# Targeting SNO-GAPDH in inflammatory neurodegeneration and mitochondrial injury > **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2024 · $200,560 ## Abstract PROJECT SUMMARY/ABSTRACT Although multiple sclerosis (MS) is classically considered a demyelinating disease, neuro-axonal loss occurs in both relapsing and progressive phases of the disease and represents the primary pathologic correlate of disa- bility. Existing therapies primarily target the peripheral immune system, preventing clinical relapses but largely failing to prevent neurodegeneration in progressive MS. Therapies with a primary neuroprotective mode of ac- tion are a major goal of current research, both to slow disability in progressive MS and to limit injury when re- lapses occur despite current therapies. Nitric oxide (NO), a toxic free radical produced by central nervous sys- tem (CNS) macrophages and microglia, contributes to neuro-axonal injury in both relapsing and progressive MS and in models of neuroinflammation, with NO-induced mitochondrial dysfunction playing a major role. Spe- cific, druggable signaling pathways that mediate this injury have not been identified. We propose to study a candidate signaling pathway involving nitrosylation of the protein GAPDH. Nitrosylated GAPDH (SNO-GAPDH) translocates to both nucleus and mitochondria, with an established role in cell death and nuclear targets, such as SIRT1 and PGC-1α, critical for mitochondrial bioenergetics. Moreover, SNO-GAPDH signaling can be blocked by CGP3466, a highly specific, oral CNS-penetrant drug with an established safety profile in humans and a low threshold for clinical translation. We have preliminary evidence that SNO-GAPDH signaling is active in an experimental autoimmune encephalomyelitis (EAE) mouse model of neuroinflammation, and in white matter tissue obtained post-mortem from MS patients. We have found that systemic administration of CGP3466 attenuates neurologic disability in C57BL/6 MOG35-55/CFA EAE and prevents impairment of neuronal mitochondrial respiration in cultured neurons exposed to NO. In the proposed studies, we plan to fully charac- terize SNO-GAPDH pathway activity in MOG35-55/CFA EAE and post-mortem human MS tissue. We will deter- mine whether the protective effects of CGP3466 in EAE derive from a primary neuroprotective mechanism in- dependent of peripheral immune effects, differentiating it from current therapies and establishing its pre-clinical potential. Finally, we will seek mechanistic insights by evaluating the effects of SNO-GAPDH on neuronal mito- chondrial function. Positive results from this mechanistic and pre-clinical therapeutic research will establish a new therapeutic approach for MS and neuroinflammatory disease more broadly. The PI's career development plan will provide new training opportunities in immunology, models of neuroinflammation, and mitochondrial bioenergetics, providing a foundation for future independent studies of inflammatory neurodegeneration. ## Key facts - **NIH application ID:** 10755646 - **Project number:** 5K08NS104266-05 - **Recipient organization:** JOHNS HOPKINS UNIVERSITY - **Principal Investigator:** Michael D Kornberg - **Activity code:** K08 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $200,560 - **Award type:** 5 - **Project period:** 2019-12-01 → 2024-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10755646 ## Citation > US National Institutes of Health, RePORTER application 10755646, Targeting SNO-GAPDH in inflammatory neurodegeneration and mitochondrial injury (5K08NS104266-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755646. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*