Development of neuroprotective agents

The failure of memantine in its large Phase III programme highlights the difficulty of demonstrating benefit.¹ The slow progression of glaucoma coupled with the variability in measurement of changes in disease status has severely hampered the development of neuroprotective agents.

Studies need to be large and long; the memantine studies recruited over 1000 patients with average follow up for over 4 years; despite this they were not able to demonstrate a difference compared with standard of care. In the recently published study comparing the alpha antagonist brimonidine with timolol, a beta-blocker, the glaucoma progression rates for the two arms did not diverge until after 24 months of treatment and, even then, the benefit may have been more pronounced due to an unexpectedly rapid progression rate in the timolol arm.²

Despite these caveats, there have been some recent developments that will facilitate future development of neuroprotectants as treatments for glaucoma. Improvements in imaging technology including Spectral Domain (SD-) OCT allows the more reliable recording of signals of progression. Identification of patient populations at higher risk of progression (the so-called 'fast progressors') allows recruitment not only of patients who will benefit most from treatment but also those in whom a benefit can most easily be observed.

One group of molecules that have received a lot of attention as potential neuroprotectants in glaucoma are neurotrophic factors. Neurotrophic factors are small, secreted proteins that play important roles in the development and maintenance of the nervous system. In particular, members of the neurotrophin-family (e.g., BDNF, NGF), the TGFβ-family (e.g., GDNF, neurturin) and the GP130family (e.g., CNTF) are thought to be implicated in the pathogenesis of glaucoma.

The neurotrophin hypothesis of retinal ganglion cell loss in glaucoma states that the obstruction of axonal transport at the optic nerve head results in a lack of neurotrophic support to retinal ganglion cells resulting in them undergoing apoptotic cell death. The evidence supporting the neurotrophin hypothesis is derived from animal models of glaucoma where it has been shown that (i) transport of neurotrophins and their receptors are impeded (ii) retinal levels of neurotrophins and their receptors can be altered and (iii) that increasing neurotrophin signalling produces neuroprotective effects.

Many neurotrophic factors have been shown to exert neuroprotective effects on retinal ganglion cells in vitro, including CNTF, NGF, NT-4, FGF-2, GDNF and neurturin, but the most widely studied neurotrophic factor in glaucoma is BDNF. Several groups have investigated the effect of BDNF in models of retinal ganglion cell death in vivo and have shown significant neuroprotection whether the BDNF was administered by direct injection,^3–8 or via adenoassociated virus (AAV)mediated gene transfer.^9–11 Furthermore, combined administration of more than one neurotrophic factor (e.g., BDNF and GDNF,^12,13 or BDNF and neurturin¹³ ) provided a greater level of protection than BDNF alone, suggesting that the neuroprotective effect may be enhanced by stimulating multiple neurotrophic factor pathways. No formal clinical studies evaluating the effect of neurotrophic factors for the treatment of glaucoma have been undertaken although three patients with advanced glaucoma have been treated with topical NGF for 3 months and each patient demonstrated long lasting improvements in visual field, optic nerve function, contrast sensitivity and visual acuity¹⁴ suggesting that the clinical utility of neurotrophic factors for the treatment of glaucoma is worthy of rigorous evaluation. However, in animal models, multiple intravitreal injections of BDNF are necessary to show efficacy, potentially reducing the clinical usefulness of intraocular delivery of BDNF protein as an adjunct to IOP reduction in glaucoma therapy. To overcome this problem several groups are developing novel delivery strategies including slowrelease drug delivery, gene therapy, and cell transplantation, but there are inherent difficulties with all of these delivery systems. An alternative approach to increasing BDNF levels is the use of small molecule compounds that can induce the endogenous production of BDNF.