Tat-cf: Final achievement and reflections
Cystic Fibrosis (CF) is caused by malfunction of CFTR, a transmembrane protein expressed in the apical membranes of epithelial tissues. Current therapeutic treatments targeting CF basic molecular defect aim to correct trafficking or folding defects preventing CFTR reaching the plasma membrane or to potentiate the activity of CFTR. There are over 2000 mutations described in the CFTR gene and these approaches are mutation specific, thus benefiting only cohorts of patients sharing the same functional defect. TAT-CF project seeks to develop molecules that mimic CFTR protein function, facilitating the permeation of anions such as chloride and bicarbonate through the membrane. By replacing CFTR function independently from the protein our approach is mutation agnostic and in principle could benefit all CF patients.
The main project innovations were to design and synthesize the appropriate compounds in the first instance. This was a challenging task and more than 200 compounds were evaluated by the different partners involved in our consortia. We needed to find the right balance between the molecular properties, transport activity, and toxicity of the candidates to select the appropriate leads for our project. In addition, we have created new research tools for cystic fibrosis such as induced pluripotent stem cell (iPSC) lines from cystic fibrosis patients and new assays to evaluate intracellular concentrations of anions.
Our most important achievement is the demonstration of the viability of this therapeutic approach. The best in vitro preclinical model of CF disease are synthetic epithelium derived from primary human bronchial epithelial cells. We have proved that our compounds can correct CF epithelia function to normal values in terms of fluid reabsorption and mucus viscosity, two key parameters in the pathophysiology of CF patients.
We have produced and studied several cell lines obtained from both patients with different mutations and through gene editing. This means that we have been able to test our compounds in cells and organoids having different functional defects as well as models in which CFTR expression was completely absent. Moreover we have tested TAT-CF compounds in combination with approved CF drugs and observed additive effects, which could also be envisaged to be a promising approach for the treatment of different mutations.
Due to the promising results obtained within the TAT-CF project, our idea is to continue these investigations. At this stage, drug development requires substantial investments to complete the preclinical assessment and proceed to clinical phases of development. A patent application has been recently submitted and we are looking for new sources of funding, both public and private, that allow us conducting the next steps for the development of the product. Although this is challenging in the context of a rare disease yet we are confident that it is possible.
Tat cf: main technical achievements
Each Technical Work Package (WPs 1 to 6) has obtained synergistic, relevant results, in order to achieve the main goals of the project. In brief, this are the main results for the mentioned WPs:
TAT-CF dissemination, exploitation and management
WP7 and WP 8 have contributed to a right dissemination, communication and exploitation strategy and to the overall coordination and management of the project. Some highlights are the filling of a PCT patent, the final conference and the continuous meetings and workshops, including the final meeting in Burgos to successfully close the project.
TAT-CF final project meeting in Burgos (Spain)
The last TAT-CF project meeting took place the first week of December in Burgos. The University of Burgos organized a 3-days meeting, including the TAT-CF workshop (Monday, 3 December), the final project conference (Tuesday, 4 December) and the meeting of the Steering Committee (Wednesday, 5 December). A summary of the activities performed throughout the entire project was presented in the workshop and a project self-evaluation was done by the consortium during the Steering Committee session.
TAT-CF final conference
TAT-CF organized its final conference “Research and New Treatments in Cystic Fibrosis”, in the context of the last project meeting. This event took place in the National Reference Centre for People with Rare Diseases (CREER), on 4th December in Burgos. This conference was aimed at associations and patients, as well as professionals in the sector and the objectives were to present the main results obtained within the TAT-CF project and establish a debate on the therapeutic advances that are currently being made in the field of Cystic Fibrosis. Around 40 people attended to this event in person, in which 7 presentations were made by renowned experts in the area. Additionally, the event was broadcast live to allow a wider participation and the videos are hosted in YouTube in the following link:
Overall the conference was very successful and the availability of the material produced in the internet will enhance the communication potential of this activity well beyond the lifetime of our project.