Pulmonary arterial hypertension: hope for a new treatment

Pulmonary arterial hypertension is a rare and serious disease, for which there is currently no cure. By identifying an unexpected therapeutic target, a multi-disciplinary scientific team has just taken a decisive step towards the development of a new treatment targeting pulmonary vascular remodelling.

Pulmonary hypertension or pulmonary arterial hypertension (PAH) is a rare disease that results from an increase in blood pressure in the pulmonary arteries which go from the right side of the heart to the lungs. Over time, the small pulmonary arteries become blocked – a process called vascular remodelling – due to uncontrolled vascular cell production. This hinders blood flow and causes higher pulmonary arterial pressure. The patients’ shortness of breath becomes chronic on the slightest exertion and sometimes even at rest. The right heart faces increasing resistance on ejecting blood to the lungs and eventually fails.

A paradigm shift outside the box

The different types of treatment currently available are mainly vasodilators. They aim to improve the patients’ exercise capacity and quality of life, prevent complications, slow down progression of the disease and prolong survival. However, none of these treatments can currently cure this disease, which can be fatal within five years from diagnosis, and the last resort is a bilateral-lung transplant or a combined heart-lung transplant.

A multi-disciplinary biology-medicine-medical chemistry-analytical chemistry research team at LabEx LERMIT (Laboratoire d’Excellence en Recherche sur le Médicament et l’Innovation Thérapeutique), a laboratory of excellence in research on medication and therapeutic innovation, has thought outside the box by exploring a new approach.

Sylvia Cohen-Kaminsky, who is the CNRS (National Centre for Scientific Research) Research Director at an Inserm/ Université Paris Sud unit (UMR_S999) at Hopital Marie Lannelongue, which is led by Professor Marc Humbert and dedicated to research on HAP, and her team, became interested in a new biological target, the NMDA (N-Methyl-D-Aspartate) receptor. These researchers discovered that the NMDA receptor, mainly known for its role as a glutamate receptor in communication between cells in the central nervous system, was unexpectedly present in pulmonary vascular cells . Even better, they have updated its role in cell proliferation in the arteries, where it contributes to pulmonary vascular remodelling and to pulmonary arterial hypertension.

These studies were conducted with the National Reference Centre for Pulmonary Arterial Hypertension and with the clinical team led by Professor Marc Humbert of the Paris-Sud Faculty of Medicine, with the support of Labex LERMIT, the ANR (National Research Agency), and the Paris Région Medical Competitiveness Hub, and were published in the journal Circulation, the American Heart Association’s flagship publication in February.

Discovery of new therapeutic molecules

On the basis of this major discovery, the researchers started looking for therapeutic molecules that could inhibit the action of these vascular NMDA receptors and make it possible to control the progression of the disease.

Furthermore, these molecules had to be safe and not cross the blood-brain barrier so that they could not reach and damage the central nervous system. This stage was entrusted to the specialised medical chemistry team, led by Mouad Alami, a CNRS Research Director and a member of the BioCIS (UPSud/CNRS) laboratory at the Paris-Sud Faculty of Pharmacy. Two series of antagonist molecules have consequently been identified.

Their physico-chemical, metabolic and pharmacokinetic properties were then analysed with Alain Pruvost’s team at the Laboratory for Medication Metabolism Studies (LEMM) at the CEA (Atomic Energy Commission), mainly to check that they did not cross the blood-brain barrier. Finally, these studies enabled the ideal candidate molecules to be selected, with the desired properties without major side effects being found.

Three patent families were filed in 2015 and 2016, mainly protecting the chemical space of these molecules. The project is currently in the technological maturation stage (lead optimisation and selection of a drug candidate) with the support of SATT Paris Saclay technology transfer company.

The researchers hope to develop a drug candidate by the end of 2018 and then team up with a manufacturing partner, or even found a start-up for clinical development. This is a real hope for many patients with this rare, serious, disabling and sometimes fatal disease.

Contact: Sylvia Cohen-Kaminsky -INSERM UMR-S 999 - Université Paris Sud – Institut Paris Saclay d’Innovation Thérapeutique (IPSIT) - sylvia.cohen-kaminsky @ u-psud.fr

Reference
NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension
Sébastien J. Dumas, Gilles Bru-Mercier, Audrey Courboulin, Marceau Quatredeniers, Catherine Rücker-Martin, Fabrice Antigny, Morad K. Nakhleh, Benoit Ranchoux, Elodie Gouadon, Maria-Candida Vinhas, Matthieu Vocelle, Nicolas Raymond, Peter Dorfmüller, Elie Fadel, Frédéric Perros, Marc Humbert and Sylvia Cohen-Kaminsky
Circulation. 2018;CIRCULATIONAHA.117.029930, originally published February 14, 2018
https://doi.org/10.1161/CIRCULATIONAHA.117.029930