Final Report Summary - THE GRAIL (Tissue in Host Engineering Guided Regeneration of Arterial Intimal Layer)
The ultimate objective of THEGRAIL project aims at developing a bioactive and bioresorbable scaffold for in vivo regeneration of intima layer after any treatment leading to an atherosclerotic plaque ablation from the obstructed arteries in patients suffering from occlusive coronary or peripheral arterial diseases.
Being the primary cause of cardiovascular disease, atherosclerosis has been the focus of much research leading to rather effective treatments. Still, current therapeutic options such as bypass or angioplasty have a major shortcoming: they are mostly short term solutions, failing to restore vessel integrity and patency. Conversely, THEGRAIL technology does not intend to stent the artery; it aims to replace the diseased and stiffened area with a soft and compliant intelligent scaffold (name Synthetic Intima Layer – SIL) that will reabsorb once its task is completed, leaving a physiologically responsive regenerated tissue.
The invention relies on two main innovations:
Smart polymers based on Elastin Like Polymers (rELP) to produce bioactive and bioresorbable scaffolds capable to induce regeneration of intima layer in vivo by means of recruiting patient circulating endothelial cells and adhere to the arterial media. THEGRAIL Project is based on the use of recombinant Elastin Like Polymers (rELP) that display Inverse Temperature Transition (ITT) feature. rELP are completely water soluble under their specific transition temperature (Tt) and switch to hydrogel state when temperature is raised over Tt.
Conical endovascular catheter development for the deployment of the bioactive scaffold delivered as liquid and spontaneously switch in situ to an elastic hydrogel at body temperature.
During the five year of project, we progressed the THEGRAIL concept from sketch to a working prototype validated in relevant environment (TRL 5). Exhaustive systemic toxicology tests coupled with in vivo observation proved the complete safety of the SIL gel. Supported by exhaustive chemico-physical characterization and biosafety data, the THEGRAIL consortium is ready to enter long-term GLP efficacy study with the ultimate goal to reach first-in-human trials within 2019. Toward this end, THEGRAIL consortium started a coordinated effort to engage VC and private funds to bring the product to the market. The exploitation strategy is based on a solid IP including 2 patents (WO2015008152 and WO2014041231A1) and several technological processes that optimally place the consortium with respect to competitors.
Project Context and Objectives:
Atherosclerosis is the primary cause of cardiovascular disease (CVD). It is a progressive, chronic degeneration of the arteries which is starts from the innermost layer of the vessel called intima and eventually compromises the integrity of the entire vessel and its patency, obstructing blood flow and causing ischemia of the downstream organ (Figure 1).
Atherosclerosis (lumen occlusion) produces a spectrum of manifestations, from unstable angina to myocardial infarction, from critical limb ischemia to gangrene of the lower extremities, from transient ischemic attack to ischemic stroke of the brain. The organs affected by atherosclerosis are not just limited to the brain and heart, but all other organs of the body as well, including the kidneys, the gastrointestinal tract and the lower limbs. The two main therapeutic options for the treatment of atherosclerosis are bypass surgery and angioplasty, both techniques tend to reestablishment of arterial flow. However, both options leave scars that eventually lead the patient back to the hospital. In the case of bypass surgery, native veins or synthetic grafts become occluded after a few years. On the other hand, recurrence of the disease in patients treated by angioplasty tends to affect the long-term patency of the treated blood vessel.
“Our driving force was the development of a regenerative approach to effectively treat arteries obstruction going beyond by-pass and angioplasty” explain Francesco Serino chairman of THEGRAIL’s scientific advisory board.
The concept of THEGRAIL project is the creation of an in vivo deployable bioactive scaffold to treat atherosclerosis. The purpose of the in vivo deployable bioactive scaffold is to offer an alternative treatment to mechanical re-channelling or by-passing of obstructed arteries by using a regenerative approach compatible with current minimally invasive surgical techniques.
“The scaffold is intended to be repopulated by resident and circulating patient cells with the aim of replacing the diseased and stiffened area of artery with the scaffold, which drives arterial regeneration, leaving physiologically responsive regenerated tissue”, says Davide De Lucrezia (Explora Biotech, Italy) coordinator of the THEGRAIL project.
“The scaffold is built with smart biopolymers based on elastin-like polypeptide that can be engineered with molecular cues capable to recruit circulating endothelial cells and induce the regeneration of the intima layer by recruiting” continues Carlos Cabello (University of Valladolid, Spain) who lead the scaffold engineering team at THEGRAIL consortium together with Israel Gonzales (Technical Protein Nanobiotechnology, Spain).
The main novelty of the elastin-like polypeptide is that they display Inverse Temperature Transition, namely they are completely water soluble under their specific transition temperature and switch to hydrogel state when temperature is raised over the transition temperature. This required a challenging engineering task for the manufacturing of the scaffold that involved advanced electrospinning procedures (Figure 2) developed by the University of Naples Federico II (Italy).
The envisaged technology is based on in situ delivery of the scaffold by means of an ad hoc catheter (Figure 3) also designed and engineered by THEGRAIL consortium led by Conic Vascular (Switzerland).
In order to meet the strict regulatory requirements for Class III medical device, the THEGRAIL device was extensively characterized from the chemico-physical point of view (Institute for Bioengineering of Catalonia, Spain), in vitro (University of Liverpool) and in vivo (Utrecht medical centre) under the supervision of the regulatory experts Donawa Lifescience Consulting (Italy).
Exhaustive systemic toxicology tests coupled with in vivo observation proved the complete safety of the SIL gel both in vitro (Figure 4) and in vivo.
The device has now reached TRL5 (prototype validation in relevant environment), and the consortium is getting ready to engage in a long-term preclinical study to demonstrate the long-term efficacy of THEGRAIL medical device
The main results obtained was the development of the THEGRAIL concept from sketch to a working prototype validated in relevant environment (TRL 5). Exhaustive systemic toxicology tests coupled with in vivo observation proved the complete safety of the SIL gel (figure 5). Supported by exhaustive chemico-physical characterization and biosafety data, the THEGRAIL consortium is ready to enter long-term GLP efficacy study with the ultimate goal to reach first-in-human trials within 2019. Toward this end, THEGRAIL consortium started a coordinated effort to engage VC and private funds to bring the product to the market. The exploitation strategy is based on a solid IP including 2 patents (WO2015008152 and WO2014041231A1) and several technological processes that optimally place the consortium with respect to competitors.
In addition, the project generated a number of foreground results. Explora Biotech (EXP, Italy) developed and validated a xeno-rection in vivo model capable to mimic intima hyperplasia. In this experimental model, xenoreactive antibodies attack and destroy the endothelium of the host and induce intima hyperplasia without the need for mechanical trauma obtained by repeated passages of an inflated balloon. This novel model mimic intima hyperplasia observed in human patience, without unwanted overstretching of the vessel. A more reliable model of intima hyperplasia will impact the entire field of cardiovascular disease and will valuable for the development of more effective therapeutics options.
Technical Protein Nanobiotechnology (TPNBT, Spain) developed the largest collection of elastin-like polymers reported on the market to date. In addition, TPNBT developed and validated a scale-up process for the production and purification of endotoxin-free elastin-like polymers. These results were instrumental in establishing TBNBT as the first commercial provider in EU of recombinant elastine-like proteins. Some of the rELRs developed in those five years already reach the market yielding a fivefold increase in turnover.
Conic Vascular (CV, Switzerland), a well-established company in the field of endovascular catheters, expanded its product portfolio and developed a new-line of products derived for the ad hoc designed catheter develop for the THEGRAIL project. In particular, CV is expected to capitalize on the 3-way catheter developed to temporarily block the blood flow while the synthetic intima layer is deployed on the innermost vessel side.
The overall impact of THEGRAIL is two-fold, both on healthcare and economy. From a healthcare perspective, THEGRAIL developed a bioactive and bioresorbable scaffold that induces the regeneration of the arterial intima leaving a physiologically responsive vessel. To this regard, the THEGRAIL technology overcomes the long term negative effect of the currently available therapy options for obstructive arterial disease (i.e. angioplasty, stenting and by pass). Considering that in-stent restenosis occurs in 20-30 % of the patients within 5-years from surgery, THEGRAIL device will reduce dramatically health care costs and patient discomfort. In addition, the bioactive and bioresorbable scaffold can be engineered à la carte to be treat arteriovenous shunts, repair of congenital defects to the pulmonary outflow tract and vascular access in hemodialysis patients.
From an economic perspective, THEGRAIL was instrumental to establish a highly competitive cluster of SMEs that will capitalize and expand on project results. It is noteworthy that the consortium was built around three research driven SMEs (Technical Protein Nanobiotechnology, Explora Biotech and Conic Vascular) with complementary expertise in order to cover the entire value-chain from material production to product sales. The three SMEs were further backed up by a European leading firm in regulatory strategy development (Donawa LifeScience Consulting) that ensured that all data were collected in order to be effectively used for the filing of the technical dossier to the notified body. Within this framework, THEGRAIL technology progressed from from sketch to a working prototype validated in relevant environment (TRL 5) and advanced due diligence are in progress to engage VCs enter long-term GLP efficacy study with the ultimate goal to reach first-in-human trials within 2019. The estimated European biomaterials-based market volume is €36-40 billion, the US market is in the range of €53-60 billion, while the Japanese market is about €13 billion. With a current growth rate of at least 22.5% p.a. no major player emerged yet. With exhaustive systemic toxicology tests coupled with in vivo observation, a solid IP including 2 patents (WO2015008152 and WO2014041231A1) and several technological processes the THEGRAIL consortium is optimally placed with respect to competitors.
On short-term, the THEGRAIL project greatly impacted local economy and boosted the growth of the three SMEs and the number of qualified works involved (Figure 6). For Explora Biotech (IT), THEGRAIL was pivotal to emerge as a leader SME in the development of innovative animal models related to cardiovascular diseases. This helped EXP to stretch out its market reach to pre-clinical service sector. Thank to this experience, EXP consolidated and grew significantly over the last five years as witnessed both by the increase in annual turnover and the number of full-time collaborators with permanent-contract. Technical Protein NanoBiotechnology (SP) greatly benefits from the THEGRAIL project, starting as an academic spin-off with no dedicated staff grew to employ 3 full-time scientists. The collection of rELP developed within the framework of THEGRAIL project was instrumental in establishing TBNBT as the first commercial provider in EU of recombinant elastin-like proteins. Some of the rELRs developed in those five years already reach the market yielding a fivefold increase in turnover. Thanks to this project, TPNBT obtain national and international visibility through the media and a carefully-planned dissemination action establishing a broad and valuable network in Europe that led to several scientific collaborations and the involvement in new EU projects to exploit the unique properties of elastin-like proteins.
Conic Vascular (CV, Spain), a well-established company in the field of endovascular catheters, expanded its product portfolio and developed a new-line of products derived for the ad hoc designed catheter develop for the THEGRAIL project. In particular, CV is expected to capitalize on the 3-way catheter developed to temporarily block the blood flow while the synthetic intima layer is deployed on the innermost vessel side.
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