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NANOATHERO Report Summary

Project ID: 309820
Funded under: FP7-NMP
Country: France

Periodic Report Summary 3 - NANOATHERO (Nanomedicine for target-specific imaging and treatment of atherosclerosis: development and initial clinical feasibility)

Project Context and Objectives:
Atherosclerosis is the buildup of a waxy plaque on the inside of blood vessels, and plaque deposits can block the flow of blood. Plaques can also rupture or crack open, causing the sudden formation of a blood clot (thrombosis). Atherosclerosis can cause a heart attack if it completely blocks the blood flow in the heart (coronary) arteries. It can cause a stroke if it completely blocks the brain (carotid) arteries. These diseases of the arterial wall leading to acute arterial thrombosis and cardiovascular events are responsible for the majority of deaths in developed countries. The Executive Summary of the Screening for Heart Attack prevention and Education task force called for a non-invasive screening of all asymptomatic men and women to detect and treat those with subclinical atherosclerosis.
NanoAthero aims to demonstrate the clinical proof-of-concept and validation (Phase I clinical trial) of nanosystems for targeted imaging AND therapy of advanced atherosclerotic diseases in humans:
• Nanosystems will be used for enhanced local delivery and improved efficacy of drugs for athero-thrombotic therapy in humans.
• New nanoimaging agents will allow non-invasive, molecular imaging of key pathological processes in vulnerable plaques using state-of-the-art multi-modality imaging.
Sixteen partners from 10 countries created a large "Nanomedicine for Atherosclerosis" consortium with expertises from the design of nanosystems, preclinical and clinical validations, through toxicology, industrial development and production.
No specific nanoparticle-based system has yet been approved for diagnosis or therapy in cardiovascular diseases, the main causes of deaths in the world. Indeed, integrating in a nanosystem an efficient transport mechanism, a stealth coating, targeting and an active molecule has not yet been clinically validated in the field of atherosclerosis. NanoAthero partners have patented and provided proof of the efficiency of different nanodelivery systems and ligands for use in targeted therapies. The project aims to take profit of nanosystems that have been validated and transfer them to proof-of-concept clinical trials.
Due to the unique features of nanosystems, preliminary existing data and extensive expertise within the consortium, NanoAthero has the opportunity to deal with both diagnosis and therapy that will be addressed in pivotal interrelated projects on thrombus and plaque.
Design and characterization of nano-systems will be achieved in WP1 (Partners 1, 2, 5, 7, 8, 9, 10, 13, 15). Establishment of preclinical proofs of concept of the efficiency of nano-systems will be done in WP2 (Partners 1, 2, 5, 6, 7, 8, 10, 13, 14, 15, 16).
NanoAthero will support and organize the GMP production of injectable nanoproducts for humans (WP3 - Partners 1, 2, 8, 10, 15), and the establishment of toxicology data and risk assessment (WP4 - Partners 1, 10, 12, 13, 14, 15, 16).
WP4 will also provide analysis and modelling support to all WPs, i.e. data mining, statistical support in all levels, clinical trials analysis utilizing advanced up to date technologies and approaches, support to toxicity analysis and prediction as well as analysing biophysical and biochemical properties, surfaces and images.
WP5 is devoted to the proof-of-concept and clinical feasibility (Partners 1, 2, 4, 15, 16).
Ethics in all steps will be rigorously defined and managed in WP6 (Partners 1, 2, 3, 4, 8, 13, 15, 16). WP6 will also include regulatory dossiers for clinical research in humans, with some subcontracting to specialized entities, such as clinical/contract research organisations.
Valorization and exploitation of the patented outcomes by companies within and/or outside the consortium will be monitored in WP7, and partners will also support European dissemination and training (WP7 - Partners 1, 3, 10, 11, 12, 13, 15, 16).
This innovative proposal is under tight and professional management & coordination (WP8 - Partners 1, 3, 13, 15).

Project Results:
WP1: A list of candidate nanosystems was established for each category for A) molecular imaging and B) treatment of plaque, and for C) therapy of thrombus. Two imaging modalities were addressed for plaque imaging: MRI (iron oxide nanoparticles or gadolinium-loaded nanoparticles) and PET (68Ga labeled nanoparticles). Ga and Gd loaded nanosystems were based on micelles or lipid nanoparticles (liposomes or solid lipid nanoparticles). Successful drug-loading was achieved with liposomal nanosystems for plaque therapy. Liposomal pterostilbene and simvastatin formulations are presently investigated in WP2. Two tPA-loaded nanocarriers were designed for thrombus therapy: polymer nanoparticles and iron oxide nanoparticles. All nanosystems (A-B-C) were characterized and were evaluated for toxicity and efficacy in WP2.
WP2: Nanosystems generated in WP1 entered the workflow .All particles were provided for in vitro cell culture and toxicity assays until period 3. First results were included in a first collaborative paper. Promising nanosystems for imaging (lipidots and Gd-micelles) and therapy (simvastatin loaded nanosystems), as well as for thrombus therapy (fucoidan-tPA-polymer) entered in vivo efficacy studies. New SPIO nanosystems designed for magnetic targeting/imaging strategies entered an alternative umbilical cord-based ex vivo validation system.
WP3: The technical batch of the radiopharmaceutical was produced by the subcontractor in January 2017. The blood pool agent B22956/1 API was synthetized and the relative analytical characterization was performed, showing that the product meets all the required specifications. The High Pressure Homogenization (HPH) process for the large scale production of 68Ga/64Cu chelating particles has been developed for plain lipidots in parallel with the associated analytical procedures.
WP4: Two nanosystems with safe characteristics have been established. One is Fucoidan, the other one is the iron-oxide containing dextran nanoparticles. These achievements give rise for the selections of specific compounds according the objectives of the program.
WP5: Our two clinical trials in period 1 evaluated the feasibility and efficacy of liposomal nanotherapy for atherosclerotic disease. In the first study, we showed that intravenously infused liposomes effectively reached the macrophages inside the human atherosclerotic plaque. In the 2nd study, we unexpectedly observed that locally delivered prednisolone resulted in an increase, rather than a decrease of inflammation. Following the results of WP5.1, we designed a plan to answer three pivotal questions prior to infusing a therapeutic nano-athero system in humans: a. what compound is best?; b. what delivery vehicle is best?; c. what plaques can be preselected in order to improve therapeutic efficacy? A and B have been completed. In the final part of the WP5.3, the third question will be addressed. Period 3 was devoted to the preparation of the clinical trial for molecular imaging of plaque thrombosis in patients.

WP6: An ongoing process of ethical overview has been maintained of the project’s work on nanosystems and preclinical animal testing, aided also by an expert Ethical Advisory Group. A notable refinement has been made in one of the animal models, which should reduce the number of animals used. High standards of care of the animals was noted in all cases.

WP7: Several workshops and talks related to NanoAthero took place in period 3. The content of the Democs card game has been finalised, with comments received from the use of the game. It is in the final stages of design work prior to printing. P7 UKER organized a training for young researchers from the NanoAthero consortium on Endothelial compatibility of nanosystem by In vitro methods. P11 organized on the day before the annual CLINAM conference a Youngsters session for young researchers from the consortium providing them with an overview of the current work in the field of nanomedicine.
Potential Impact:
Cardiovascular diseases (CVD) represent the largest cause of death in Europe with ~four million deaths a year, i.e. half of all deaths. These mostly relate to coronary artery disease (CAD) and stroke. Despite a 30% relative risk reduction achieved by best therapies targeting systemic risk factor for CVD, the majority of events is not prevented.
Indeed, current revascularisation strategies focus on the treatment of hemodynamically significant coronary stenoses, whereas cardiovascular events are mainly caused by acute plaque rupture of non-stenotic plaques. Hence, novel strategies targeting the atherosclerotic plaque beyond ‘traditional’ systemic risk factors (blood pressure, dyslipidemia and hypertension) may help in further lowering this huge residual cardiovascular burden. Directly targeting the disease process itself, i.e. the atherosclerotic plaque, is a promising strategy provided that ‘plaque’ efficacy can be combined with systemic safety, thereby enabling a paradigm shift from ‘systemic’ to ‘local’ treatment modalities. In NanoAthero, we aim to provide proof-of-concept for efficacy and systemic safety of Nano-delivery in patients at increased risk of cardiovascular events. By bridging research centres and companies under the same umbrella, NanoAthero creates a multidisciplinary environment facilitating transfer of innovation and technology in nanomedicine from “bench to bedside”.

The expected outcomes of the NanoAthero project are nanosystems for diagnosis (imaging) and/or therapy, validated in Phase I clinical trials. This will be a world “premiere” because no nanomedicine approved so far either in the US or in Europe is addressing the unmet clinical need of improving diagnosis and providing targeted therapeutic strategies to detect and treat the residual cardiovascular risk.
Early diagnosis and efficient therapeutic treatment will significantly improve the health of EU-citizens and will decrease the overall costs to society. Keeping healthier society, reducing the number of sick patients and handicaps are major issues. The proposed targeted nanomedicines will give Europe significant savings in pharmaceutical spending, which continues to grow progressively.
The use of targeted nanocarriers will represent a major step towards targeted therapies in cardiovascular applications, and later on to some other major diseases like auto- and allo-immune diseases, infectious diseases, and cancer.
The detailed main expected outcomes of NanoAthero are:
1) Completed phase I trial for thrombus imaging
2) Preparation of a new thrombolytic nanosystem in stroke
3) Recommendations and files to start phase I study of a nanosystem for molecular imaging of the plaque
4) Completed proof-of-concept for local delivery of a nanosytem with a drug in atherosclerotic patients
5) Phase I trial for the treatment of vulnerable plaques using a novel therapeutic nanosystem
6) Advice on new regulatory guidelines for nanosystems in the cardiovascular field

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