©N.Caillat-Vigneron/Serimedis

A genetic marker localised on chromosome 18 is associated with a doubling of the risk of pulmonary arterial hypertension (PAH). A gene close to this marker is suspected of being responsible for an increased risk of the disease, according to an academic study (letter) published in Nature Genetics* on 17 March 2013.

PAH is a rare but severe condition that specifically affects the small arteries of the lung and causes serious heart failure. The condition is more like to affect young women and occurs without explanation in 50% of cases. Apart from mutations mainly identified in family forms of the condition, other genetic predisposition factors are as yet little understood.

This result was obtained through research performed by three French teams which involved collaboration in Europe and the United States. By studying patients suffering from PAH who were being treated by pneumologists at the French national PAH reference centre at the Bicêtre Hospital (team headed by Professors Gérald Simonneau and Marc Humbert, AP-HP, UMRS 999, Université Paris-Sud, INSERM, DHU-TORINO), geneticists (Professor Florent Soubrier’s team, UMRS 956) and biostatisticians (Dr David Tregouët’s team, UMRS 937) at the Pitié-Salpêtrière Hospital (AP-HP, Université Pierre and Marie Curie, IHU-ICAN) implemented a genetic analysis covering several hundred cases and control subjects. The analysis used DNA chip techniques that made it possible to study hundreds of thousands of genetic markers simultaneously that are distributed throughout the genome.

Thanks to international collaboration, these researchers were able to show the existence of a genetic marker situated on chromosome 18, the presence of which makes an individual twice as likely to contract PAH.

The marker is situated close to a gene which, according to the preliminary work conducted by these researchers, may participate in a vascular regulatory system that has so far not been described.

Sixteen partners from 10 European countries got together to create the “Nanomedicine for Atherosclerosis” consortium. Its aim is to study and develop the clinical feasibility of nanomedicine for targeted diagnosis and treatment of atherosclerosis. Coordinated by Inserm, the project has just obtaining funding amounting to 10 million euros over five years from the European Commission.

The 16 partners will meet in Graz in Austria on March 6 and 7^th next, in order to kick off the NanoAthero project.

To an application of nanomedicine to cardiovascular diseases

Atherosclerosis means that fatty deposits (known as atheromatous plaques) build up on the walls of the arteries, blocking the flow of blood and causing damage. The plaque may also break away and cause the sudden formation of a blood clot. Atherosclerosis can lead to a heart attack if it completely blocks the arteries leading to the heart, or it can cause a stroke if it affects the arteries leading to the brain.

The risk factors of artery wall diseases are: high levels of cholesterol or triglycerides, diabetes, smoking and high blood pressure, making theses the major causes of death in developed countries¹. At present, the predominant strategies used to fight the consequences of atherosclerosis are either encouraging people to live a healthy life² and administering pharmacological treatment of the risk factors, or later strategies such as the implantation of medical devices³, thrombolysis (using medication to break up the blood clots), etc… However, thrombolytic treatment needs to be improved in order to enhance its efficiency and to reduce its adverse effects (bleeding in the brain, for example).

“In spite of these therapeutic devices, the occurrence of clinical events remains very high¹. This highlights the need for better diagnosis and therapies⁴”

Although nanoparticle-based therapy is becoming more and more common in cancerology, no specific nanoparticle-based system has yet been approved for diagnosis or therapy in cardiovascular diseases. Indeed, integrating a transport mechanism, a furtive coating, targeting and an active molecule into one and the same nanosystem (known as a third-generation nanosystem) has not yet been clinically validated in the field of atherosclerosis⁵.

NanoAthero: 16 partners on their way to clinical trials

© Inserm

Several NanoAthero partners have patented and provided proof of the efficiency of different nanodelivery systems and ligands for use in targeted therapies. This recent progress is of major importance for the development of new molecular and therapeutic diagnosis tools. In the opinion of the NanoAthero consortium, the nanovectors proposed to route compounds that can show up “vulnerable” plaques and to deliver therapeutic agents to stabilize the plaques^6,7 are ready to be transferred to the clinical trials stage.

But developing nanoparticle systems that are efficient, safe and innovatory and are capable of reaching a selected target is a complex process that involves several stages. There is an increasing need to select and/or identify suitable materials, nanoparticle surface coatings and targeting ligands with innovatory properties⁸. The agents (small molecules, but also macromolecules such as proteins and nucleic acids) to be loaded into the nanovectors vary widely by their physical and chemical properties, so it is a major challenge to try to balance the nanometric dimensions of the particle with respect to the types and quantities of agents that are clinically required. Well-determined structural, physical and chemical properties (size, surface charge, shape, stability) are vital to guarantee reproducible effects in vivo.

NanoAthero is aiming to take nanodelivery systems that have been validated prior to clinical trials and transfer them to proof-of-concept clinical trials. The consortium is an opportunity to update our knowledge of atherothrombosis pathologies and the definition of cell and molecule targets. Therefore, NanoAthero has a store of knowledge ranging from the design of nanosystems, preclinical and clinical validations, through toxicology, to industrial development and production.

References:

1. Wayne R, Katherine, F, Gary, F, et al. Heart disease and Stroke statistics-2007 update. Circulation. 2007;115:e69-e171.

2. Kahn R, Robertson RM, Smith R, Eddy D. The impact of prevention on reducing the burden of cardiovascular disease. Circulation. 2008;118(5):576-585.

3. Miloro P, Sinibaldi E, Menciassi A, Dario P. Removing vascular obstructions: a challenge, yet an opportunity for interventional microdevices. Biomed Microdevices. 2012:PMID: 22331446.

4. Klink A, Hyafil F, Rudd J, Faries P, Fuster V, Mallat Z, Meilhac O, Mulder WJ, Michel JB, Ramirez F, Storm G, Thompson R, Turnbull IC, Egido J, Martin-Ventura JL, Zaragoza C, Letourneur D, Fayad ZA. Diagnostic and therapeutic strategies for small abdominal aortic aneurysms. Nat Rev Cardiol. 2011;8(6):338-347.

5. Lobatto ME, Fuster V, Fayad ZA, Mulder WJ. Perspectives and opportunities for nanomedicine in the management of atherosclerosis. Nat Rev Drug Discov. 2011;10(11):835-852.

6. Lammers T, Aime S, Hennink WE, Storm G, Kiessling F. Theranostic nanomedicine. Acc Chem Res. 2011;44(10):1029-1038.

7. Lewis DR, Kamisoglu K, York AW, Moghe PV. Polymer-based therapeutics: nanoassemblies and nanoparticles for management of atherosclerosis. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011;3(4):400-420.

8. Wei S, Wang Q, Zhu J, Sun L, Lin H, Guo Z. Multifunctional composite core-shell nanoparticles. Nanoscale. 2011;3(11):4474-4502.