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Prolonged inhibition of semaphorine3a pathway via a bio-degradable implant towards a better therapy for visual sensory impairments

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Biodegradable intraocular implant arrests retinal ganglion cell death

Glaucoma is the second leading cause of blindness in the world. Innovative therapy that inhibits neuronal cell death in glaucoma through controlled release of therapeutic molecules from a minimally invasive biodegradable implant is highly desirable.

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Glaucoma affects the optic nerve and is characterised by the degeneration of optic nerve axons and cell bodies (retinal ganglion cells (RGCs)). As neuronal cell death is irreversible and leads to blindness, slowing down its progression offers a possibility of inhibiting the glaucoma damage. The EU-funded project VISION (Prolonged inhibition of semaphorine3a pathway via a bio-degradable implant towards a better therapy for visual sensory impairments) developed a biodegradable implant that slowly releases compounds inhibiting neuronal cell death to prevent blindness arising from glaucoma. This was achieved by targeting Semaphorin 3A (Sema3A), a protein that participates in axonal guidance pathways and is also capable of inducing programmed neuronal cell death. A small molecule peptoid inhibitor of Sema3A resulted in reduction of RGC death. The team constructed chemical libraries of this peptoid derivative and identified an analogue called CSIC002 that shows great promise as a lead compound. Researchers also discovered that suppressing Sema3A using specific antibodies such as Fab 3H4 inhibited the apoptotic pathway. VISION developed two types of Sema3A inhibitors: low molecular weight (MW) compounds and Sema3A-targeted antibodies. Using electrospinning or extrusion, the team produced implants made of biodegradable polymers that are loaded with CSIC002 and Fab 3H4 for Sema3A inhibition. In vivo studies in mice, rabbit and rat models clearly demonstrated a protective effect on RGCs with no toxic or inflammatory reactions. The consortium is currently planning a three-month phase Iib clinical trial in Europe for their drug delivery system consisting of a polymeric implant and a Sema3A inhibitor. As these polymers have previously been deemed acceptable by regulatory authorities for usage in medical devices, obtaining marketing approval should not be a Herculean task. The VISION study has revealed the potential therapeutic effect of their implant system for disorders involving acute optic nerve injury, ischaemic optic neuropathy and glaucoma. Although the project has ended, efforts are ongoing to commercialise this product to benefit millions of people suffering from such blindness-inducing conditions.

Keywords

Biodegradable, intraocular implant, glaucoma, VISION, Semaphorin 3A, CSCI002, Fab 3H4

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