Efficacy and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-mutation-mediated Cystic Fibrosis (CF)

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

7 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-11-01

Study Completion Date

2015-04-16

Brief Summary

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* Working Hypothesis: EGCG and Tocotrienol can act as genetic modifiers and increase the level of correctly spliced CFTR transcripts.
* Aims of the Study: To determine in patients with CF if oral administration of EGCG and Tocotrienol, both separate and in combination, modify CFTR splicing towards normal splicing as evaluated by improved Transepithelial Potential Difference (TEPD) assessment of chloride secretion.

To assess the effect of EGCG and Tocotrienol, both separate and in combination, on (1) additional TEPD measures of ion channel activity, (2) levels of correctly spliced CFTR mRNA in nasal mucosa, (3) cytokine levels in sputum and (4) changes in pulmonary function over the course of the study.

* Potential Implications to Medicine: Alternative splicing mechanisms are a common cause of genetic disease as \~15% of all known human mutations result in defective pre-mRNA splicing. Therapies based on augmenting the levels of full length or fully functioning proteins may have a substantial impact on the treatment of patients with genetic diseases.
* Contribution of the expected outcome to society Today genetic diseases can be treated but not healed. This proposal may be a step in the direction of finding a cure for patients carrying splicing mutations.

Detailed Description

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Background: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF trans-membrane conductance regulator protein. Despite substantial progress achieved in the understanding of the molecular basis and physiopathology of CF, a cure is not available. Mutation specific therapy is a novel approach to overcome the molecular defect in CF. We have previously shown that gentamicin and PTC 124 can induce read-through of nonsense CFTR mutations, and lead to functional CFTR. In addition we have shown that in vitro treatment with (-)epigallocatechin gallate (EGCG) and or Tocotrienol of cells harboring splicing mutations can augment production of full-length transcripts of affected proteins.

Working hypothesis and aims: EGCG and tocotrienol can act as genetic modifiers and increase the level of correctly spliced CFTR transcripts. Aim: To determine in CF patients if oral administration of EGCG and/or Tocotrienol, will modify CFTR splicing, as assessed by (1) Transepithelial Potential Difference (TEPD) as a measurement of ion channel activity, (2) levels of correctly spliced CFTR mRNA in nasal mucosa, (3) cytokine levels in sputum and (4) pulmonary function (FEV1).

Methods: Patients with CF carrying splicing mutations will be treated with EGCG 200 mg/day, Tocotrienol 600mg/day or both for 28 day cycles. Clinical parameters (TEPD, FEV1 and cytokine levels in sputum) and molecular parameters (mRNA levels,) will be analyzed to determine the effectiveness of the treatment.

Expected results: In vitro studies with cell cultures derived from CF patients have shown positive results; therefore an improvement in TEPD will be an indication for CFTR expression. An increase in mRNA levels and changes in FEV1, and cytokine levels will confirm the results.

Importance: Genetic therapy has encountered many technical difficulties. It is therefore of importance to develop alternative molecular strategies that will lead to an improvement or to a cure of genetic diseases.

Probable implications to Medicine: Alternative splicing mechanisms are a common cause of genetic disease as \~15% of all known human mutations result in defective pre-mRNA splicing. Therapies based on augmenting the levels of full length or fully functioning proteins may have a substantial impact on the treatment of patients with genetic diseases.

Conditions

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Cystic Fibrosis

Keywords

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Cystic fibrosis splicing mutations molecular therapy EGCG Tocotrienol Splicing-mutation-mediated Cystic Fibrosis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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EGCG

Two cycles comprising 28 days of continuous daily treatment with EGCGgiven 2 times/6 soft gel capsules (total 600 mg) /day (BID) in the morning and in the evening with food followed by a 14 day wash out period without drug.

Group Type ACTIVE_COMPARATOR