The effect of curcumin and genistein in CF patients with a class III mutation

The cystic fibrosis trans membrane conductance regulator (CFTR), a chloride and
bicarbonate channel encoded by the CF gene, is essential for fluid and
electrolyte homeostasis at the epithelial surfaces of many organs, including
the lung, intestine, and sweat gland. Over 1900 CFTR mutations have been
identified causing impaired protein production (class I), folding (class II),
channel gating (class III), conductance (class IV), or reduced synthesis (class
V).

Currently, several CF patients with gating mutations use curcumin and genistein
because of anecdotally reported beneficial effects of these self-administered
food supplements. Curcumin and genistein are freely available plant extracts
which can be bought on the internet. Formal efficacy studies of these
supplements have never been done. Recently, using various primary cell models
from CF patients (organoids), we found the natural food components curcumin and
genistein as potent correctors of the channel gating defect, capable of
enhancing the activity of class III gating mutants (e.g. G551D; S1251N).

Primary objective:
To investigate the clinical response to treatment with curcumin and genistein
in CF-patients with a class III S1251N mutation..

Secondary objectives:
1.To evaluate the correlations between individual curcumin+genistein induced
CFTR function in vitro (organoid-based
measurements) and the in vivo treatment effect (lungfunction, airway
resistance and SCC);
2.To assess whether the dosage of curcumin+genistein used in the clinical study
is sufficient to stimulate CFTR function. We will
evaluate the CFTR stimulating ability of the concentration of
curcumin+genistein in the patient*s blood samples. We will examine this by in
vitro testing (in the organoid model), evaluating the CFTR stimulating ability
of the concentration of curcumin+genistein and Ivacaftor in the patient*s blood
samples. we will also determine the serum levels of curcumin and genistein.

This study will be a multi centre pilot open label intervention-study.

After baseline measurements all patients will receive curcumin and genistein
during 8 weeks. Study measurements will be performed during two visits; before
and after receiving curcumin+genistein.

In this study patients will receive the natural food components curcumin and
genistein and the drug Ivacaftor. Curcumin and genistein are registered natural
food supplements, widely and freely available on internet and in reform-shops
and used by millions of people world-wide. Unless we will give these components
in a higher dose, we do not expect serious problems or side effects during this
study because of the limited side effects that have been described in earlier
studies with higher doses (also see Investigator Brochures) and the positive
experience of the four patients who are already being treated. In the context
of this study, patients have to visit the hospital 2 times during 2,5 hours and
at home they need to write down their use of curcumin+genistein in a diary and
perform a FEV1 test every week.

A number of patients with a S1251N class III gating mutation use curcumin and
genistein themselves as part of their regular care and they show a clear
diminution of their CF symptoms, without detectable side-effects. When our
hypothesis is confirmed and curcumin and genistein turn out to improve the CFTR
function in patients with a class III gating mutation and therefore diminish CF
symptoms, this is a major benefit not for these patients.

When this study also confirms our hypothesis that organoids can predict
clinical responders, this is a major benefit not only for the individual
patient but for the entire CF-population. With the use of organoids we will be
able to generate optimal treatment strategies for individuals based on
(combinations of) current and future drugs with only limited patient
discomfort.