Extending the range of tamponades for the delivery of therapeutic agents to treat proliferative vitreoretinopathy

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

Abstract

This proposal will develop novel silicone oil tamponades providing controlled drug delivery to the back of the eye to prevent proliferative vitreoretinopathy, a blinding condition with no gold standard for treatment. Proliferative vitreoretinopathy (PVR) is a disease that can develop following retinal detachment. It is the primary cause of failure following surgery to re-attach the retina and often results in poor visual outcome. Despite many strategies, there has been no improvement in outcome over the last 20 years and these patients can lose their sight. Complicated retinal detachments require silicone oil to re-attach the retina. Effective pharmacological treatment of PVR requires controlled, sustained release of a drug. A key challenge is that certain drugs that could be used to control PVR cannot dissolve in the oil. If injected into the eye they accumulate around the oil and cause toxicity to the retina. Furthermore, repeat injections increase the risk of complications. Thus, an entirely new approach is required.
This proposal uniquely aims to develop a silicone oil tamponade with a dual role, firstly to act as a tamponade agent and secondly to be a novel drug-delivery system. It will use non-steroidal anti-inflammatory drugs (NSAIDS), which have the potential to address the inflammatory as well as the proliferative stages of PVR. The project will use novel chemical techniques to bind drugs to the silicone oil so that they will be released in a sustained, controlled manner. Preliminary data has demonstrated that drugs can be bound to silicone oil, and that the release profile of the drug can be changed by varying the blend of the oil. An in vitro model of the oil-filled eye, incorporating the flow of aqueous out of the eye, has also been developed. This will allow studies of drug clearance from the eye.
This programme proposes the combined development and in vitro biological evaluation of a new drug delivery system, focussed on NSAIDS, with additional drug candidates for risk mitigation. Furthermore, it will develop a new approach to biological evaluation that will make future animal trials more efficient. Drugs will be bound to silicone oil using several strategies and release studies undertaken. The conditions required to release the drug under clinically relevant conditions, at a concentration identified as being non-toxic but effective at controlling cell behaviour, will be identified. Drug-oil products will also be assessed in a variety of laboratory models to assess how effective they are at controlling PVR-like behaviour, using techniques that are well-established in the host laboratories. The testing will be iterative, with results being fed back to inform the development of the prototype oils. The physical and optical properties of the drug-oil products, as well as suitable methods for sterilisation, will also be assessed.
Development of new methods for drug delivery could have significant benefits for industry and the healthcare system. Furthermore, the repurposing of existing drugs for treatment of PVR would speed the translation of treatments to the clinic and represent a new stream of revenue for these drugs. The potential to protect any intellectual property from this project will be kept under review, with a view to future commercial exploitation. Results will also be shared with patient groups in St Paul's Eye Hospital, ensuring end-user engagement. Output from this project will stimulate research into novel routes of ocular drug delivery and further development of in vitro modelling of the eye. Both aspects of the research will be of great interest to academic and industrial researchers.
This project will deliver a novel, drug-containing oil that can release drugs at therapeutic levels over several weeks and that will be ready to be tested in animals prior to human trials. This is designed to be an effective therapy for a sight-threatening condition that at the moment has no reliable treatment.

Planned Impact

Economy
Successful drug treatment for proliferative vitreoretinopathy (PVR), scar tissue formed following repair of a detached retina, would be a major step forward in the treatment of vision loss. Relevant exploitation of research on this subject will provide significant benefits for the pharmaceutical industry and the healthcare sector. It is anticipated that the re-purposing of non-steroidal anti-inflammatory drugs will be of great interest to pharmaceutical companies because of the wide range of conditions this type of drug delivery could be applied to. Further, re-purposing would save companies huge resources normally required to bring a new drug to market. The proposed research could lead to improved application of silicones throughout the biomedical sector. In addition, silicone is an industrial lubricant and the controlled binding and release of additives may improve performance in some applications (e.g. manufacturing processes). The University will seek to protect and exploit any new intellectual property and, building on a strong track record of previous successful industry collaborations, would expect to attract significant investment in new start-up companies to commercialise this technology, creating new jobs and contributing to local wealth creation. For the NHS and other healthcare providers, drug delivery via novel silicone oils could lead to significant time and cost savings through the reduction in the number of invasive treatments and associated hospital visits.

Society
Silicone oil able to act as a drug delivery device would change clinical practice: this would reduce the burden (time and cost) to the NHS, dramatically improve quality of life for patients and finally offer an effective treatment for a blinding condition. The incidences of PVR and the high number of surgical re-interventions required following retinal detachment surgery could be reduced significantly, thus avoiding the need for patients to undergo further invasive treatments and regular hospital visits. A reduction in PVR would leave patients with improved sight in the long term.
The proposed project is also an important step towards developing an in vitro model of drug delivery to the eye, which would reduce the number of animal studies required to take a product through to development. Such a model would be invaluable for companies as it offers a much cheaper and ethically beneficial alternative to expensive animal studies.

Knowledge
The proposed work will provide more knowledge on the synthesis of silicone oil-drug conjugates, providing data for future grant applications, publications and product development. The PI will be a direct beneficiary of this project, gaining experience in a discipline outside, but related to, her current training which is vital for progression in the field of biomaterials.
The academic community will benefit directly from the new knowledge generated by this project. It will be of specific interest to groups in the universities of Sheffield, Ulster, and UCL, where there is already research into the development of biomaterials for ophthalmic applications. The knowledge generated will have applications outside of ocular drug delivery, including biomedical research and wider industrial applications of silicones.

People
The PI will continue to gain valuable experience in the protection and exploitation of intellectual property, direct experience of working with industry and valuable new skills in inter-related disciplines such as drug delivery and nanoparticle chemistry. The PDRA will gain experience in the field of silicone chemistry and drug delivery, and of working in the biomaterials arena, in particular working with clinicians. Prof Rannard will gain a better understanding of ophthalmic bioengineering and in particular has an interest in exploring further applications of the drug delivery techniques he is developing for treatment of HIV/AIDS.

Publications

10 25 50
 
Description The aim of this grant was to develop silicone oils that could deliver drugs. We have developed a number of prototype oils that release drug, using different chemical techniques. We have developed methods to use radiochemistry to measure the drug loading and release with high-precision, and have demonstrated the ability to release drugs over a period of time. Our modifications extend the time over which the drug is released when compared to simply mixing the drug into standard silicone oil. The toxicity of existing prototypes has been assessed, as have some of the clinically-relevant physical properties.
Exploitation Route We have filed a patent based on the technology developed within the grant, and are in discussions with a commercial partner regarding their licencing of the technology.
The radiochemistry methods developed in the project have been vital to this and other projects, and will continue to be so.
The findings are being used to support further funding applications.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The findings have been used to support a patent application and in ongoing discussions over licencing, and follow-on funding with an industrial partner. They have also supported the award of EPSRC funding of over £2m, including funding of a Healthcare Impact partnership. This funding means that the technology developed within this award is being further developed towards clinical and commercial use, as the partnership includes two industrial and one clinical partner. Have increased patient/user/general public engagement by interaction with relevant patient/charitable organisations and public events
First Year Of Impact 2014
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description Crossley Barnes PhD
Amount £90,000 (GBP)
Organisation University of Liverpool 
Department Institute of Ageing and Chronic Disease
Sector Academic/University
Country United Kingdom
Start 11/2014 
End 10/2017
 
Description EPSRC Impact Acceleration Award
Amount £16,037 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 03/2017
 
Description Funding
Amount £30,000 (GBP)
Organisation The H B Allen Charitable Trust 
Sector Charity/Non Profit
Country Unknown
Start 04/2015 
End 09/2016
 
Description Healthcare Impact Partnership
Amount £1,048,001 (GBP)
Funding ID EP/R024839/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description Standard proposal
Amount £1,176,838 (GBP)
Funding ID EP/S012265/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 03/2022
 
Description Bangor University modelling 
Organisation Bangor University
Department School of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Management of collaboration and provision of experimental data
Collaborator Contribution Provision of mathematical modelling data
Impact Data for grant application
Start Year 2013
 
Description Fluoron 
Organisation Fluoron
Country Germany 
Sector Private 
PI Contribution Research into drug delivery from oils. We have been discussing options for further development, licencing of the technology and follow-on funding.
Collaborator Contribution Provision of silicone oil and technical expertise, protocols to allow us to test our technology to industry-standard levels, plus documented support of research to support funding applications
Impact Letters of support have been used in successful applications for funding. Collaboration is multidisciplinary (biology, bioengineering, clinical)
Start Year 2011
 
Description Hong Kong/Anderson Shum 
Organisation University of Hong Kong
Department Department of Mechanical Engineering
Country Hong Kong 
Sector Academic/University 
PI Contribution A visitor from the collaborator's lab will spend several months in my lab, where they will learn new technical skills and generate data to cement the collaboration, plus contribute towards data for the development of an ex vivo model we will use for further development of the technology developed within this award. One of my PhD students is currently in Hong Kong learning new methods for assessment of the technology developed within this award.
Collaborator Contribution The collaborators will provide intellectual input on model design, plus training to a member of my group. It will also enable access to different manufacturing facilities
Impact A PhD student will spend several months in the collaborator's lab, where they will work on in vitro models. The collaboration is multidisciplinary, and the student will learn and bring back new skills in fluid dynamics and rapid prototyping.
Start Year 2014
 
Description Serban modelling collaboration 
Organisation Oxford Brookes University
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of experimental data, PhD student
Collaborator Contribution Provision of expertise in mathematical and computer modelling of flow in the eye. Hosting student placement
Impact Collaboration contributed to award of Crossley Barnes PhD studentship (University of Liverpool) for Dr Kearns
Start Year 2014
 
Description Serban modelling collaboration 
Organisation University of Chester
Department Department of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of experimental data, PhD student
Collaborator Contribution Provision of expertise in mathematical and computer modelling of flow in the eye. Hosting student placement
Impact Collaboration contributed to award of Crossley Barnes PhD studentship (University of Liverpool) for Dr Kearns
Start Year 2014
 
Description Cafe Scientifique, Manchester 
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 spoke about eye research topics at Cafe Scientifique, Manchester. This sparked a lot of interaction with the audience, both during and after the talk. As a result, I was invited to do a similar talk at a University of the Third Age branch, and also received some further questions via email.
Year(s) Of Engagement Activity 2017
URL http://www.cafescientifique.manchester.ac.uk/past-events/
 
Description Judging Medical Society presentations for Cronton Sixth Form 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Was able to provide constructive feedback to students

Students reported surprise at the scope of the research and would consider investigating medical engineering as a career
Year(s) Of Engagement Activity 2014,2015
 
Description Presentation at PPIER December 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Patients were interested in the research into drug delivery to the posterior segment and asked several pertinent questions.

One of the group asked if I could assist them with a future Macular Society presentation
Year(s) Of Engagement Activity 2013
 
Description Presentation at PPIER December 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Spoke to patient group (PPIER) at St Paul's Eye Hospital about use of biomaterials to treat retinal diseases. The group enjoyed the talk, interjecting with questions and resulting in a long discussion about the talk and wider research issues afterwards.
Year(s) Of Engagement Activity 2015
 
Description Talk at Macular Society Top Doctors event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Supporters
Results and Impact Talk lead to lots of questions from the audience and discussion after the event formally finished.

Good feedback from Macular Society
Year(s) Of Engagement Activity 2014
URL http://www.macularsociety.org/Shop/conference-tickets/top-doctors-seminar-liverpool
 
Description The Girls Network mentoring 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Ongoing mentoring activity
Year(s) Of Engagement Activity 2013
URL http://thegirlsnetwork.org.uk/
 
Description U3A Bury 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Spoke about eye research for the "Today's World" group of the Bury University of the Third Age. This group has an interest in science and technology. The talk sparked a lot of interesting questions throughout. Some members of the audience asked for me to send further, more detailed information on some of the topics covered.
Year(s) Of Engagement Activity 2018