NIH grant: Harnessing endogenous neural progenitor cells with a natural product-derived Notchsignaling inhibitor for CNS repair in multiple sclerosis (1R01NS153446-01)

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NIH grant 1R01NS153446-01: Harnessing endogenous neural progenitor cells with a natural product-derived Notchsignaling inhibitor for CNS repair in multiple sclerosis
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Makoto  Inoue. Award: $407211.
Start: 2026-08-21T00:00:00.
Natural products and their synthetic mimetics account for 46% of recently discovered drugs, highlighting their
immense potential in therapeutic development. Our research has successfully identified a Notch1 signaling
inhibitor, (+)-3d-spiro-oxindole, a synthetic mimetics of natural products. Notch1 signaling is known to inhibit
neural progenitor/stem cell (NPC) differentiation while exacerbating inflammation. Multiple sclerosis (MS) is a
chronic autoimmune, neurodegenerative, and demyelinating disease of the central nervous system (CNS).
Notably, endogenous NPC upregulation has been observed in CNS lesions of MS patients and experimental
autoimmune encephalomyelitis (EAE), a preclinical MS model. We hypothesize that our natural product-derived
compounds can effectively harness this endogenous NPC response, promoting their differentiation into neurons
and oligodendrocytes while suppressing neuroinflammation, thereby serving as promising MS therapeutics.
Preliminary studies demonstrated the potent neurogenic capabilities of (+)-3d-spirooxindole in vitro and in vivo.
Specifically, (+)-3d-spirooxindole markedly improved motor dysfunction, enhanced motor neuron regeneration,
promoted remyelination, and reduced neuroinflammation in the spinal cord of EAE mice. The objective of this
proposed project is to elucidate the mechanisms by which these compounds drive NPC differentiation into
neurons and oligodendrocytes, both in vitro and in vivo, and to evaluate their therapeutic potential using multiple
MS mouse models. This objective will be addressed through three specific aims: (1) Determine the
mechanisms of neurogenesis and oligodendrogenesis induced by (+)-3d-spirooxindol by targeting its
binding partner, CYB5R3, and assess its effects on human NPCs. (2) Define the neurogenic and
oligodendrogenic potential of (+)-3d-spirooxindole in MS models by characterizing NPC fate, spatial
distribution, timing, and functional integration using fluorescence-tagged lineage-tracing transgenic mice in EAE
and cuprizone models. (3) Validate the therapeutic potential of systemic (+)-3d-spirooxindole
administration, focusing on its ability to repair CNS damage, improve disease outcomes, achieve high CNS
penetration, and minimize adverse effects. This research is both significant and innovative because it targets
endogenous NPCs to address core pathological features of MS, including severe motor dysfunction, neuronal
loss, demyelination, and neuroinflammation. By moving beyond traditional immune modulation, this approach
directly promotes CNS repair and suppress CNS neuroinflammation, meeting an urgent need in MS therapeutics.
The immediate outcome of this project will be a deeper mechanistic understanding of how harnessing
endogenous NPCs mitigates MS pathology, laying the groundwork for the development of transformative
therapies for MS and other neurodegenerative diseases.

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