NEDD8 pathway targeting to reduce neuroinflammation in parkinson's disease
A therapeutic approach using phosphorodiamidate morpholino oligonucleotides (PMOs) to selectively target the NEDD8 pathway, reducing CD8+ T cell-mediated neuroinflammation in Parkinson's disease while preserving NEDD8-driven autophagy and proteostasis. Validated in vitro with planned canine clinical studies.
Overview
This research addresses neuroinflammation in Parkinson's disease by targeting the NEDD8 pathway, a ubiquitin-like modification system that becomes dysregulated during periods of oxidative and proteotoxic stress. The approach uses phosphorodiamidate morpholino oligonucleotides (PMOs) to selectively inhibit NEDD8-mediated MHC class I antigen presentation, which drives cytotoxic T cell infiltration in the brain. By preserving NEDD8-driven autophagy while reducing inflammatory antigen presentation, the strategy aims to ameliorate neuroinflammation without disrupting essential cellular proteostasis functions.
Technical specifications
Key features:
- PMO-based antisense oligonucleotides targeting NEDP1 (deneddylase), NUB1L, and NEDD8
- Peptide-conjugated PMOs (PPMOs) designed to cross the blood brain barrier
- Tunable biological activity through peptide conjugation for controlled therapeutic windows
- Selective targeting of NEDD8-mediated MHC class I antigen presentation pathways
- Preservation of NEDD8-driven autophagy and proteasomal degradation functions
- Built on previously validated NUB1-dependent NEDD8-driven MHC class I presentation findings
Research approach:
- In vitro validation using HEK293 cells expressing alpha-synuclein-GFP fusion constructs
- Confocal microscopy and Western blot analysis of protein aggregates
- PMO knockdown validation via Western blot
- Canine clinical trials at the Carlson College of Veterinary Medicine for dosing, disease staging, and efficacy assessment
- Estimated two-year timeline including initial efficacy and safety studies
Technology readiness level
The research is at an early-to-mid stage of preclinical development. PMOs against various targets have been generated and tested in vitro in collaboration with specialized partners. Key prior validations include published work on NUB1-dependent NEDD8-driven MHC class I presentation and unpublished data showing decreased effector T cell response following NUB1 knockdown. The next phase involves in vitro optimization of PMO-mediated knockdown effects on alpha-synuclein aggregates, followed by canine clinical trials to evaluate therapeutic potential for Parkinson's disease treatment.
About Oregon State University
Oregon State University is a comprehensive public research university and Oregon’s land‑grant institution, with a main campus in Corvallis and a statewide footprint. Industry partners tap a statewide Extension network and county offices to pilot and scale solutions with communities and companies across Oregon. A coastal marine science campus in Newport anchors ocean research and provides access to open‑ocean wave‑energy test ranges and grid‑connected infrastructure under development nearby, enabling sea‑to‑shore prototyping. Field stations and university‑managed research forests support long‑term trials and product validation in real‑world environments. A dedicated technology transfer office and the OSU Advantage programs—including the Advantage Accelerator—streamline IP, licensing, startup formation, and industry agreements.
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