An Optimal Form of Nerve Growth Factor as a New Neuroprotective Drug for Glaucoma

We developed an optimized nerve growth factor, painless NGF (NGFp), that has the same neuroprotective properties as natural NGF but lacks adverse effects, such as pain and cell death signalling. NGFp, without the pitfalls of natural NGF, is a promising therapeutic candidate for glaucoma, able to rescue RGC degeneration through a synergistic action of neuroprotection and inflammatory modulation.

NGFp is a variant of NGF with superior neuroprotective properties. We will carry out head-to-head experiments on glaucoma murine models, to compare the neuroprotective effectiveness and the superior efficacy of NGFp with respect to NGF. We will then assess if the RGC neuroprotection by NGFp is directed by microglia, using a microglia-depleted murine model of glaucoma. Finally, we will test if NGFp, like NGF, shows no effect on intraocular pressure. If so, we will evaluate a possible synergic retinal neuroprotection by the coadministration of NGFp with an ocular hypotensive agent.

In this project, we propose two innovations:
i) the molecule: NGFp is a step ahead with respect to NGF because it binds TrkA and not p75NTR, targeting the neuroprotective and anti-inflammatory TrkA signalling pathways and not the p75NTR apoptotic and neurotoxic ones. Unlike NGF, it does not generate pain. The absence of the pain side effect improves patient compliance and increases the NGFp therapeutic index. ii) The treatment mechanism: targets disease-relevant retinal microglia, thereby ensuring neuroprotection on RGC by controlling pathological inflammatory processes.

If the expected results are obtained, this project will set the basis for an NGFp therapy to help decrease visual loss in patients suffering from glaucoma and other ocular diseases underlined by RGC degeneration. Moreover, it will boost the current GMP production of clinical-grade batches of NGFp. Notably, a recent phase 1b/2a clinical trial investigating NGFp neuroprotective action on RGCs in optic pathway glioma was started. Therefore, if justified by the results of the present study, the clinical grade NGFp protein for undertaking glaucoma clinical trials could become available.