Physio-mechanical investigation of a synthetic elastic protein as a molecular prothesis to heal arteriopathies related to elastic fibre defects – Arterylastic

WP1: SEP production and cell biology.
Synthetic elastic protein (SEP) production to provide material to the whole consortium, and effect on arterial cells in vitro.
- SEP production at 100 mg scale
- SEP stability, purity and injectable formulation
- Biological effects on human vascular cells
- Biological effects on pathological mouse vascular cells

WP2: Endothelial permeability, thrombogenicity, inflammation and SEP integration in arterial elastic lamellae.
SEP mechanism of action in vitro and in vivo. Many conditions are tested (concentration, duration, drug); therefore, the low-cost and high-throughput zebrafish model organism presents many advantages to screen the best conditions.
- In vitro blood-barrier passage evaluation
- Blood-barrier passage analysis in zebrafish model
- Neutrophil and thrombocytes recruitment zebrafish model
- Ultrastructural evaluation of SEP integration in vascular walls

WP3: Physiopathological mouse models: pharmacological and physiological analyses.
Potential benefit of SEP treatment through three murine models that recapitulates the three pathological contexts of arterial elastic fibres deficiency: ageing, Eln+/- and intermittent hypoxia. Efficiency is evaluated at physiological, histological and biomechanical levels.
- Physiopathological mouse model treatment
- Ex vivo pharmacological response to soluble SEP
- Ex vivo pharmacological evaluation of treated mice

WP4: Mechanical evaluation and numerical modelling.
Mechanical behaviour of the cross-linked SEP and arterial samples from treated mouse models. A numerical model is developed to better predict treatment parameters.
- Cross-linked SEP mechanical evaluation
- Predictive numerical model development
- Mechanical and vasoreactive characterization of aortas in treated mice
- Dialog between the predictive model and experimental data

Confidential data at this stage of the project.

Not applicable at this stage of the project

Fhayli et al, Biomolecules 2020. PMID 31979322
Fhayli et al, Cell Signal 2019. PMID 31176018
Fhayli et al, Matrix Biol 2019. PMID 31493460

The passive stiffness of elastic arteries is mainly determined by two major extracellular matrix proteins of the arterial wall, i.e. elastin and collagen. Elastin provides reversible extensibility during cyclic loading of the cardiac cycle, while collagen provides stiffness and strength at high pressures. Loss of elasticity and induced consequences on the vascular function are observed in normal ageing, and in syndromic elastogenesis-related genetic diseases which include Williams-Beuren syndrome, supra-valvular aortic stenosis and autosomal dominant cutis laxa. Recent studies have also shown it can be associated with pathological conditions such as the sleep apnea syndrome (SAS). Knowing that SAS concerns about 10% of the general population and affects 20% in the elderly, in 2015 in France, 837,000 people were treated for SAS. Williams-Beuren syndrome is a rare disease but represents 3,000 people in France and is estimated at 300,000 patients over the world. The age-related cardiovascular dysfunctions, involving elastic fibre alterations, concern a large and growing part of the population. If we could introduce new elastin in the existing elastic scaffold of arteries, and if this provides increased elasticity, we would have a revolutionary treatment related to a very large market in the pharmaceutical field.

Arterylastic project aims at restoring the function and mechanical properties of blood vessels using an original synthetic elastic protein recently developed by the principal investigator (“DHERMIC”, ANR 2012-2016). This represents a very important breakthrough since this compound might serve as an elastic molecular prosthesis in tissues to compensate or restore the lack of elasticity. To reach this ambitious goal, the Arterylastic project will investigate and optimize the following properties of this synthetic compound:
- delivering the right signal to cells with no deleterious effect;
- reaching the right location through the endothelial barrier;
- being integrated into elastic fibres within vascular walls;
- improving arterial wall elasticity and/or physiological parameters in relevant animal models;
- developing an injectable formulation of the compound with a pharmaceutical grade.

We have large convincing data set available on skin for the synthetic elastic protein (DHERMIC project) and we recently obtained preliminary very promising results for blood vessel integration in fish and mouse. The success of the proposal will also rely on strong complementarities between the three internationally recognised academic partners: LBTI is expert in biology of elastic fibres and therapeutic engineering; HP2 has a strong expertise in vascular physiology and in elastin hemizygous and intermittent hypoxia mice models mimicking sleep apnea syndrome (SAS); and ARMINES-CIS is a very active laboratory in the field of biomechanics and numerical modelling of soft tissues.
To ensure a certified pharmaceutical grade formulation, the FRI Pharm facility core from Lyon hospital is involved in the project. After achieving the scientific investigations, a partnership with a pharmaceutic company will be addressed to allow for further industrial and clinical developments. Moreover, a startup company will be created in order to accelerate the industrial transfer and at mid-term to participate in local socio-economic dynamism.