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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ARREST BLINDNESS (Advanced Regenerative and REStorative Therapies to combat corneal BLINDNESS)

Teaser

Summary

Approximately 30 million Europeans are currently blind or visually impaired, leading to a reduced quality of life and a tremendous increase in health care costs and lost productivity. Corneal blindness is the second largest cause of blindness globally after cataract, and millions remain unnecessarily blind due to problems of access to or lack of effective treatments. The current state-of-the art is characterized by an acute shortage of donor tissue, non-standardized use of donor cells, and a lack of targeted molecular therapies. The main goal of ARREST BLINDNESS is therefore to develop advanced technologies to regenerate or restore the cornea at the tissue, cell, and molecular levels, to maintain corneal transparency thereby preventing blindness.
Scarce donor tissue for corneal transplantation will be replaced with cell-free tissue-engineered scaffolds. Tissue-engineered porcine skin collagen is being evaluated pre-clinically, while a fish-scale collagen patch is being tested in a first-in-man Phase I clinical study.
Cell-based therapies are being investigated to address a lack of standardized, approved therapies to restore the corneal epithelial and endothelial cell layers. Human corneal endothelial and epithelial stem cell sheets are being evaluated in pre-clinical and Phase II transplantation studies, respectively, to obtain regulatory approval for Phase I studies and for wider adoption in patients.
Finally, new molecular agents and drug delivery approaches are being evaluated for restoring the neural and immune environment, to address the lack of approved therapies for these blinding complications.
ARREST BLINDNESS bridges the gap between advanced regenerative medicine, biomaterials, imaging, and drug delivery technologies and the millions of blind and vision-impaired people who could most benefit from these.

Work performed

A cornerstone of ARREST BLINDNESS is four clinical studies, each addressing a different cause of blindness using advanced technologies to regenerate and restore tissue. During the reporting period, a tissue-engineered porcine collagen implant was tested pre-clinically with 6-months follow up, with positive results subsequently reported to the regulatory authority in Sweden. Ethical approval for a first clinical study was granted in Sweden and regulatory approval is currently pending. Another advanced device, an emergency corneal patch made from fish scale collagen, was implanted in five patients in a first-in-man study in Germany. The patch functioned as designed in all cases, and an additional trial site has been instated. Regulatory engagement by device manufacturer in The Netherlands is ongoing, in preparation for further Product approvals.
A Phase II clinical trial of a limbal stem cell advanced therapy medicinal product is underway in Belgium and over two-thirds of patients have been recruited. New quality control measures and advanced preoperative and intra-operative corneal imaging have been integrated into routine practice to improve the success rate of the stem cell transplantation procedure. Ethical aspects of living donation of corneal tissue have been explored with the project Ethical Advisor and will form the basis of a set of recommendations. Furthermore, a tool for consistent grading of limbal stem cell deficiency has been developed to aid in reporting of oucomes for this type of advanced surgery. Additionally a new high-resolution optical coherence tomography system has been integrated into a standard ophthalmic slit lamp microscope, to allow the possibility of immune imaging of the ocular surface for improved transplantation prognosis. The device has received CE-mark and will be used in a Clinical study in high-risk corneal transplantation, which is now recruiting patients in Germany. The study aims to test new preclinically validated approaches for restoring corneal transparency after loss of immune privilege and ingrowth of pathologic blood and lymph vessels into the cornea. Several SME partners are developing these new medical device and drug delivery technologies, which provides access to new markets thereby stimulating the growth of these companies. Another novel regenerative agent, a biologic neuroregenerative factor, has been evaluated for the promotion of epithelial wound healing, nerve regeneration and tear film and blink restoration after corneal injury in preclinical models in Spain. Positive results in these models are being followed by further in vivo studies in a relevant corneal transplantation model, further using a novel hydrogel-based drug delivery device manufactured in Sweden.
Finally, a new advanced therapy of endothelial cell sheets for endothelial transplantation is being validated for GMP compliance in Austria while in parallel this cell sheet has been optimized in terms of cell culture conditions, substrate material and surgical implantation technique in The Netherlands. The cell sheet is being validated in a preclinical study being conducted in Denmark.

Final results

A new porcine skin based collagen scaffold was developed to overcome deficiencies of previous attempts at tissue-engineering the bulk of the corneal tissue. By the end of the Project it is expected that Clinical data with this device will enable larger-scale multi-center randomized studies to be conducted within the EU, to gather more Clinical data in support of a CE-mark application. Also within the Project, a fish scale collagen-based device, designed as a temporary emergency corneal patch, has been implanted in five patients in a first-in-man trial, and by the end of the Project the results will indicate whether this technology can meet the great demand for an off-the-shelf solution to preserve vision in emergency corneal rupture cases, often seen in traumatic injury, for example in small remote clinics and in locations where other options or infrastructures are unavailable. Both these devices are defining the state-of the art in the field of corneal replacements, where no similar technologies exist. By the end of the project, these devices have the potential to alleviate the high demand and long waiting times for human donor corneas, which today keeps millions of cornea-blind people from being productive members of society.
While stem cell transplantation can treat corneal blindness, the procedure still carries high risks of tissue rejection and transplant failure. During the reporting period, a multi-center clinical trial of limbal stem cell transplantation using a GMP xenogenic-free process has applied new advanced stem cell imaging and real-time surgical imaging tools to optimize tissue harvesting and surgery, to improve patient outcomes. By the project end, these procedures have the potential to set a best-practice standard for this type of surgery.
New non-invasive diagnostic imaging is developed for management of high risk vascularized corneas. The technique has been tested in preclinical models and in the first human subjects with positive results, with a novel device having received CE-mark and entering clinical studies. Combined with this innovation, new angio-regressive therapies targeting the immune response of the cornea have been tested with positive results. These innovations have the potential to prevent corneal graft failure. Each surviving corneal transplant saves â‚¬170,000 in longâ€term health care costs, for a total savings of â‚¬6.8B if the current European transplantation rate of 2% could be doubled.