Nogo Decoy Receptor Therapy for the Treatment of Glaucoma

描述（由申请人提供）：本I期STTR申请的目的是继续评估Nogo诱饵受体治疗青光眼的相关性和可行性。第二个目标是获得药代动力学数据，这对设计更多的临床前疗效研究和制定青光眼药物开发计划很重要。我们的长期目标是通过开发一种治疗方案来改善青光眼的破坏性后果，这种治疗方案不仅可以减缓进展，还可以提供功能再生。青光眼是全球第二大致盲原因。目前将降低眼压（IOP）作为减缓疾病进展手段的治疗方法并不完全有效。我们的建议旨在进一步评估Nogo诱饵受体作为一种潜在的神经保护和再生治疗，不依赖于降低IOP。利用大鼠Nogo诱骗受体（rNgR(310)Fc）和操纵Nogo受体基因（ngr1）表达的初步研究表明，Nogo诱骗受体治疗有可能成为青光眼的一流治疗方法，以防止视网膜神经节细胞（RGC）丢失并促进视神经轴突再生。本研究计划的目标将在1年内完成，以满足三个具体目标，包括：1)确定人类Nogo诱饵受体（hNgR（310)Fc）在间接损伤模型中预防视网膜神经节细胞（RGC）损失的功效：青光眼大鼠头模型；2）评估人类Nogo诱饵受体治疗在直接损伤模型中促进RGC存活和视神经再生的效果；3)评价Nogo诱骗受体入眼后的药代动力学和组织分布。这些特异性目标的完成将为开发用于治疗青光眼的Nogo诱饵受体疗法提供关键数据。具体来说，这些数据将用于确定适当的配方和递送策略，用于其他临床前青光眼模型，并确定最合适的开发策略，以推进治疗的临床评估。因此，未来的研究将包括眼部给药的初步配方开发。这可能包括眼内控释制剂，这取决于当前提案中的药代动力学和体内药理学研究的结果。我们将进一步开展临床前疗效研究和研究，以阐明Nogo诱饵受体保护RGC的机制。

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.