Establishing a neuroprotection model in the nonhuman primate to support translati -
Optic nerve and retinal diseases profoundly impact quality of life and overall health care burden. Demetrios
Vavvas and colleagues at the Mass Eye and Ear Infirmary (MEEI) have revealed a critical redundant role of
mediators of both apoptosis and necrosis in cell death in the neuroretina and optic nerve in multiple ophthalmic
disease models, supporting their importance as possible drug targets. Most notably, blockade of RIP kinase 1,
a regulator of necrosis, pharmacologically or by gene knockout, acts synergistically with the arrest of apoptosis
by pan-caspase inhibition to achieve remarkable preservation of neuronal viability and function. Specifically,
when treated with pan-caspase inhibitors, Rip3-/- mice, lacking activated RIP kinase 1, are highly resistant to
photoreceptor cell loss in the setting of models of retinal detachment, retinitis pigmentosa and age related
macular degeneration (AMD), and retinal ganglion cells (RGCs) loss in disease models specifically impacting
inner retinal and optic nerve function. This synergistic protective effect has additionally been demonstrated in
wild type mice co-dosed with RIP kinase 1 and pan-caspase inhibitors. Despite the promise of applying this
newly defined dual pathway inhibition to prevalent conditions such as AMD and glaucoma, the challenges of
sustained therapeutic delivery to the back of the eye, and the design of clinical trials for slowly progressing
neurodegenerative diseases favors pursuit of early clinical applications to conditions with rapid onset
secondary to acute, minimally progressing pathology with anticipated short treatment periods, and clear
efficacy endpoints and subject recruitment criteria. One such condition is non-arteritic ischemic optic
neuropathy (NAION), the most common cause of acute optic nerve related vision loss, for which there are
limited therapeutic options. After an initial focal ischemia associated with reduced perfusion of the
microvasculature of the optic disc, often in the setting of an anatomically susceptible disc and/or systemic
hypotension, a cascade of events contributes to axonal injury and RCG endangerment, culminating in
caspace-associated apoptosis. There is additional abundant corollary evidence to suggest a critical roll of RIP
kinase as an ultimate contributor to RGC fate via the necrotic pathway. Vavvas et al. have demonstrated
rescue of RGCs in rodents by the synergistic RIP kinase 1/pan-caspase inhibition in the setting of traumatic
optic neuropathy and NMDA-associated excitotoxicity. They have further established a laser photoembolic
model of NAION in the rodent, employing mesoporphyrin as a fluorophore to achieve focal microvessel
disruption at the disc by targeted laser photoexcitation. In this proposal, we will characterize the mesopophyrin
model in the nonhuman primate and apply robustly defined clinically relevant endpoints to evaluate the efficacy
of intravitreal (IVT) co-injection of the inhibitor Nec-1 and IDN-6556, both of which have been demonstrated to
be potent inhibitors of RIP kinase 1 and caspases, respectively, and to be well tolerated and bioavailable
following IVT injection, with combined clinical application encompassed by MEEI intellectual property that we
are partnering to advance.
!
