VISION

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

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 Obiettivo del progetto (Objective)

'The visual pathway is a component of the central nervous system (CNS) and therefore is not regenerative. Acute optic nerve injury, ischemic optic neuropathy and glaucoma are conditions that initially lead to partial blindness and eventually could lead to total blindness. Extensive neuron and retinal ganglion cells (RGC) death is evidenced in these pathologies. Semaphorin 3A (Sema3A) is a cell secreted protein that participates in the axonal guidance pathways. Partner TAU was the first to show that Sema-3A is also capable of inducing neuronal cell death. Elevated levels of Sema3A were than found in glaucoma. TAU further showed the viscous role of Sema3a that is mediating the vast RCG apoptosis following optic nerve injury. Importantly, marked inhibition of RGC loss was achieved when axotomized eyes were co-treated by intravitreous injection of antibodies against the Sema3A providing the proof of concept for the therapeutic approach to inhibit the Sema3A pathway following optic nerve injury. This concept was recently validated by partner SIC who developed a small molecule weight inhibitor of Sema3A and showed that this inhibitor promotes neural regeneration of damaged axons. Acute or chronic assault to neural cells create an immediate death of part of the population and a signal for further death of the remaining cells close to the damaged area. The project goal is to develop a therapeutic approach to stop further death of neural cells by providing prolonged inhibition of the apopototic pathway of Sema-3A using antibody targeted to this protein or a low MW inhibitor of sema3A. The Sema3A inhibitors would be constantly released from a novel intraocular biodegradable implant. The clinical efficacy of this approach will be evaluated in two common devastating pathologies: optic nerve injury and glaucoma.'

Introduzione (Teaser)

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

Descrizione progetto (Article)

Glaucoma, one of many degenerative disease of optic nerve, is characterised by the degeneration of optic nerve axons and cell bodies (retinal ganglion cells (RGCs). As neuronal cell death occurring in glaucoma is irreversible and leads to blindness, slowing down its progression offers a possibility for glaucoma treatment.

The EU-funded project http://fp7-vision.eu/ (VISION) aims at novel glaucoma therapy. Its goal is to develop a therapeutic biodegradable implant that will slowly release compounds inhibiting neuronal cell death. The inhibition will be achieved by targeting Semaphorin 3A (Sema3A). This protein participates in the axonal guidance pathways and is also capable of inducing programed neuronal cell death.

Researchers discovered that inhibiting Sema3A using specific antibodies resulted in inhibition of the apoptotic pathway. Furthermore, a small molecule peptoid inhibitor of Sema3A resulted in reduction of RGC death. Thus, VISION is developing two types of Sema3A inhibitors: low molecular weight (MW) compounds and Sema3A-targeted antibodies.

VISION has already achieved significant progress. Several Sema3A-specific antibodies were selected from a phage library and synthesised in human antibody format. The antibodies were tested in cell-based assays and confirmed to be inhibitory to Sema3A. Low MW inhibitors were selected and showed satisfactory inhibition of Sema3A in vitro.

Implant prototypes loaded with low MW inhibitors and antibodies were prepared by electrospinning biodegradable polymers polycaprolactone and poly-lactic-co-glycolic acid. Implantations in rats of blank implants were demonstrated to be safe and tolerable. A sustained release profile of the small molecule from the implant for a period of over 30 days was demonstrated in vitro.

Finally, in vivo studies in rats demonstrated that both the antibody Fab 3H4 and the small molecule CSIC2 prevented RGC loss in a statistically significant manner. Obtained results reveal the potential therapeutic effect of these compounds to treat disorders involving optic nerve injury, including glaucoma.