RAP as a therapeutic for regeneration of the optic nerve after insult

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 LRP 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 LRP 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 week injury course to assess histological regeneration of damaged neurons with RAP treatment As LRP 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 PUBLIC HEALTH RELEVANCE Retinal ganglion cells fail to regenerate and often die after axon damage such as occurs during optic nerve stroke resulting in vision loss LRP is a novel receptor mediating neuroregenerative failure and blocking LRP in vivo with the LRP antagonist receptor associated protein RAP promotes regeneration The goal of this project is to assess RAP for restoration of axon growth after optic nerve injury as a proof of concept work necessary to continue into pre clinical development