Development of an opticin-based anti-angiogenic therapeutic for the treatment of ocular disease.

There are a number of blinding conditions where abnormal blood vessels grow into the vitreous humour, a normally transparent, jelly-like structure that occupies the middle of the eye; these include retinopathy of prematurity (affecting preterm babies) and proliferative diabetic retinopathy (a common cause of sight loss in diabetes). Currently these conditions are treated with laser therapy that destroys large parts of the retina; this sacrifices side-vision with the aim of preventing complete sight loss and preserving the central part of the vision. Laser treatment was introduced about 50 years ago and the treatment for these conditions has not changed substantially since then. Given the side-effects of laser treatment, and that it does not always work, better treatments are need.

We discovered a molecule in the vitreous humour that we called opticin, and more recently we found that opticin inhibits blood vessel growth. In diseases where blood vessels grow into the vitreous there is not enough opticin present to stop the blood vessels growing. However, we now have evidence that by injecting more opticin into the vitreous than is normally present, we can prevent the blood vessel growth and thereby treat these diseases. Injections into the vitreous are now routine procedures for other eye conditions and injecting opticin could replace laser treatment, or could be used in conjunction with laser therapy.

This project will build upon the data we have at present to substantiate the case for developing opticin as a treatment for these conditions. Studies will include further work to determine how effective opticin will be as a treatment, some initial safety studies, investigations into how long the opticin stays in the vitreous humour after it is injected, and some further work to analyse how opticin works at a molecular level. This preclinical research will allow us to detemine whether opticin should continue to be developed as a treatment, and if it does, will facilitate future research as it moves towards clinical trials. In addition, it will provide the data needed to attract a commercial partner with whom we can develop opticin into an exciting, new sight-saving treatment.

Several blinding eye conditions, including retinopathy of prematurity and proliferative diabetic retinopathy, are characterised by preretinal neovascularisation, i.e. pathological angiogenesis with new blood vessels growing from the retina into the vitreous. The new blood vessels cause visual loss through bleeding and/or tractional retinal detachment. Current management includes panretinal photocoagulation and surgery. Both are associated with predictable side-effects and better treatments are needed. Our solution is to develop recombinant human opticin as a therapeutic that is delivered by intravitreal injection.

Opticin is a glycoprotein that occurs naturally in vitreous. We have shown that opticin inhibits preretinal neovascularisation in a dose-dependant manner, with excess opticin having a greater anti-angiogenic effect than endogenous levels. We have elucidated its mechanism of action: it binds to collagen and thereby inhibits endothelial cell adhesion and collagen-mediated pro-angiogenic signalling that is essential for angiogenesis.

Aims of this proposal are to:
- Investigate whether intravitreal opticin injection induces vascular regression,
- Perform ocular PK studies to investigate the half-life of opticin in the vitreous cavity and to determine whether any injected opticin escapes into the circulation or brain,
- Determine whether therapeutic levels of opticin affect retinal vascular development, morphology or function,
- Undertake additional mechanistic studies to confirm results with fibrillar rather than monomeric collagen.

The above experiments are key to determining the potential of opticin as a therapeutic for preretinal neovascularisation, and for attracting funding for further preclinical development and subsequent clinical trials.

This research aims to continue the preclinical development of opticin as an anti-angiogenic drug. It will allow key go/no go decisions to be made with regard to developing it as a treatment for conditions characterised by preretinal neovascularisation. Potential beneficiaries might include patients, the pharmaceutical industry, academics and wider society.

If the efficacy, safety or pharmacokinetic data do not support the continued development of opticin for these indications then the decision to stop the programme will prevent the waste of money, time and other resources on the project. Even if the project does not produced the results that are hoped for, important new research data will emerge and be published.

If the resultant data suggests that opticin has the potential to be an effective treatment for these conditions then the project has, in the longer term, the potential to deliver better treatments for patients with diseases including retinopathy of prematurity and proliferative diabetic retinopathy. There would be socioeconomic benefit if the treatment prevented blindness and improved the quality of life of patients, who might otherwise have debilitating side-effects from current treatments. Other beneficiaries would be investors who contributed to the delivery of the opticin therapeutic and other industry that is involved in manufacture and delivery of the product.

Opticin, if it is developed as a therapeutic for preretinal neovascularisation, may also benefit patients with other causes such as retinal vein occlusion, sickle cell retinopathy, Eales disease etc. It could be developed for other conditions which are characterised by pathological angiogenesis including ocular conditions such as "wet" age-related macular degeneration and corneal angiogenesis, and non-ocular conditions such as cancer. If the project demonstrates that opticin has a very long-half life in the vitreous the research could be taken in new directions, linking opticin to other therapeutic proteins so that sustained delivery can be achieved following intraocular injection and this could benefit patients with a wide variety of ophthalmic conditions.

The research will benefit academics in a variety of disciplines including ophthalmic, angiogenesis and matrix biology research, by providing new knowledge.