Neuroprotection
In glaucoma, neuroprotection is any therapeutic strategy that prevents the degeneration of RGCs due to sensitivity to IOP. Two types of neuroprotective agents prevail in glaucoma research: those that indirectly delay RGC degeneration by reducing IOP; and those that slow degeneration through direct effects on components of the optic projection (e.g. RGCs). Our lab is working on both neuroprotective strategies with a goal of maintaining RGC structure and function. For more information, please see Shih 2012 on the Publication page.
Indirect Neuroprotection
Currently there is no cure for glaucoma. The main goal of glaucoma therapy is to lower IOP to slow RGC neurodegeneration. In the majority of cases this involves the use topical eye drops. The biggest issue with this therapy is patient compliance—patients remembering to use their drops every day, sometimes multiple times per day. To overcome this issue, we are testing nanoparticle delivery of IOP-lowering drugs via intravitreal injection. Following microbead injection to elevate IOP, single topical applications of drug X (trx; top left) on day 4 and day 7 reduced IOP by ~27% compared to saline. This reduction in IOP only lasted 2 days. In contrast, a single intravitreal injection of a 700nm drug X NP (NP; top right) lowered IOP ~26% for 30 days compared to intravitreal saline injection. inj: microbead injection; trx: treatment drug X either topically (left) or NP (right).
Nanoparticle delivery of neuroprotective drugs directly to RGCs in the retina would be a significant advance in glaucoma therapy. To test this, we loaded nanoparticles (NP) with Neuro-DiO, a lipophilic tracer, and injected them into the vitreal cavity. Confocal images of a whole mount retina 1 week after injection show Neuro-DiO (green) was released from NP and deposited on the retinal surface (top left; arrows). Uptake of Neuro-DiO by phosphorylated neurofilament-positive RGCs (pNF; red) was also seen (dotted circles). Neuro-DiO surrounding pNF-positive RGC somas is better seen in orthogonal projections (middle) and an orthogonal view rotated about the Z-axis (right). The yellow dotted lines indicate the position of the orthogonal views.
Direct Neuroprotection
Brimonidine (BMD) is currently prescribed to glaucoma patients as a topical drop to lower IOP. This drug is interesting in that if given systemically BMD has no effect on IOP, but is neuroprotective to RGCs after injury. Following microbead injection to elevate IOP, systemic BMD preserved axonal transport of CTB to the SC when compared to vehicle (top panels; left graph). Similarly, systemic BMD preserved RGC axons in the optic nerve after microbead injection (middle panels; right graph). For more information, please see Lambert 2011 on Publication page. For SC maps colorimetric scale indicates levels of transport from 100% (red) to 50% (green) to 0% (blue).
Following elevation of IOP by microbead injection, topical application of a p38 MAPK inhibitor prevented axonal transport deficits in the SC and degeneration of RGC axons in the optic nerve. Treatment with the p38 inhibitor also reduced the phosphorylation of tau (left panels) and heat-shock protein 27 (Hsp-27; right panels) in the retina. Both of these proteins have been implicated in glaucomatous progression. For more information, please see Dapper 2013 on Publication page.