Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease

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dc.creatorSumien, Nathalie
dc.creatorWells, Matthew S.
dc.creatorSidhu, Akram
dc.creatorWong, Jessica M.
dc.creatorForster, Michael J.
dc.creatorZheng, Qiao-Xi
dc.creatorKelleher-Andersson, Judith A.
dc.creator.orcid0000-0002-0077-9873 (Sumien, Nathalie)
dc.date.accessioned2022-07-11T15:29:26Z
dc.date.available2022-07-11T15:29:26Z
dc.date.issued2021-01-13
dc.description.abstractAging is known to slow the neurogenic capacity of the hippocampus, one of only two mammalian adult neurogenic niches. The reduction of adult-born neurons with age may initiate cognitive decline progression which is exacerbated in chronic neurodegenerative disorders, e.g., Alzheimer's disease (AD). With physiologic neurogenesis diminished, but still viable in aging, non-invasive therapeutic modulation of this neuron regeneration process remains possible. The discovery of truly novel neuron regenerative therapies could be identified through phenotypic screening of small molecules that promote adult-born neurons from human neural progenitor cells (hNPCs). By identifying neuron-generating therapeutics and potentially novel mechanism of actions, therapeutic benefit could be confirmed through in vivo proof-of-concept studies. The key aging and longevity mTOR/p70S6 kinase axis, a commonly targeted pathway, is substrate for potential selective kinase modulators to promote new hippocampal neurons from NPCs. The highly regulated downstream substrate of mTOR, p70S6 kinase, directly controls pleiotropic cellular activities, including translation and cell growth. Stimulating this kinase, selectively in an adult neurogenic niche, should promote NPC proliferation, and cell growth and survival in the hippocampus. Studies of kinase profiling and immunocytochemistry of human progenitor neurogenesis suggest that the novel small molecule NNI-362 stimulates p70S6 kinase phosphorylation, which, in turn, promotes proliferation and differentiation of NPCs to neurons. NNI-362 promoted the associative reversal of age- and disease-related cognitive deficits in aged mice and Down syndrome-modeled mice. This oral, allosteric modulator may ultimately be beneficial for age-related neurodegenerative disorders involving hippocampal-dependent cognitive impairment, specifically AD, by promoting endogenous hippocampal regeneration.
dc.description.sponsorshipThis work was supported by Neuronascent, Inc., and the National Institutes of Health [2P01 AG022550 (PI-NS)]. NIA has supported the development of NNI-362 through a translational safety program (Dr. Petanceska-directed program) and through the IND/phase 1a clinical trial (R01 AG056561, PI-JAK). NNI-362 is presently in phase 1a clinical trial for Alzheimer's disease NCT04074837.
dc.identifier.citationSumien, N., Wells, M. S., Sidhu, A., Wong, J. M., Forster, M. J., Zheng, Q. X., & Kelleher-Andersson, J. A. (2021). Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease. Stem cell research & therapy, 12(1), 59. https://doi.org/10.1186/s13287-020-02126-3
dc.identifier.issn1757-6512
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31559
dc.identifier.volume12
dc.publisherBioMed Central Ltd.
dc.relation.urihttps://doi.org/10.1186/s13287-020-02126-3
dc.rights.holder© The Author(s). 2021
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceStem Cell Research & Therapy
dc.subjectallosteric modulator
dc.subjectAlzheimer's disease
dc.subjectBrdU+ neuron survival
dc.subjecthippocampal neuron regeneration
dc.subjecthuman neural progenitors
dc.subjectmTOR/p70S6 kinase axis
dc.subject.meshAging
dc.subject.meshAlzheimer Disease / drug therapy
dc.subject.meshAnimals
dc.subject.meshCognition
dc.subject.meshHippocampus
dc.subject.meshMice
dc.subject.meshMice, Transgenic
dc.subject.meshNeurogenesis
dc.subject.meshRibosomal Protein S6 Kinases, 70-kDa
dc.titleNovel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease
dc.typeArticle
dc.type.materialtext

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