A Novel Disease Modifying Therapeutic for Dry Eye Disease
DRY EYE DISEASE – A GROWING PROBLEM WITH HIGH UNMET NEED
Dry eye disease (DED), is a common inflammatory disease – estimated to affect approximately 100 million people worldwide and increasing as the population ages and as a result of modern lifestyles. Its prevalence is elevated in patients with autoimmune disease (around 8% of the population) or diabetes and is worsened by factors such as air conditioning, driving and screen time.
DED is characterized by insufficient moisture and lubrication in the anterior surface of the eye, leading to dryness, inflammation, pain, discomfort, irritation and, in severe cases, decreased vision. If untreated, it can lead to inflammatory damage to the cornea and conjunctiva, yet in many cases it remains undiagnosed.
Currently, only three drugs are approved by the FDA for the treatment of moderate to severe DED – and these are largely unavailable outside of the USA. Restasis and Klarity-C are cyclosporine-A medications, whilst Shire’s Xiidra targets the interaction of LFA-1 with ICAM-1. Therapy for DED, including with these drugs, is generally considered by patients and physicians to be inadequate, with high cost and poor compliance representing additional hurdles. OTC remedies, such as eye drops, ointments and sprays typically have suboptimal residence times in the eye, difficult application and lead to blurred vision.
Patients with severe cases of DED may require corticosteroids in addition to approved therapy. However, corticosteroids are associated with severe ocular toxicities, including cataract formation and glaucoma (elevation of intraocular pressure that can lead to loss of vision).
Our aim is to develop a protein biological therapeutic for dry eye with disease modifying activities, which can be delivered in the form of an eye drop.
The technology – Link_TSG6
We are developing the recombinant Link module domain from human TSG-6 (termed Link_TSG6) as a protein biological for use in DED and with the potential to be applied to additional ophthalmic (and other) indications.
The full-length TSG-6 protein has been found to mediate many of the anti-inflammatory and tissue-protective effects of mesnchymal stem/stromal cells and has broad therapeutic potential across a wide range of disease models. This includes models of DED, age-related macular degeneration, corneal wounding and corneal allogeneic transplant rejection. For example, full-length TSG-6 was shown to be efficacious in models of Sjögren’s syndrome and non-Sjögren’s (concanavalin-A-induced) dry eye; in the former, TSG-6 was more effective than prednisolone and had a comparable effect to Restasis.
However, the full-length recombinant TSG-6 protein is not suitable as a therapeutic due to its poor expression, poor solubility and poor stability. Conversely, the recombinant Link module domain of human TSG-6 (Link_TSG6) can be readily produced and has good solubility and stability. Link_TSG6 retains many of the biological activities of the full-length protein and we have generated data demonstrating that it has therapeutic utility in a mouse model of DED.
The ~11-kDa recombinant Link_TSG6 protein can be made in E. coli; we have developed a scalable GMP-compatible manufacturing process (but not yet transferred it to scale). The protein is highly soluble and we have identified conditions where it is stable in solution that are likely suitable for formulation.
Pre-clinical proof of concept in DED
Following 7-days of topical treatment in a mouse model of primary ocular Sjögren’s syndrome, our data indicate that Link_TSG6:
- Reduces the severity of corneal epithelial lesions (left panel)
- Reduces inflammation in the cornea and in the lacrimal glands
- Restores tear production by the lacrimal gland
- Preserves the conjunctival goblet cells, responsible for production of the mucin tear film (right panel)
Link_TSG6 has a unique combination of activities (wound healing, anti-inflammatory and tissue protective) relevant to the treatment dry eye and potentially other ophthalmic conditions.
We have a well-developed, scalable method for cost-effective production of the Link_TSG6 protein.
We have identified solution formulations where Link_TSG6 is highly stable.
The technology is being developed as a biological therapeutic for Sjögren’s and non-Sjögren’s DED.
Published data on the full-length TSG-6 protein, indicate the likelihood that Link_TSG6 could also be used in other ophthalmic indications, including age-related macular degeneration, corneal wounding and corneal allogeneic transplant rejection.
We have proprietary know-how on the method to manufacture our therapeutic and its formulation. There is considerable scope for patentable IP relating to the formulation of this therapeutic.
We would like to collaborate with an industry partner for further preclinical and clinical investigations with a view to licensing the technology.