Preclinical evaluation of a new chemical cross-linker for the treatment of keratoconus

The aim of the proposal is to determine the safety and efficacy of a novel technology for the safer and more effective treatment of the sight threatening disease keratoconus. The cornea is the clear window at the front of the eye that allows light to enter and provides 80% of the refractive power to focus the light onto the retina at the back of the eye. The transparency of the cornea is influenced by the alignment of collagen fibres and its shape has a major involvement in refraction of the light. Keratoconus is a progressive condition, affecting young and working age people, in which the cornea becomes misshapen significantly disrupting the refraction of light into the eye. It is a lifelong condition and a significant health and economic burden in work-age adults; and is a leading cause of corneal transplantation in the UK. One of the key features of keratoconus is the thinning of the cornea and disruption of the alignment of the collagen fibres leading to a loss of mechanical stability, with the stiffness of the cornea reducing by up to 40 % compared to a normal cornea. The potential to increase the stiffness of the collagen structure by forming cross-links between the fibres has led to the development of corneal cross-linking procedures. Increasing the stiffness of the cornea can reduce the progression of the disease by preserving corneal integrity due to strong bonds formed within the collagen structure. Over the past decade, collagen cross-linking using ultraviolet A (UVA) radiation combined with the photosensitiser riboflavin has been used clinically but it has several limitations. In particular, the exposure to UVA radiation risks toxicity to cells throughout the cornea. This includes the keratocytes within the collagen structure which can result in scarring and haze over the long term. More importantly, it can damage the corneal endothelium which is a monolayer of cells on the inner surface of the cornea. If damaged these cells do not recover and this can lead to severe loss of vision. Also for effective stiffening it is necessary to remove the corneal epithelium, the layer of protective cells on the outer corneal surface, to allow penetration of the photosensitiser. This is painful for the patient and increases the risk of infection.
We have developed a chemical cross-linking solution and demonstrated that it stiffens the cornea in ex vivo pig tissue to a similar extent to the existing treatment. Also we have shown that it penetrates into the cornea without needing to remove the epithelium. Furthermore, in contrast to the UVA treatment, we have demonstrated no toxicity to the cells in the cornea. It is a simple chemical solution that can be delivered to the patient as an eye drop which we believe could be done in primary care rather than in a hospital clinic. This study is designed to develop our novel patented technology along the translational pathway. We will demonstrate its biological safety in an in vivo rat model. We will determine the amount of stiffening produced in a rabbit model and the stability of the stiffening over a 4 month period and use this to optimise the clinical procedure. We will work closely with our clinical partners to ensure the technology progresses towards the clinic. We aim to build a partnership with a company to ensure commercial translation. At the end of this project we aim to have the technology ready to proceed to a first-in-man safety study.

Keratoconus is a progressive condition, affecting young and working age people, in which the cornea becomes misshapen significantly disrupting the refraction of light into the eye. It is a lifelong condition and a significant health burden in work-age adults, and is a leading cause of corneal transplantation in the UK. One of the key features of keratoconus is a loss of corneal mechanical stability, with the stiffness of the cornea reducing by up to 40 % compared to a normal cornea. Corneal collagen cross-linking increases the stiffness of the cornea and can reduce the progression of this disease by preserving corneal integrity due to strong bonds formed within the collagen. Over the past decade, collagen cross-linking using ultraviolet A (UVA) radiation combined with the photosensitiser riboflavin has been used but it has several limitations. In particular, the exposure to UVA radiation risks toxicity to cells in the stroma and the corneal endothelium. Also for effective stiffening it is necessary to remove the corneal epithelium to allow penetration of the photosensitiser which is painful for the patient and increases the risk of infection. We have developed a cross-linking solution and demonstrated that it stiffens the cornea in ex vivo porcine and human tissue to a similar extent to the existing treatment. Also we have shown that it penetrates into the cornea without needing to remove the epithelium. Furthermore, in contrast to the UVA treatment, we have demonstrated no toxicity to the cells in the cornea. It is a simple chemical solution that is dissolved at the time of use and delivered to the patient's eye after mixing. This study is designed to develop our novel patented technology along the translational pathway through an in vivo preclinical trial using rat and rabbit models. During this time we will build a partnership with a commercial partner and MHRA approval for a phase 1 safety trial to follow.