Validation of *in vitro counterpart* models to enable personalized care in CF

Cystic Fibrosis is a lethal disease for which only symptomatic treatment is
available. Emerging knowledge on upcoming drugs targeting the basic defect of
CF announces new opportunities for curative treatment. Proper targeting of
these drugs to responsive patients will be very important to demonstrate their
clinical efficacy, and to achieve maximal cost-effectiveness of care. We
recently developed two novel unique patient derived in vitro models that are
very promising for prediction of clinical effects of CF basic defect-restoring
compounds in single patients. In this project we will validate the predictive
capacity of these 'in vitro counterparts' for clinical outcome in CF patients
with different clinical and genetic expressions of the disease. In vitro
measurements will be related to clinical outcomes in homozygous F508del
patients with severe and mild phenotype and in F508del/A455E compound
heterozygous patients that display a mild phenotype. This study is a crucial
intermediate for development of personalized care in CF.

The specific objectives are:
1. What is the difference of in vitro CFTR function in CF patients with either
mild (compound heterozygote A455E) mutations or severe (homozygote F508del)
mutations with mild or severe clinical disease?
2. What is the association of in vitro CFTR function with clinical correlates
of heterozygote A455E CF patients or F508del/F508del CF patients that display
mild or severe clinical disease?
3. What is the association of novel in vitro CFTR function measurements with
existing ex vivo intestinal current measurements (ICM) in rectal biopsies?

This study will be a multicenter, observational study.

The study will be performed in adults aged 18 years or older depending on the
mutation, which enables proper documentation of the patients' clinical
phenotype over a long time-span.
Since there is a broad diversity in clinical phenotype depending on the CFTR
mutation, but also in patients carrying the same mutation (dF508), three groups
will need to be included.
The study will lead to one extra visit besides the scheduled follow-up visits.
Nasal brushes can cause some irritation of the nasal mucosa for several hours
and/or some self-limiting light bleeding in case of damaged mucosa prior to the
study. Rectal biopsies are painless because of the insensitivity of the upper
layer of the rectal mucosa. The risk of complications is very low, the patient
can encounter some slight loss of rectal blood. This is benign and in almost
all cases self-limiting.
A rectal biopsy might be a psychological loaden procedure, when patients agree
to participate the risks in this study can be considered low, whereas the
benefits might be substantial.
Direct benefits for the individual patient lie in the value of the in vitro
model in directing individual patient tailored care. We can use the patients*
unique material to predict individual responses to CFTR-restoring drugs in
follow up studies. After validation of this model we plan to set up a follow-up
study to use the in vitro models of all study patients to assess the most
effective individualized treatment strategy.