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Member of the research team - Dr. Valeria Raia
Could you describe the Cystic fibrosis treatment approach that you have developed? We have developed and applied a totally new approach that restores the function of the most common disease causing mutation, the F508-CFTR by restoring defective autophagy in CF airways. This provides hope without hype.
How is it different from other therapies that are currently available for CF patients?
Current therapies for CF include digestive enzymes, mucolytics and antibiotics (to reduce the symptoms of CF lung disease) whereas new approaches target defective CFTR in a mutation specific manner. CFTR modulators include (1) channel potentiators to improve ion transport (class III mutations), (2) correctors to improve abnormal CFTR protein folding and its trafficking (class II mutations) and (3) stop codon mutation read-through drugs relevant for patients with premature stop codons (most class I mutations) as recently reviewed by Amaral (J Intern Med. 2014 29. doi: 10.1111/joim.12314). In total contrast, our approach focuses on rescuing CFTR function, by restoring the deranged intracellular environment of CF cells through which the defective mutated protein has to navigate to reach its correct location at the surface of the cell. Our approach sweeps the cell clean of its littered debris, left scattered by defective autophagy.
Member of the research team - Dr. Guido Kroemer
How did you discover this treatment?
We previously reported (Luciani et al Nat Cell Biol. 2010;12 (9):863-75. doi: 10.1038/ncb2090) that defective CFTR in the airways of CF patients induces upregulation firstly, of damaging free radicals ’reactive oxygen species (or ROS) and secondly, a protein ’spot-welder’ tissue transglutaminase (TG2). This, in turn, drives the crosslinking of an important regulatory protein beclin 1, leading to sequestration of a cell controller, phosphatidylinositol-3-kinase (PI(3)K) complex III, finally leading to defective autophagy and accumulation of p62 which normally regulates ’aggresome’ formation (a cellular garbage bin). Our recent data demonstrate that a simple molecule known for decades (cystamine and/or its reduced form cysteamine), by inhibiting TG2, acts as a cell restorer (proteostasis regulator) and can rescue and stabilize F508-CFTR at the plasma membrane, through restoring defective autophagy in CF airways (Luciani et al Autophagy. 2012;8(11):1657-72.; Villella et al Cell Death Differ. 2013;20(8):1101-15; Villella et al Autophagy. 2013;9(9):1431-4). Furthermore, we selected the green tea-derived flavonoid epigallocatechin gallate (EGCG) on the basis of its ability to modulate the activity of one particular Ser/Thr kinase, CSNK2, a "master protein kinase” involved in the proteolytic degradation of CFTR F508 at the plasma membrane (Venerando A et al, PLoS One. 2013 18;8(9); Tosoni K et al, Biochem J 2013 1;449(1):295-305). This combined radically alternative approach allows EGCG to sustain F508del-CFTR function beyond cysteamine washout as determined by many assays.
Member of the research team - Dr. Anil Mehta
Who does your multinational team consist of?
Pediatricians, cell biologists, pharmacologists, otorhinolaryngologists, immunologists, statisticians, engineers and biochemists.
What are the benefits of this international collaboration?
The research groups amalgamate leading experts with unique but complementary expertise in cell biology, autophagy, proteostasis regulation, biochemistry, immunology, statistics and clinical aspects of CF. This is a well-balanced group of research partners that provide the complementary expertise required to carry out the research goals. The partnership has been designed to use resources and strengths from each participating faculty providing the best research networking opportunities available, delivered by leaders in their fields, from both research and clinical academia. A perfect integration and sharing of know-how allowed each partner to brings their own solutions, techniques and experience and crucially, funding. These experts have already been involved in previous CF research efforts achieving noteworthy.
Can you mention some of the challenges you faced during the development of this treatment approach?
Our ambition aimed at translating our basic research into a pragmatic clinical approach. We wished to identify a new option for treatment of CF patients by a combinatory treatment targeting different disease-relevant pathogenic steps, allowing a bottom-up pathogenic-based drug discovery strategy for CF. We also targeted pathogenic-based biomarkers of efficacy of CF therapy, whilst assessing markers of autophagy, CFTR function and inflammatory cytokines in freshly isolated primary nasal cells in order to obtain a priceless practical tool to predict treatment efficacy in a given CF patient.
Member of the research team - Prof. Luigi Maiuri
In what way does your work impact Cystic fibrosis patients around the world?
We believe that since our experience is based on a pilot clinical trial we cannot give a definitive answer at the present time. However, we hypothesize that patients might have a better quality of life, given that this approach is not just symptomatic alleviation. In addition, the compounds we propose for such a new therapeutic approach are already commercially available. Thus, this combined treatment is not prohibitive in predicted costs, even for a developing nation. Rescuing and keeping CFTR protein function ’alive’ could impact on the longer-term clinical effects contributing to ameliorating the quality of life of these patients.
Does your work contribute to the goals of IRDiRC? How?
Yes it does contribute to the goals of IRDiRC by boosting translational, preclinical and clinical research with a candidate therapy.
What advice would you provide to other researchers and pharmaceuticals who are working on developing treatments for rare disease patients?
We suggest to identify the molecular mechanisms that constitute the milestones of a clinical manifestation. Translational research needs, in addition, a cooperative group of several types of researchers with complementary skills. We strongly support the idea to start this experience with a small pilot clinical trial, having in this manner the possibility of efficiently harnessing the feedback from the patients in terms of acceptability safety and efficacy. Our patients are our teachers.
Consult the Pubmed abstract of their paper published in Autophagy