Rare diseases, like Cystic Fibrosis (CF), mean a major health problem for a significant number of people in total, but with the particularity of affecting small amount of patients for each individual diseases. In Europe, a disease is considered to be rare when it affects 1 person per 2000. In the current moment, around 60 to 70 thousand different diseases belong to this category. Rare diseases may affect just some dozens of patients in the World or a considerable amount of them, (tens of thousands) like in the case of CF.
This situation leads to a deficit of medical and scientific advances. Rare diseases have been ignored as a global concept for a long time, as population is quite scattered and diagnosis tools are not available in many cases. This implies little or directly no research around rare diseases in many cases, due to this in the current moment there is no cure for many of the existent rare diseases. On the other hand, there have been significant advances for some of them, showing that with and adequate investment and innovation model, progress towards cure of many rare diseases is possible. Nevertheless, people affected by rare diseases face similar difficulties regarding diagnosis, identification, treatments (curative or palliative), psychological problems which require social, economic and political support.
Fortunately, during the last decade this situation is changing. Efforts from private and public initiatives (IRDiRC, the European Commission, patient associations, foundations and NGOs), together with a major compromise from the Pharma industry, is leading to the development of novel treatments and diagnosis tools for rare diseases. The industry is conscious of the demands of the world of rare diseases, and is getting more and more compromised with the problem. This is due to several factors, as social responsibility convincement, personal compromise of the major shareholders (as happens with Praxis and CF) and opportunities to face projects prioritized by unmet medical needs with a different concept of commercial benefit and more innovative business models. This new approach should be faced using open innovation paradigms, which means developing solutions through collaboration with different partners, sharing technology, intellectual property, knowledge, etc, allowing the obtaining of solutions with low cost and lower risk. TAT-CF project is a clear example of this strategy, putting together academics and industry in order to obtain a revolutionary, more efficient, cheaper and safer treatment for CF.
The regulation of transmembrane transport of ions is an essential function in cells. Cell homeostasis is involved in a wide range of crucial cell functions. Ions and charged molecules are not able to diffuse across phospholipid membranes. The transmembrane transport of these species is facilitated by transmembrane proteins. These proteins can function as channels, pores and pumps and grouped in to different families according to their selectivity. The importance of this function is also a point of vulnerability. Malfunction of ion transport systems is associated with a number of diseases termed channelophaties. Cystic fibrosis (CF) is one of these conditions. It is a genetic disease resulting from the loss of function of the CFTR protein, a chloride and bicarbonate permeable transmembrane protein. TAT-CF project seeks to evaluate new therapeutic approaches to CF and in particular small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate, thus replacing the loss of CFTR function in CF patients. This is a potential universal solution for all CF patients regardless of the mutation they harbor.
In order to develop such class of small molecules TAT-CF took inspiration from ionophores, natural products capable of facilitating the transmembrane transport of ions. In particular there are two families of compounds, prodiginines and tambjamines which have been shown to be active chloride and bicarbonate selective anionophores (Figure 1). These molecules present a hydrogen bonding cleft with three N-H groups capable of coordinating anions very efficiently.
In our laboratories small organic molecules are synthesized mimicking the characteristics of naturally occurring anionophores. These molecules form supramolecular ion pairs which are lipophilic enough to transverse the lipid bilayer facilitating anion transport. Model phospholipid liposomes are used in the first instance to determine the efficacy of these molecules as anionophores. These vesicles can be prepared with a precise control of size and internal/external contents. The trafficking of anions such as chloride and bicarbonate from the interior to the exterior of the vesicles can be monitored using different experimental techniques such as NMR and emission spectroscopies or chloride selective electrodes. This last technique allows us to study the ability of the receptors to exchange Cl- and other anions like NO3- and HCO3- through the membrane of POPC vesicles (Figure 2). Once the experimental data have been fitted, EC50 values, which allow us to quantitatively assess the transport activity of the studied compounds, can be determined.
An iterative process allows the refining of the proposed structures to achieve the adequate level of transport activity as well as having the appropriate druggability.
TAT-CF will hold its next periodic meeting in the second half of January 2017. The meeting of the Steering Committee will include the review of the project progress, milestones and planning of actions for the next six months together with the first TAT-CF Workshop. During these workshops there will be scientific presentations by TAT-CF partners. These presentations will serve to enhance the collaboration among partners, reinforce the sense of unity of the consortium and serve as learning experience for TAT-CF recruited researchers, at an operational level. The meeting will be hosted by SIZ Zellkultur technik at their premises in Mannheim, Germany.
Five years have passed since the initial launch of IRDiRC in 2011 and considerable advances have been made in rare diseases research. This conference presents a unique opportunity to reflect upon this progress, confront barriers, and together, form new collaborations to take on challenges posed by rare diseases. Past conferences were held in Dublin, Ireland and Shenzhen, China.
All stakeholders – investigators, policy makers, opinion leaders, critical thinkers, young researchers, patient advocates and industry alike – active in the area of rare diseases from across the globe are invited to join us to celebrate achievements in the field, identify future milestones and goals, and work toward bringing diagnoses and therapies to all rare disease patients.