Nogo Decoy Receptor Therapy for the Treatment of Glaucoma

DESCRIPTION (provided by applicant): The objective of this phase I STTR application is to continue assessment of the relevance and feasibility of Nogo decoy receptor therapy for the treatment of glaucoma. The secondary objective is to obtain pharmacokinetic data important for designing additional preclinical efficacy studies and formulating a drug development plan for glaucoma. Our long term objective is to ameliorate the devastating consequences of glaucoma by developing a treatment option that not only slows progression but also may provide functional regeneration. Glaucoma is the second leading cause of blindness worldwide. Current therapies that lower intraocular pressure (IOP) as a means of slowing disease progression are not fully effective. Our proposal seeks to further evaluate Nogo decoy receptor as a potential neuroprotective and regenerative therapy that does not rely on lowering IOP. Preliminary studies employing rat Nogo decoy receptor (rNgR(310)Fc) and manipulation of Nogo receptor gene (ngr1) expression suggest that Nogo decoy receptor therapy has the potential to become a first-in-class therapy for glaucoma to prevent retinal ganglion cell (RGC) loss and promote optic nerve axonal regeneration. The research proposal objectives will be accomplished within a 1 year period by meeting three Specific Aims which include: 1) determining the efficacy of human Nogo decoy receptor (hNgR(310)Fc) in preventing retinal ganglion cell (RGC) loss in a model of indirect injury: rat bead model of glaucoma, 2), evaluating the effect of human Nogo decoy receptor therapy in promoting RGC survival and optic nerve regeneration in a model of direct injury: optic nerve crush injury in rats, and 3) evaluating the pharmacokinetics and tissue distribution of Nogo decoy receptor when administered into the eye. Completion of these Specific Aims will provide critical data needed to initiate development of Nogo decoy receptor therapy for the treatment of glaucoma. Specifically, the data will be used to define an appropriate formulation and delivery strategy for use in additional preclinical glaucoma models and to determine the most appropriate development strategy to advance the therapy to clinical evaluation. Accordingly, Future Studies will include preliminary formulation development for ocular delivery. This may include formulation for controlled release in the eye depending on the outcome of the pharmacokinetics and in vivo pharmacology investigations in the current proposal. Further preclinical efficacy studies will be conducted as well as investigations to elucidate the mechanism for RGC protection by Nogo decoy receptor. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Glaucoma is the second leading cause of blindness worldwide. Current therapies that lower intraocular pressure (IOP) as a means of slowing disease progression are not fully effective. Axerion Therapeutics seeks to develop Nogo decoy receptor as a potential neuroprotective and regenerative therapy for glaucoma that does not rely on lowering IOP.