreatable. Novel compounds have to be identified, and
tailored in combination to specific CFTR mutations, to different tissues, or
even to the individual patient.
Immortalized cell lines overexpressing mutant CFTR are typically used to screen
candidate molecules but have proven to be poor predictors of clinical efficacy.
The complexity of CFTR maturation and turnover requires the use of cellular
models that closely recapitulate the specific properties of the clinically most
affected organs. Importantly, current screening efforts based on primary airway
cells or intestinal organoids cannot specifically target single rare CFTR
mutations, or mimic multiple cell types.
To address these unmet needs we generate induced pluripotent stem cells (iPSCs)
from patients homozygous or compound heterozygous for the common F508del and
rare trafficking mutations. The iPSCs will be genetically corrected to provide
adequate isogenic controls and to express CFTR from one allele only with the
mutation of interest. Reporters will be introduced to facilitate high
throughput screening. Identified compounds will be functionally validated and
the mechanism of action will be elucidated in iPSC-derived and primary
organotypic culture. This approach allows testing compound combinations in
personalized surrogate models of CF lung and liver disease, up to the
pre-clinical stage in particular targeting rare CFTR trafficking mutations.

The objective of the present application is to obtain cell material in the form
of blood, from two patients homozygous for the trafficking mutation N1303K rare
mutations for which no effective treatment is available, to generate induced
pluripotent stem cells (iPSCs) and primary cells for functional assays.

Collected cell materials from the two selected CF patients will be used to
generate induced pluripotent stem cells (iPS), to identify (by high throughput
screening) and validate (in organotypic cell culture models) novel CFTR
targeted therapeutics.

Only CF patients with known mutations of interest (rare CFTR trafficking
mutations) and well described pathology are eligible, in this case two patients
with a N1303K CFTR trafficking mutation aged 11 and 24 years. These studies
will contribute to the development of an effective treatment for patients
carrying these mutations, for which an effective treatment does not exist.


Blood samples are drawn using standard procedures during routine examination of
the patients, so that no additional puncture is necessary. The procedure is
widely used in clinical practice and usually well tolerated, involving limited
discomfort and negligible risk. For this study a 20 ml blood additional sample
will be drawn.