Elastin-based biotherapeutic approaches for treating lung emphysema – TherAlveo

Lung emphysema is a major pathologic component of chronic obstructive pulmonary disease (COPD) characterized by damage to the air sacs in the lungs. The symptoms are indeed caused by the physical destruction of the elastic fibers in the lung parenchyma, together with a sharp increase in cell senescence. These physiopathological features lead to breathing difficulties for patients and vascular complications would arise overtime if the progression of the disease is not stopped. Referring to the World Health Organization, we estimate that COPD is the third leading cause of death worldwide, causing 3.23 million deaths in 2019, and it concerns 3 million patients in France and 66 million at the European scale. Moreover, the age-related lung dysfunctions, involving elastic fiber alterations, concern a large and growing part of the population. To date, available treatments for lung emphysema are symptomatic and include bronchodilators, corticosteroids, and oxygen. No effective curative treatments exist, and the use of senolytic compounds (elimination of senescent cells) remains limited due to organ-dependent side effects and the protective role of senescent cells in tumorigenesis. If we could improve lung function and structure by increasing elasticity and decreasing lung cell senescence, we would have a revolutionary treatment to address a very large market in the pharmaceutical field.

The TherAlveo project aims at improving pulmonary structure and mechanical function in emphysematous lung context. Our working hypothesis is that a close link exists between elasticity and senescence. Converging evidences indicate that senescence can be regulated either by a mechanobiological phenomenon that could be related to elasticity, or by an epigenetic mechanism depending on a protein of interest mRNA expression level.

Our objectives are therefore based on the development of biotherapeutic solutions allowing:
1) to directly repair the pulmonary parenchyma elasticity by the introduction of a protein of interest,
2) to act more specifically on pulmonary cell senescence by the exogenous introduction of a sequence encoding the protein of interest in liponanoparticles currently used in RNA vaccines.

Specific pharmaceutical formulations will be developed to address the lung elastic tissue and to facilitate the transfer of results to subsequent clinical applications. The efficacy of these treatments will be evaluated in relevant murine models of lung emphysema (pre-treatment with elastase, cigarette smoke exposure).

The feasibility of this project is ensured by a contribution of validated proof of concept and preliminary results. The consortium made up of scientists, pharmacists and clinicians brings together a panel of complementary skills in bioproduction, formulation, cellular and molecular biology and pulmonary pathophysiology. If successful, this project will offer an innovative therapeutic solution to the patients with COPD and emphysema, and a significant socio-economic potential in the field of biotherapies.