Scientists at the VIB-UGent Center for Inflammation Research have managed to unravel the functioning of what is thought to be the ‘master protein’ that drives a range of widespread allergic diseases, such as asthma and eczema. On a molecular level, the team described how a protein called TSLP assembles with its molecular partners at the surface of cells. This is the cornerstone of TSLP’s bioactivity. These insights, published in the leading scientific journal Nature Communications, also enabled the team to develop a new molecule that can block TSLP’s activity. Due to the molecule’s promise in terms of the development of new therapies for widespread allergic conditions, the researchers are currently planning follow-up studies and seeking industrial partnerships.
Millions of people worldwide suffer from common allergies – ranging from light asthmatic symptoms to severe atopic dermatitis, a frequent form of eczema. Such diseases cause a heavy burden in the quality of life of people suffering from them, and at the same impose a gigantic socioeconomic and healthcare footprint. The exact causes of such diseases are not known yet, although the answer probably lies in a combination of genetic, molecular, and environmental factors. While some treatments may reduce the severity and frequency of symptoms, a comprehensive cure has yet to be found.
Fundamental science paves the way to new therapeutics against allergic diseases
To tackle the complex issue of studying diseases at the molecular level, Savvas Savvides coordinated a multidisciplinary team spearheaded by his postdoc Kenneth Verstraete. This team united expertise from three VIB-UGent research centers, Ghent University, the University of Antwerp, The Pontifical Catholic University of Peru, and the University of Toulouse in France. The researchers focused on understanding the molecular and structural mechanism of how TSLP interacts with its two molecular receptors at the cell surface. A key undertaking has been the elucidation of the three dimensional structure of the molecular assembly mediated by TSLP. In parallel, the team developed and characterized a novel protein-based inhibitor of TSLP that can efficiently capture TSLP to prevent its association with its natural receptors on the cell surface. In this way, the bioactivity of TSLP can be blocked. The study has been supported by funding from nationaland international sources, as well as research infrastructure at the European level.
Savvas: “For the first time, we have obtained detailed snapshots of TSLP’s function. More specifically we unraveled how it mediates the protein assembly at the cell surface responsible for several atopic diseases, including asthma and atopic dermatitis. TSLP has been the focus of many prominent academic laboratories worldwide, as well as major pharmaceutical companies. This knowledge offers them a new tool for therapeutic intervention. Our study proves that basic research at the molecular level is the pillar for developing new therapeutic strategies.”
Savvas’ team is currently working closely with the partner team led by Rudi Beyaert and with VIB’s Technology Transfer department towards follow-up studies, with a twofold goal: to optimize the TSLP inhibitor on one hand, and to test the molecule in appropriate animal models for a range of allergic conditions on the other.
Rudi: “The detailed structural and biochemical insights are a key source of information for understanding and optimizing the potency of our inhibitory molecule against TSLP. We are very excited about the implications and promise of this work.”
Savvas: “We strongly believe in our discovery’s potential in the development of new therapies against allergic diseases. At the same time, we hope that the insights and tools we have generated in this study will catalyze further developments in the field. The TSLP story is far from done, as recent reports have added intriguing new twists to TSLP’s function. We will take advantage of our pole position in the field to continue to contribute to our understanding of this fascinating protein. Nonetheless, our priority now is to identify possible industrial partnerships to actually develop a novel therapeutic tool.”
Verstraete et al., Nature Communications 2017