Research Project
8780535
DESCRIPTION (provided by applicant): Like all neurons of the central nervous system (CNS), retinal ganglion cells fail to regenerate, and often die, after damage to the optic nerve such as occurs in optic nerve stroke or other optic neuropathies. Loss of axonal connectivity and neuronal death that occurs after damage to the optic nerve results in vision loss. While therapeutics targeting secondary damage after neuronal insult have shown benefit in reducing functional deficits after neuronal damage, there are currently no approved agents capable of addressing axon regenerative failure, the primary cause of visual dysfunction after optic nerve damage. As such, novel approaches capable of improving axonal growth (neuroregeneration) have potential to restore visual capacity after damage to the optic nerve. LRP1 was recently identified as a novel receptor of myelin-associated inhibitors (MAIs), the components of degraded myelin responsible for the extrinsic component of regenerative failure. We have shown in vivo that infusion of the LRP1 antagonist RAP into the CNS after injury results in attenuation of RhoA activity, the critical signal involved in extrinsic causes of regenerative failure. Direct inhibition of RhoA enhances neuronal regeneration in rodent models and a pan-RhoA inhibitor has shown evidence of efficacy in humans in exploratory clinical trials. However, current therapeutic candidates have several critical limitations such as lack of neuronal specificity and poor bioavailability limiting drug delivery. In contrast, RAP is readily available o the CNS from the peripheral circulation. Because RAP is both readily soluble and can be delivered to the CNS via multiple doses, it possesses desirable therapeutic advantages over current pan-RhoA inhibitors. As beneficial results have already been observed using direct infusion to the injury site, we first wish to assess whether peripheral administration of RAP has comparable beneficial effects on the signaling events associated with regenerative failure after optic nerve insult. To accomplish this, an intravenous administration protocol capable of resulting in sufficient levels of RAP in the CNS must first be established. We will then perform long term studies (8-week injury course) to assess histological regeneration of damaged neurons with RAP treatment. As LRP1 has been shown to be a critical facilitator of myelin- mediated neuroregenerative failure, we hypothesize that therapeutic application of RAP will result in significant neuronal regeneration of retinal ganglion cells in the optic nerve. Additionally, the unique biological characteristics of RAP such as CNS bioavailability and specific RhoA inhibition in neurons could make it a superior therapeutic approach to the current pan-RhoA inhibitors. As such, RAP is an important candidate to bring through pre-clinical proof-of-concept testing as a high-value potential therapeutic for restoring axonal growth after damage to the optic nerve.
