Optimisation and preclinical development of small molecule inhibitors of SRPK1 for topical application in the treatment of wet Age Related Macular Degeneration (wAMD) through modulation of VEGF splicing
A drug candidate for wet age-related macular degeneration (wAMD) and diabetic macular oedema (DME) is being optimised for use as a topical eye drop, rather than an injection into the eye. These two conditions are leading causes of blindness in the Western world. Current treatments block all forms of a protein called VEGF, which is needed for both healthy blood vessel maintenance and abnormal vessel growth. The drugs must be injected directly into the eye every few weeks. The new approach uses small molecules that inhibit the kinase SRPK1, selectively blocking only the pro-angiogenic (vessel-growing) splice variant of VEGF while leaving the protective forms intact. If successful, this project could replace repeated intravitreal injections with a non-invasive eye drop. That would reduce the burden on patients and healthcare systems, and potentially improve compliance and outcomes. The funded work will take several inhibitors through an optimisation programme, select a preclinical candidate, and run regulatory toxicology and safety pharmacology studies. The goal is to submit an application for clinical evaluation by early 2020.
View original technical description
Exudative age-related macular degeneration (wAMD) and diabetic macular oedema (DME) are the leading causes of blindness in the Western world. wAMD affects 1.3 per cent of people over 50 years old with a global incidence of 1. 5 million. Diabetes affects 382 million people worldwide, expected to increase to 592 million by 2035 and is the leading cause of severe vision loss in working age adults. Diabetic macular oedema is the major cause of visual loss in diabetic patients. Approximately 14% of diabetes patients develop DME and the prevalence increases to 29% (696, 000) for patients using insulin for more than 20 years. Current treatment options for these conditions are limited. Anti-Vascular Endothelial Growth Factor (VEGF) agents improve vision in some patients and slow its deterioration in most, but they must be administered by regular intravitreal injections and non-specifically block both pro-angiogenic and antiangiogenic isoforms of VEGF. There is therefore an incentive to develop a non-invasive therapeutic modality with efficacious and safe agents. Exonate has developed small molecules that inhibit production of proangiogenic VEGF through selective inhibition of Serine/threonine-protein kinase 1 (SRPK1)-mediated VEGF splicing. These inhibitors have already demonstrated superior efficacy as topical agents in preclinical models of wAMD. Thanks to the support of the Wei/come Trust, Exonate will take several of these inhibitors into an optimisation programme culminating in the nomination of a preclinical candidate drug with optimal characteristics for clinical development. The funded project will also involve the assessment of the candidate in regulatory toxicology and safety pharmacology studies to support an application to the regulatory authorities for clinical evaluation at the end of the funding. Exonate expects to reach this milestone and enter the clinic in early 2020.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know