ADV127-FXS for Fragile X Syndrome:

  • First-in-class Sigma1 agonist
  • High Potency​
  • Higher Selectivity​
  • Unambiguous activity
  • Oral monotherapy
  • Pharmaceutical profile​
  • Low potential for clinical drug-drug interactions

Mechanism of Action on Fragile X Syndrome

Candidate ADV127 has been designed to exert a disease-modifying effect in fragile X syndrome (FXS), a synaptic disorder with characteristic deficits in long-term potentiation and neuronal homeostatic plasticity, as well as increases in long-term depression due to an excessive group I metabotropic glutamate (mGlu) receptor activity, and caused by atypical gene methylation and transcriptional silencing with subsequent reduced synthesis of fragile X mental retardation protein (FMRP). Mitochondrial dysfunction has also recently been associated with FXS, with reports of increased markers of oxidative stress, reactive oxygen species and lipid peroxidation present in brain tissue.
FMRP deficiency is linked to multiple cell signaling abnormalities, including the adenylate cyclase/ protein kinase A (PKA), phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and glycogen synthase kinase 3 beta (GSK-3β) pathways, and to FMRP interacting regulatory complexes such as Ras-related C3 botulinum toxin substrate 1 (Rac1)-Wave which ultimately result in gene dysregulation and synaptic abnormalities. A key pathway affected in FXS and to which brain-derived neurotrophic factor (BDNF) signaling converges bidirectionally.
Activation of Sigma-1 receptor by ADV127 restores BDNF levels in the hippocampus, compensating multiple signaling and synaptic disorders, and other regulatory pathways, and restores mitochondrial dysfunction affected by FMRP deficiency.
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FXS signaling pathways
Schematic representation of PI3K/Akt/mTOR, ERK1/2-MAPK, and Wnt/β-catenin pathways. (a) PI3K/Akt/mTOR signaling pathway key elements for oligodendrocyte maturation and myelination. Arrowheads imply positive interactions while bars indicate inhibitory signals. BDNF: brain-derived neurotrophic factor, NGF: nerve growth factor, NT3: neurotrophin 3, (s)Nrg1-III: (soluble) Neuregulin 1 type III, BACE1: β-site amyloid precursor protein cleaving enzyme 1, RTKs: receptors tyrosine kinase, IRS-1: insulin receptor substrate 1, PI3K: phosphoinositide-3 kinase, PIP2: phosphatidylinositol (4,5)-biphosphate, PIP3: phosphatidylinositol (3,4,5)-triphosphate, PTEN: phosphatase and tensin homolog, PDK-1: 3-phosphoinositide-dependent protein kinase 1, Akt: protein kinase B, TSC1/2: tuberous sclerosis complex, Rheb: Ras homolog enriched in brain, mTOR: mammalian target of rapamycin, mLST8: target of rapamycin complex subunit LST8, Raptor: regulatory associated protein of mTOR, Rictor: rapamycin-insensitive companion of mTOR, SIN1: Target of rapamycin complex 2 subunit MAPKAP1, p70S6K: Ribosomal protein S6 kinase beta-1, S6RP: Ribosomal protein S6, SREBPs: Sterol regulatory element-binding proteins. (b) ERK1/2-MAPK signaling pathway crucial elements for oligodendrocyte maturation and myelination. Alcover-Sanchez, Berta & Garcia-Martin, Gonzalo & Wandosell, Francisco & Cubelos, Beatriz. (2020). R-Ras GTPases Signaling Role in Myelin Neurodegenerative Diseases. International Journal of Molecular Sciences. 21. 5911. 10.3390/ijms21165911.

In-vivo preclinical validation in progress.

  • Genetic mouse model of Fragile X syndrome​ (Fmr1)
    V-Maze: ADV127 reverses cognitive impairment in object recognition
    ADV127 FXS V-Maze