T1-2

New therapeutic targets to treat Pulmonary Arterial Hypertension

Coordinators: S. Cohen-Kaminsky (Partner 6) and M. Alami (Partner 15)
Starting date: January 2012

Pulmonary arterial hypertension (PAH) describes a group of non-infectious rare (50/million) and lethal pulmonary vascular diseases due to subsequent right HF. There is unfortunately no cure of PAH. In spite of treatments that are now available to improve quality of life and survival, median survival of PAH remains <5 years and refractory cases are candidates for heart-lung transplantation. Right HF in PAH is secondary to remodeling of small pulmonary vessels, a complex and multifactor process in which inflammation plays a determinant role. Partner 6 has demonstrated that inflammation influences vessel remodeling and that immune dysfunction and autoimmunity contribute to the pathophysiology of PAH. On the basis of a unique biobank with pulmonary tissues collected during transplantation, he has identified an ion channel as a novel therapeutic target in PAH. This ion channel is involved in the 3 tissues interacting to cause PAH: the heart, the pulmonary circulation, and the immune system, and seems to play a major role in accumulation of perivascular inflammatory cells and vascular and cardiac remodeling.
Thus, new compounds targeting this ion channel in the 3 systems (cardiac, pulmonary, immune) concerned in PAH without central effects would be of great value to treat PAH. To date, most antagonists that reached clinical development cannot be used in the periphery without major secondary effects.

Objectives
1. Search for dysfunction of this ion channel in PAH pathophysiology at the vascular and cardiac cell levels and the contribution of immune/inflammatory cells to its activation (partner 6)
2. Design of new molecule hybrids to serve as potent allosteric effectors of this channel and thus modulate its function (partner 15)
3. Conception of pH-dependent antagonists that do not cross the blood-brain barrier, in order to target pulmonary inflammatory sites without central effects (partner 15)
4. Evaluate the new molecules in the classical and newly developed models of PAH (partner 6)
5. Understand how this channel is involved in PAH pathophysiology to propose a mechanism of action for these compounds in treating PAH, integrating data obtained from the 3 systems (immune, heart and lung) (partner 6)
6. Provide structural modeling for the interaction of the new compounds with the channel. The conformational changes of its subunits in presence/absence of the activation co-factors/modulators will be characterized through molecular dynamics approaches and potentially new therapeutic agents able to disturb such interactions will be designed or determined by in silico screening (partner 10)
7. Any opportunity of patenting will be examined with attention by the two arms of this project Pathophysiology/Biology-Chemistry (partners 6, 10, 15)