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NIH grant 1R61NS146354-01A1: Preclinical development of a prenyltransferase inhibitor to treat inflammatory neuropathy
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Kelly A Langert. Award: $342420.
Start: 2026-08-21T00:00:00.
Inflammatory neuropathies are one of the largest and least understood spectrums of neurologic disorders.
Among them is the acute inflammatory demyelinating polyneuropathy (AIDP) variant of Guillain-Barré syndrome,
a disabling autoimmune disease that affects the peripheral nerves. Despite representing a major socioeconomic
strain, treatment options available for patients suffering from AIDP remain palliative, non-specific, and ineffective.
Statin treatment therapeutically attenuates the experimental autoimmune neuritis (EAN) rat model of AIDP by
limiting immune cell trafficking into nerves. While statins’ widely observed beneficial pleiotropic effects support
this finding, their association with muscle toxicity and potential to disrupt cholesterol homeostasis in nerve myelin
preclude further clinical translation. We seek to identify alternatives to statins that may achieve similar anti-
inflammatory effects. Our in vitro data suggest that statins attenuate GTPase-dependent release of inflammatory
chemokines from blood nerve barrier (BNB) endothelial cells. This effect is mimicked by protein prenyltransferase
inhibitors. Co-I on this application, Dr. Sebti, has developed dozens of prenyltransferase inhibitors, including
most recently FGTI-2734. Preliminary data from our lab and others demonstrate that FGTI-2734 exerts anti-
inflammatory effects by several different mechanisms. This R61/R33 IGNITE application will investigate the
potential of FGTI-2734 as a novel therapeutic in the EAN model of AIDP. The R61 phase will 1) assess dose-
dependent effects on chemokine release from rat BNB endothelial cells and human endothelial cells, 2)
investigate acute PK, PD, and toxicity in naïve rats and rats at EAN peak and 3) assess clinical protection,
chronic PK, PD, and toxicity in rats with EAN. The R33 phase will 1) evaluate clinical and functional improvement
and 2) assess nerve myelination and immune cell infiltration in EAN rats receiving a therapeutic course of FGTI-
2734 or vehicle. The overall goal of this milestone-driven IGNITE proposal is to develop FGTI-2734 as a therapy
for AIDP.document fetched 2026-08-30 02:46