title: NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome.
abstract: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients.
authors.affiliation: Neuro-DVI LLP, London, UK.
authors.forename: Robert M J
authors.initials: RM
authors.lastname: Deacon
authors.forename: Larry
authors.initials: L
authors.lastname: Glass
authors.forename: Mike
authors.initials: M
authors.lastname: Snape
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hurley
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Altimiras
authors.forename: Rodolfo R
authors.initials: RR
authors.lastname: Biekofsky
authors.forename: Patricia
authors.initials: P
authors.lastname: Cogram
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D001007:Anxiety / Q000188:drug therapy; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D003214:Conditioning, Classical / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D004353:Drug Evaluation, Preclinical; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D007398:Interpersonal Relations; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009425:Nesting Behavior / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013737:Testis / Q000002:abnormalities; D005971:Glutamates
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D007334:Insulin-Like Growth Factor I; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009842:Oligopeptides; D051057:Proto-Oncogene Proteins c-akt; D005971:Glutamates; C514862:Akt1 protein, mouse; C497684:Fmr1 protein, mouse; C000656362:trofinetide