Restoration of vision with new generation Artficial Theranostic Cornea

The cornea is the outermost transparent part of the eye, which acts as the main refractive element to transmit light to the retina, giving us sight. Any damage or disease to the cornea that causes permanent loss of its transparency results in corneal blindness. The World Health Organization in their 2017 report estimated that 253 million people live with visual impairment, with 23 million suffering with one eye condition. It is clear that increasing donations alone will no way be sufficient to make up for the donor cornea shortage. More importantly, even if donor corneas were available, patients with severe pathologies would not benefit from donor as they are at high risk of rejecting the donor cornea, thereby necessitating an alternative approach.
I shall develop nanotechnology assisted pro-regenerative artificial cornea (ARCs) that can combat the clinical challenges associated with corneal blindness to promote functional regeneration and restore vision. ARCs will be developed together with an in-built theranostic (diagnostic cum therapeutic) monitoring system to identify and treat factors leading to rejection and failure of the transplant. The new artificial cornea will be anti-infective, anti-inflammatory and will have cell-proliferative activity. Information will be gathered in this pre-clinical project would guide towards future clinical trials and in translation of research to patients with corneal blindness. My proposed approach is never been addressed and is completely new to the field to restore vision might revolutionise the present cornea transplantation regime could have significant impact and quality of life in UK and beyond.

During MRC Career Development Award, my aim is to develop a clinically applicable host acceptable Assisted-Regeneration artificial Corneas (ARCs) focused on requirements of high-risk patient to combat with infection, inflammation, and will test to evaluate and establish this as cell-free pro-regenerative corneal implants for custom-fit personalised medicine. The ARC with its built-in monitoring system to alert these high-risk patients and doctors of potential problems like rejection before irreversible damage or failure occurs represents the future of personalized medicine.
Over the 5 years, I aim to complete:
1. To an immune-compatible nano toolbox of materials that can be used to develop theranostic nanoparticles.
2. To integrate the nanoparticles into an implant, i, e this case the ARC.
3. To completely characterise the function of ARCs in vitro, focussing perfecting the diagnostics aspects, and test potential incorporation into a clinically used prosthesis, the Boston KPro.
4. To evaluate clinical feasibility of ARCs by monitoring the safety and efficacy of ARCs with both diagnostics and therapeutic functions with established models within the state-of-the-art artificial cornea facilities of my mentioned collaborators.
We will develop our nano toolbox mainly with gold, iron and self-assembled small peptides for nanoparticles that will incorporate drugs and bioactive anti-infective and anti-inflammatory peptides such as KR12. The loaded nanoparticles will then be incorporated into constructs made mainly from collagen and collagen-mimetic peptides. The implants will be tested in vitro for biocompatibility and efficacy. The best composite ARC implants will then be tested with pre-clinical model with our collaborator Prof Grifith and finally evaluate the clinical feasibility with Prof Chodosh. Successful testing of ARC will provide knowledge for development of further theranostic systems that can be extended to use in other target organ systems.

Summary:
Visual impairment has a broad negative impact on society and life quality (e.g., reduce mobility, effectiveness and live hood for elders and severely affecting educational and social development of children). Integrative artificial cornea is a real need and a clinically unmet solution. My proposed ARCs strategy with real-time monitoring ability will certainly open up new therapeutic solutions. The success of this MRC Career Development Award might lead to develop ARCs that can potentially be used as a stand-alone artificial cornea or as a carrier for the FDA approved artificial cornea system BKPro in moderate to severe diseased conditions. My proposed approach to restore vision has never been addressed and is completely new to the field and could revolutionise the present cornea transplantation regime. This could have significant impact on the quality of life in the UK and beyond.

The success of this research will eventually benefit several groups of patients with blindness:
1. Pre-medicated artificial Cornea from bench to bedside in restoring vision - Only 1 out of 70 patients are treated with available donor cornea. Therefore, more than 75% patient can be treated who are desperately waiting for donor cornea. (5-10 years)

2. Mitigate cornea transplant rejection - At least 80% reduction in cornea transplant rejection due to infection, inflammation and host mediated immune (complement) activation. (4-7 years)

3. Strategy to prevent corneal implant rejection in high risk condition - More than 90% patients in high risk condition of repeated graft failure will be benefitted more immediately. (4-7 years)

4. Strategies to monitor cell-free bioengineered cornea regeneration and early alarming system for risk of irreversible rejection - At least 90% patients will get benefits from early detection of complications. (5-10 years)

5. Personalised approach for the management of corneal blindness - First ever personalised corneal graft possible with ARCs that can serve specific requirement to individual patient (e.g., cross-linked ARCs for keratoconus). It will therefore contribute to the MRC's objective to bring therapies to the clinic. (4-7 years)

Academic circles:
A national and international academic circle will derive immediate and long-term benefit from this research and include basic bio-scientists, researchers looking to understand what corneal blindness is and how it manifests, the crisis with donor cornea, and technologists whose research is directed towards development of artificial organ and how to assess it.

Commercial/private sector:
Potential long term interest could come for the development of clinically applicable bioengineered artificial cornea to invest more into development on pre-medicated implants those are resistant to melting and infection.

Policy makers, government agencies or regulators:
Could benefit through an improved knowledge base to prepare policy driving a health economy and society as blindness has a very deep impact on both.
Public sector- Clinical practitioners, ophthalmologists and associated health professionals will benefit from improved knowledge of corneal blindness, artificial cornea and the unmet clinical need. Healthcare decision makers may benefit through knowledge of risks involved with transplantations and how it may pertain to severe disease condition in children, diabetic and an ageing population. This would add synergy where GPs and or clinical academics, ophthalmologists and policy makers have greater information on which to decide benefit options of transplantation in at risk populations.

The public and third sector- Will derive long term benefit through the ARCs of the identified beneficiaries making more informed policy decision through to the general public. They will also benefit through charities and the media to improve ocular health using newly identified ARCs as the basis. We will ensure results are highlighted to beneficiaries.