Development of an Ophthalmic Therapeutic, Noregen, with the NEI SBIR/STTR Program

Document Type

Conference Proceeding

Publication Date

6-2023

Publication Title

Investigative Ophthalmology and Visual Science

Abstract

Purpose : Human Norrin (Norrie Disease Protein) is essential for neural retinal vasculature formation and promotes maintenance of the blood-retinal barrier through modulation of tight junctions and transcytosis. We developed a biotech solution for manufacturing Noregen, based on human Norrin, through an academic research lab and small business research collaboration. Several challenges required attention to move from bench towards bedside. These included demonstrating the feasibility of producing pure and biologically active protein and planning for drug investigation and commercial development.

Methods : A teamwork approach included basic science, ophthalmology, and business development. The fundamental partnership was an academic research lab skilled in molecular biotechnology and cell signaling, with an ophthalmic small business, to design a biotech production strategy. A second stage used a Phase-1 STTR to demonstrate feasibility. The disulfide-rich protein was refolded using redox disulfide-reshuffling. The small business partner began GMP manufacturing tests.

Results : Noregen was produced using a tag-less protein in a bacterial inclusion-body format. Noregen was denatured and purified by denaturing size exclusion chromatography. The refolded protein demonstrated Norrin-like biological activity including binding to FZD4, activation of Norrin-induced gene expression changes in primary human microvascular endothelial cells, and the acceleration of vascular regrowth in a mouse OIR model. The protein was tested by intravitreal injection (rat) and was free of toxicity based on SD-OCT, fluorescein angiography, and full-field ERG. Protein prepared from 30-liter GMP units was also biologically active using the same refolding process.

Conclusions : In addition to the fundamental bench results, there is more we desire to communicate about the bench-to-bedside process. For vision scientists who want to shepherd a biological therapeutic from bench to bedside there are several key considerations. These include forming clinical collaborations and the small business partner's early development of a business plan to gain financial support from federal small business development programs and private funding. Also intellectual property and careful selection of milestones for feasibility within very the short project timelines for a Phase-1 STTR/SBIR. The Phase-2 SBIR mode is being utilized to continue preclinical testing.

Volume

64

Issue

8

First Page

746

Comments

Annual Meeting Association for Research in Vision and Ophthalmology, ARVO 2023, April 23-27, 2023, New Orleans, LA

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