Inhibitors of Rho GTPase are neuroprotective for retinal ganglion cell (RGCs) and may be effective in treating eye diseases such as glaucoma. RGC death in glaucoma is associated with RGC axonal loss. Once neurons lose connections, normal circuitry is affected, and the loss of target-derived signals contributes to cell death. Such loss of signals may be dendritic or axonal, and prevention of RGC cell death would be improved by drugs that stimulate plasticity and/or prevent axonal die back. BA-210 is a Phase II investigational drug (in clinical trial for acute spinal cord injury) that has strong neuroprotective effects and also stimulates dendritic plasticity and axonal regeneration. We have strong preclinical data for neuroprotection of RGCs after intravitreal injection in rats after axotomy of the optic nerve and in a rat model of elevated intraocular pressure (IOP). To improve the pharmacodynamics and safety of BA-210 for use in ophthalmology, we will make PEGylated BA-210. We will determine dose-response and compare retention in the retina and efficacy with BA-210, with rho kinase inhibitors. We have preliminary results to show that PEG-BA-210 retains enzymatic activity and is retained in the retinal longer than BA-210. Neuroprotection of RGCS will be investigated after optic nerve transection and in a rat glaucoma model of IOP. In additional experiments we will investigate safety of PEG-BA-210 after injection into rabbit eyes. For these experiments, we will follow clinical signs and histopathology. Together, these experiments will help translate preclinical data on RGC protection towards clinical development.
Public Health Relevance Statement: Public Health Relevance: Glaucoma is the second most common cause of blindness in the world, and vision loss is caused by the selective degeneration of retinal ganglion cells that die by apoptosis. Current treatment is the use of medications to reduce elevated intraocular pressure, but there is no effective treatment for normal-tension glaucoma. BA-210 is a clinical-stage drug that blocks neuronal apoptosis and enhances plasticity by targeting the Rho signaling pathway, and our proposal is to improve the pharmacological properties of BA-210 for treatment of retinal ganglion cell death in glaucoma.
Project Terms: Acute; ADP ribosylation; Affect; Animals; Antibodies; Apoptosis; axon regeneration; Axotomy; Back; Blindness; Cell Count; Cell Death; Cell Survival; Clinical; Clinical Research; Clinical Trials; comparative efficacy; Complex; Crush Injury; Cytoprotection; Data; Development; Disease; Dose; Drops; drug candidate; drug development; Drug Kinetics; effective therapy; Evaluation; experience; Eye; Eye diseases; Future; Glaucoma; Histology; Histopathology; Hour; immunocytochemistry; improved; inhibitor/antagonist; Injection of therapeutic agent; intravenous injection; intravitreal injection; Investigation; Investigational Drugs; kinase inhibitor; Label; Modeling; Modification; Molecular Weight; Mydriatics; neuron apoptosis; Neurons; neuroprotection; Norway; ophthalmic artery; Ophthalmology; Ophthalmoscopy; Optic Nerve; Optic Nerve Transections; Oryctolagus cuniculus; Paraffin; Patients; PC12 Cells; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiologic Intraocular Pressure; pre-clinical; Preclinical Testing; prevent; Prevention; Primates; Property; public health relevance; Rattus; Reaction Time; regenerative; research study; response; Retina; Retinal; Retinal Ganglion Cells; rho; rho GTP-Binding Proteins; Rho-associated kinase; Safety; safety study; Series; Signal Pathway; Signal Transduction; Spinal cord injury; Spinal cord injury patients; Staging; Testing; Time; Toxic effect; Translating; Variant; Veins; Western Blotting
