Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS


BIOMAGSCAR Informe resumido

Project ID: 278313
Financiado con arreglo a: FP7-HEALTH
País: United Kingdom

Periodic Report Summary 1 - BIOMAGSCAR (Biodegradable Magnetic Stent for Coronary Artery Luminal Regeneration)

Project Context and Objectives:

Project concept

Cardiovascular disease is the biggest killer in the European Union. The direct and indirect costs to the European Union of this problem amount to 300bn Euros per year. Great progress has been made in treating cardiovascular disease by therapeutic interventions including drugs and devices, however, it still remains the number one killer. The coronary artery stent has revolutionised the management of patients with coronary artery disease and its use is on the increase across Europe. Although outcome for patients has improved, stents still fail because of restenosis and because of early and late thrombosis occurring at the site of the implantation. While drug eluting stents have helped to reduce the problem of restenosis, neointimal proliferation causing restenosis can still occur. Additionally, concern exists regarding the long-term safety of drug eluting stents as there appears to be a small but real increase in late and very late stent thrombosis, seen particularly after the discontinuation of antiplatelet therapy.

The concept we propose is use of a biodegradable magnetised stent (BMS) as a novel delivery device for regenerative medicine solutions that target the coronary artery vessel wall. Specifically we will develop the stent technology as a platform to attract endothelial progenitor cells that are tagged with iron nanoparticles in vitro. Once redeployed into the patient, the endothelial cells will be attracted to the already implanted BMS and will proliferate to form a new endothelium. Over time the BMS will undergo a predictable degradation to leave a wholly biological artery through regeneration of native tissues.

An additional technique we will be investigating to ensure a rapid endothelialisation of the BMS makes use of an adenoviral gene transfection to promote rapid, but ordered, endothelialisation in the selected area of the vessel wall where the adenovirus coated stent has been deployed.

Project objectives

Our objective, using the magnetic biodegradable stent as a tool, is to reduce the incidence of in stent restenosis and thrombosis. Given the involved nature of using the magnetisable stent/magnetic cell combination it is envisaged that that this solution to the restenosis and late stent thrombosis problems will initially only be used as a secondary therapy in patients who are perceived to be high risk, as identified by existing occurrence of restenosis or a thrombotic event. It is hoped that with successful clinical trials of this approach, and refinement of the methodologies to be used, use of the stent will widen to become a primary therapy option.

We have developed a detailed programme of work to deliver these strategies culminating in clinical trials and have defined a set of objectives that are initially scientific in focus following on to clinical/societally beneficial objectives. During the BIOMAGSCAR project our objectives are to:

• Create a preclinical dossier for a biodegradable magnetic stent based on a stent platform under development at QualiMed as a tool for delivery of regenerative therapies to the coronary artery wall;
• Optimise the magnetic characteristics of the stent and the stem cell magnetic labelling system so that the ideal number of cells is captured by the stent on first pass;
• Enhance the biodegradable magnetic/stem cell system using a novel adenovirus gene transfection (European Medicines Agency approved) platform developed by Ark Therapeutics to enhance the expression of our chosen gene on the vessel walls to provide further attraction to the stem cells and ensure that regeneration and recovery of the coronary artery vessel wall is optimised and protected from restenosis and thrombosis.
• Develop the gene therapy enhanced biodegradable magnetic stent project for Phase I clinical trials in man.

Project Results:

Development of a new magnesium stent, and completion of its “Design Process”, began with Design Input Specification to define the characteristics of the device in accordance with the relevant ISO 25539-2 and FDA Guidelines for Vascular Implants. Once these were defined we chose the material and structural design of the new stent. To determine optimal configuration of the magnetisable stent we targeted different designs by varying: Tube configuration, Strut thickness, Electro polishing and Polymer coating. This led to a range of stents that have been characterised and their suitability for the application assessed.

For magnetisation of the magnesium stent our initial focus was on selection of a suitable polymer coating to contain nano-particles that would allow the magnesium stent to be magnetised. Biodegradable polymers such as polyesters are well suited for this purpose and in this case PLLA coating proved to be our first choice for incorporation of the magnetisable nano-particles. Work on the particles began with the assumption that ultra-small iron oxide nanoparticles (USPIO) can be magnetised and hold a magnetic field for a few hours or days enabling the capture of iron labelled cells. However, it quickly became apparent that USPIO cannot serve this purpose because of their superparamagnetic characteristics. To rectify this we doped USPIO with platinum to slow the realignment of magnetic dipoles and enable long term magnetisation. Our work to date has shown that iron-platinum nanoparticles can hold a magnetic field for at least 60 days post magnetisation in a 1.5 T magnet for 24 hours.

With a focus on endothelial progenitor cells (EPCs), a large body of evidence indicates that cells expressing the surface markers CD133 and CD34 constitute a phenotypically and functionally distinct population of circulating EPCs that may play a role in regenerative angiogenesis. The BIOMAGSCAR consortium therefore established a protocol for efficient isolation of CD34+ cells initially from an available human source known to be enriched in progenitor cells (human umbilical cord blood), and have demonstrated that these cells can be differentiated into functional endothelial cells. In order to optimise the cell labelling with iron nanoparticles the UCL group has also quantified the numbers of surface AC133 and CD34 binding sites on freshly isolated EPCs.

Another project requirement is to develop an adenoviral vector encoding Neuropilin-1 (NRP1) that can be efficiently delivered and expressed to arteries in vivo. We have developed an adenoviral vector encoding wild-type human NRP1 (Ad.NRP1) and characterized its expression in cells. Furthermore, we also demonstrated delivery and efficient expression of Ad.NRP1 in balloon-injured rat carotid arteries in vivo, thus supporting the use of this adenoviral vector for efficient expression of NRP1 in human coronary arteries.

Experiments comparing the in vivo gene delivery properties of pluronic and poly(lactic-co-glycolic acid, PLGA) gels were carried out to determine the best material to coat the BIOMAGSCAR stent. Both polymers exhibit reversible thermogelation and have been used as vehicles for oligonucleotide, peptide and naked gene delivery. The advantage of PLGA over pluronic gel is that its integrity lasts for more than one month at the site of administration, compared to 2-4 days for pluronic gel, thus PLGA is a more suitable polymer.

Our work to test the stents in vitro has involved the design and building of a bioreactor in Yale that can be used to evaluate stent degradation in conjunction with X-Ray microtomography. The stent will be further evaluated with cells using the bioreactor in the next period to examine the effect of stent magnetisation.

In vivo work in rabbits and pigs has examined the effect on vessel response of different methods of coating the magnesium stents with polymer and also evaluated vessel restenosis up to day 42 following implantation of various stent design iterations.

Potential Impact:

BIOMAGSCAR aims to reduce the incidence of restenosis and late stent thrombosis by 50% by employing two key elements:

1) A new biodegradable magnetic stent technology
2) Increased endothelialisation of vessel walls using gene therapy

Longer term/wider impacts

Demonstration that autologous stem cells can be attracted to a stent in the coronary artery means this could also be done in the carotid and renal arteries. This project will define the conditions necessary for the expansion of magnetic direction of cells in a wide number of therapeutic applications.

If the attraction of autologous cells to the gene transfected vessel is successful, then this methodology could be applied to the treatment of cancers or other diseases such as rheumatoid arthritis where there is anatomical access to the diseased organ that would allow gene transfection to encourage the regeneration of diseased or damaged tissues.

BIOMAGSCAR is therefore a pivotal study which will open the way to the treatment of several diseases by autologous stem cells. Later the methodology could be applied to non autologous cells.

The magnetic biodegradable stent in itself also offers a novel stent platform for the targeting of other therapies (e.g. gene therapy) to the coronary artery around the stent. Ultimately this technology may have wider application to non-coronary practice e.g. carotid and aortic stenting as well as noncardiovascular application e.g. targeting blood supply to tumours.

Socio-economic impact

Stenting is the only revascularization procedure to have stood the test of time and matured to become the default technique. It has been determined that by 2010 1.5 million stents per year would be deployed in Europe. The prevalence of late in-stent thrombosis is 0.8%, hence approximately 12,000 European Citizens per year will suffer a late in stent thrombosis. With the knowledge and technologies developed through the BIOMAGSCAR project our long term aim is to halve this number and save 6,000 people from unnecessary suffering.

With bare metal stent restenosis rates at nearly 16% at 1 year, if half of the 1.5M stents implanted by 2010 are bare metal then there is potential for 120,000 instances of restenosis, costing €4000 for each repeat PCI. Following successful completion of the BIOMAGSCAR project, and introduction of the refined technique as a primary treatment option, we aim to reduce this number by half to only 60,000 a year. Given our target objectives to halve the number of patients suffering restenosis or a thrombotic event we believe that the BIOMAGSCAR project can save the European healthcare system €274.8 million p.a. in direct costs. This cost saving is increased further when we consider the wider associated social cost of the procedures (i.e. patient productivity & work related losses, outpatient care, medications, primary care, social support and care costs) which would increase this direct cost by at least a factor of ten. Consequently, we conservatively forecast that the return on investment on the initial grant funding for the BIOMAGSCAR project will be over €2.7 billion per annum.

Commercial impact

The worldwide market for coronary stents is estimated as greater than $7 billion with annual growth at more than 5%. The European share of the global market for bare metal coronary stents is expected to be 35% by 2017. Core to our strategy is to improve the market share of the absorbable stent having demonstrated anti-restenotic and anti-thrombotic efficacy of our stent-cell combination. Once the BIOMAGSCAR project’s regenerative medicine strategy becomes available as a primary method of preventing restenosis and in-stent thrombosis we will be able to generate significant sales growth. Therefore the objective of this consortium is to realise the full impact of this technology, not only in solving a major clinical problem, but also establishing commercial success and generating jobs and wealth within European industry.

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