Novel Chemical Crosslinking of the Cornea for Treatment of Keratoconus

Lead Research Organisation: University of Liverpool
Department Name: Institute of Ageing and Chronic Disease

Abstract

The Aravind Eye Care System in Southern India was established as a health care model that could supplement the efforts of the government and also be self-supporting to overcome the problem of avoidable blindness in a developing country. The company Aurolab is an integral part of the Aravind Eye Care System. It manufactures a wide range of high quality ophthalmic consumables. Developing a translational alliance with the Aravind Eye Care System and Aurolab will provide us with the opportunities to gain access to a commercial infra-structure which includes support for polymer technologies and manufacture, product commercialisation in terms of regulatory approvals, IP protection and advertising, as well as distribution and labelling. Aurolab's products are exported to 130 and more countries worldwide and their products meet the regulatory requirements of the USA, EU and WHO. All Aurolab products are manufactured on efficient production lines with strict quality assurance measures.
We intend to develop this translational alliance with Aurolab and the Aravind Eye Care System to exploit our novel chemical cross-linking therapy for the treatment of keratoconus. Keratoconus is a progressive condition, often affecting young and working age people, in which the cornea becomes misshapen significantly disrupting the refraction of light into the eye. One of the key features of keratoconus is a loss of corneal mechanical stability. Increasing the stiffness of the cornea can reduce the progression of this debilitating eye disease. Corneal collagen cross-linking focuses on stiffening the cornea in order to preserve corneal integrity due to strong bonds formed within the collagen. Using our understanding of the engineering principles that define the relationship between the structure and mechanical properties of materials we will develop a novel collagen cross-linking therapy using di-carboxylic acids thus this proposal lies clearly at the interface between Engineering and Healthcare Technologies and aligns closely with the Synthetic Biology for Health area.
To establish the partnership we will make multiple visits to India regularly over the 2 years of the project. We will also host visits from senior scientists and clinicians from India. In particular we will host a 3 month research exchange for a Product Development Scientist from Aurolab to learn about our research and facilitate a research exchange for our PDRA to spend 3 months at Aurolab to learn about product manufacture and scale up. We will jointly supervise a clinical research fellow at the Aravind Eye Care System and we will establish an in vivo animal model facility in Liverpool which will support this project and future development projects as part of the long term partnership. These other project areas that would benefit greatly from the alliance could lead to translational opportunities and impact to the health and wealth of societies in the UK and globally. By working together to design these projects we will ensure that they address the clinical and commercial requirements for India, the UK and globally. Specific examples could include the extrapolation of the cross-linking therapy to the development of a strategy to increase the mechanical properties of ulcerated cornea to protect against perforation and aid healing and the potential to increase the stiffness of the sclera as a treatment for myopia and/or glaucoma. A further area of particular interest to our project partners is the development of bandage contact lenses with the potential to deliver anti-fungal agents such as voriconazole for the treatment of fungal keratitis which is a major clinical problem in India. In the more longer term there are several projects within the Department of Eye and Vision Science at the University of Liverpool that would benefit from this alliance such as the development of drug delivery devices for the front and back of the eye.

Planned Impact

The development of a long term translational alliance between the Department of Eye and Vision Science at the University of Liverpool and Aurolab in the Aravind Eye Care System in Southern India has the potential to lead to the exploitation of a number of innovative research projects that could lead to new strategies and therapies to treat vision loss worldwide. Specifically, working with Aurolab will allow the development of cost effective solutions appropriate for developing countries as well as other world markets. UK Vision Strategy is an RNIB initiative. Research is a key part of this strategy and in 2011 key stakeholders came together and through the James Lind Alliance produced The Sight Loss and Vision Priority Setting Partnership (http://fightforsight.org.uk/sightlosspsp). Corneal and external eye disease was established as one of the 12 priority areas for research and within this area one of the main questions was 'What causes keratoconus to progress and can progression be prevented?'. This proposal could have a significant impact on addressing this issue. Keratoconus affects around 1 in 2000 people worldwide and is a lifelong, degenerative corneal disease and is a significant health burden in young adults. The condition is associated with low vision and as a consequence a poor quality of life, and ultimately loss of vision. As well as the devastating loss to the patient, the loss of sight has a significant cost to the UK economy both in terms of healthcare costs and indirect costs such as loss of employment and carer costs. Keratoconus is the leading cause of corneal transplantation in the Western world and accounts for 25 % of the corneal transplants performed annually in the UK. Each transplant is estimated to cost the NHS £5000 and is not always a successful procedure due to rejection or complications due to infection. The development of an effective strategy to stiffen the cornea could reduce the number of patients requiring corneal transplants. Furthermore the simplicity of the proposed treatment could lead to it being available to more patients in more healthcare settings.
The potential to develop other ophthalmic devices and therapies in the longer term could lead to major healthcare impact, for example, the development of bandage contact lenses with the capability to deliver antimicrobials, both anti-fungal and anti-bacterial, could significantly improve the treatment of corneal infections both in terms of reducing the microbial load and the comfort for the patient during treatment, possibly removing the need for hospital admission in many cases.
All Aurolab products are manufactured on efficient production lines with strict quality assurance measures that comply with US FDA, EU GMP, WHO GMP norms. Thus products developed and testing in Aurolab will be translatable to the UK markets for use in the NHS. With the expertise of the Clinical Research Department in Aurolab and the Clinical Eye Research Centre with St. Paul's Eye Unit, Liverpool we will be able to run Phase I, Phase II and Phase III clinical trials to produce clinical data to support the translation of the new products into the clinic. Liverpool was the first centre in the UK to offer corneal cross-linking using riboflavin and UVA and has been awarded an NIHR EME grant (KERALINK): Efficacy and safety of cross-linking in children with keratoconus with London (Moorfields) and Sheffield.

Publications

10 25 50
 
Description This project was designed to develop a novel chemical cross-linker to stiffen the cornea to help in the treatment of keratoconus. We have defined the formulation of our novel chemical cross-linker and demonstrated that it can stiffen corneal tissue (ex vivo) to the same extent as the currently clinical procedure. However, our treatment has significant advantages over the current treatment in that it does not require the epithelium to be removed, it causes significantly less cytotoxicity, the treatment time is only 15 minutes rather than 60 minutes and it does not require the use of UVA facilities.
We continue to progress this research with further funding and have now developed a new formulation with a more appropriate pH. With the future funding we will complete an in vivo study to demonstrate safety and stiffening in vivo
Exploitation Route We are in discussion with several potential commercial partners to take this technology forward
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Further funding has been secured to progress this study to an in vivo study. Further discussions have been conducted with potential industrial partners to commercialise the output from this study.
First Year Of Impact 2017
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Delivery of a novel chemical cross-linker for the treatment of keratoconus
Amount £14,941 (GBP)
Organisation University of Liverpool 
Department EPSRC Impact Acceleration Account
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 04/2018
 
Description EPSRC GCRF
Amount £25,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 08/2016 
End 03/2017
 
Description Enterprise Board, University of Liverpool
Amount £50,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 01/2020 
End 07/2020
 
Description Preclinical Evaluation of a New Chemical Cross-Linker for the Treatment of Keratoconus
Amount £1,000,000 (GBP)
Funding ID EP/R511729 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2019 
End 03/2020
 
Description Preclinical Evaluation of a New Chemical Cross-Linker for the Treatment of Keratoconus
Amount £50,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 03/2019 
End 12/2019
 
Description Preclinical evaluation of a new chemical crosslinker for the treatment of keratoonus
Amount £77,000 (GBP)
Funding ID EP/R511729 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 03/2020
 
Description Rapid, point of care diagnostic device for corneal infection
Amount £12,257 (GBP)
Organisation United Kingdom Research and Innovation 
Department Global Challenges Research Fund
Sector Public
Country United Kingdom
Start 11/2018 
End 03/2019
 
Description Aravind Eye Care System 
Organisation Aravind Medical Research Foundtion
Country India 
Sector Public 
PI Contribution joint research on the development of a novel chemical cross-linker for the treatment of keratoconus
Collaborator Contribution Laboratory research, clinical advice, human normal and diseased tissue
Impact Joint conference presentation patent mulitidisciplinary
Start Year 2015
 
Description Cross-linking of the Sclera 
Organisation Santen Pharmaceutical Co., Ltd
Country Japan 
Sector Private 
PI Contribution Provision of our novel cross-linking technology
Collaborator Contribution Evaluation of our technology in in vitro and in vivo experiments on the stiffening of the sclera
Impact No outputs yet, multidisciplinary collaboration including pharmaceutical company, bioengineering and clinical ophthalmology
Start Year 2007
 
Description Rapid diagnosis of corneal infection 
Organisation University of Edinburgh
Department Queen's Medical Research Institute Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Evaluation of antimicrobial peptides with environmentally sensitive fluorescent probes that can detect Gram +ve and Gram -ve bacterial species attached to our novel peptide bandage contact lenses and their development as a rapid diagnostic tool for corneal infection
Collaborator Contribution Contribution of the anitmicrobial peptides and know how
Impact Research data resulting from a new collaboration, submission of research grants to continue collaboration, introduction to our Indian partners
Start Year 2017
 
Title COMPOSITION COMPRISING DIACID DERIVATIVES AND THEIR USE IN THE TREATMENT OF COLLAGENIC EYE DISORDERS 
Description The present invention relates to novel pharmaceutical formulations. More specifically, the present invention relates to novel pharmaceutical formulations that are suitable for intraocular administration. The present invention also relates to the use of these formulations for the treatment of collagenic eye disorder such as, for example, the treatment of keratoconus. 
IP Reference WO2017077300 
Protection Patent granted
Year Protection Granted 2017
Licensed No
Impact Discussions are in progress about licencing this IP to commercial partners
 
Description Boehringer Ingelheim Office Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact This was an invited opportunity to guage industrial/commercial interest in our technology and learn how to take the next steps to commercialisation. We gained a lot of helpful feedback
Year(s) Of Engagement Activity 2019
 
Description Improving the world though engineering - Engineering Day, Wirral Arts Festival (sponsored by IMechE) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public lecture designed to highlight the breadth of engineering and how it influences our lives. It involved a lecture and a panel discussion to answer questions
Year(s) Of Engagement Activity 2019
 
Description Invited presentation at RAMS2019 (recent appointments in materials science) - Liverpool 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact RAMS2019 aims to connect and support early career academics and senior post-doctoral researchers in industry or academia working in Materials Science. The event involved being a plenary speaker as well as joining in the panel discussion to mentor and inspire early career academics and researchers.
Year(s) Of Engagement Activity 2019
 
Description Invited presentation at the Asia Pacific Association in Ophthalmology conference in Hong Kong 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited lecture in a session on Application of Nanotechnology in Eye Disease highlighting new opportunities to the predominantly clinical audience
Year(s) Of Engagement Activity 2018
 
Description Invited presentation at the President's session of the Royal College of Ophthalmology on Biomaterials and their Optimisation for Use in the Treatment of Vision Loss 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prestigious presentation at a major clinical conference
Year(s) Of Engagement Activity 2017
 
Description Invited presentation at the University of Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Presentation of this research activity to widen participation and knowledge. Demosntrated wide reanging discussion
Year(s) Of Engagement Activity 2019
 
Description Invited seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research seminar to Biomedical Engineers at the University of Glasgow. Introducing the Ophthalmic Bioengieering research topic. Developing new collaborations
Year(s) Of Engagement Activity 2020
 
Description Invited seminar at the Hong Kong Polytechnic University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited seminar aimed to encourage new research collaborations
Year(s) Of Engagement Activity 2018
 
Description Lean Launch pad programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact This was a 3 day event over a 6 week period providing opportunities to engage with commercial and clinical users of our technology and determine the next steps for translation of our technology
Year(s) Of Engagement Activity 2019
 
Description Lecture for Fight for Sight speaker network 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Lecture of Biomaterials and their role in the treatment of vision loss at EYECARE2018 conference and exhibition for optometrists and ophthalmologists representing Fight for Sight and to spread the word about their research and its impact
Year(s) Of Engagement Activity 2018
 
Description Materials to shape our vision; How advanced materials are fighting the loss of sight 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I presented to around 20 members of the general public in a pub. There was a lot of interest in the materials I showed them and this generated a lot of discussion. On the back of this i have been invited to take part in two more similar events
Year(s) Of Engagement Activity 2019
 
Description RISE connect - Please do not let me be misunderstood: Making sense of science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Talkeoke style debate designed to help help participants make connections with with politicians and policy makers and communicate their science
Year(s) Of Engagement Activity 2018
 
Description SciBar presentation - Kirby, Liverpool 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation in a Pub in Liverpool to highlight sciences to the public
Year(s) Of Engagement Activity 2019
 
Description Women in Engineering 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact This was an event organised by the IET to encourage young women into engineering careers by presenting the steps I had taken to build my career
Year(s) Of Engagement Activity 2019