Fayçal Guedj1, Diana W Bianchi, Jean-Maurice Delabar. 1. aMother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, Massachusetts, USA bUniv Paris Diderot, Sorbonne Paris Cité, CNRS UMR 8251, Adaptive Functional Biology, Paris, France.
Abstract
PURPOSE OF REVIEW: Down syndrome affects more than 5 million people globally. During the last 10 years, there has been a dramatic increase in the research efforts focused on therapeutic interventions to improve learning and memory in Down syndrome. RECENT FINDINGS: This review summarizes the different functional abnormalities targeted by researchers in mouse models of Down syndrome. Three main strategies have been used: neural stem cell implantation; environmental enrichment and physical exercise; and pharmacotherapy. Pharmacological targets include the choline pathway, GABA and NMDA receptors, DYRK1A protein, oxidative stress and pathways involved in development and neurogenesis. Many strategies have improved learning and memory as well as electrophysiological and molecular alterations in affected animals. To date, eight molecules have been tested in human adult clinical trials. No studies have yet been performed on infants. However, compelling studies reveal that permanent brain alterations originate during fetal life in Down syndrome. Early prenatal diagnosis offers a 28 weeks window to positively impact brain development and improve postnatal cognitive outcome in affected individuals. Only a few approaches (Epigallocatechine gallate, NAP/SAL, fluoxetine, and apigenin) have been used to treat mice in utero; these showed therapeutic effects that persisted to adulthood. SUMMARY: In this article, we discuss the challenges, recent progress, and lessons learned that pave the way for new therapeutic approaches in Down syndrome.
PURPOSE OF REVIEW: Down syndrome affects more than 5 million people globally. During the last 10 years, there has been a dramatic increase in the research efforts focused on therapeutic interventions to improve learning and memory in Down syndrome. RECENT FINDINGS: This review summarizes the different functional abnormalities targeted by researchers in mouse models of Down syndrome. Three main strategies have been used: neural stem cell implantation; environmental enrichment and physical exercise; and pharmacotherapy. Pharmacological targets include the choline pathway, GABA and NMDA receptors, DYRK1A protein, oxidative stress and pathways involved in development and neurogenesis. Many strategies have improved learning and memory as well as electrophysiological and molecular alterations in affected animals. To date, eight molecules have been tested in human adult clinical trials. No studies have yet been performed on infants. However, compelling studies reveal that permanent brain alterations originate during fetal life in Down syndrome. Early prenatal diagnosis offers a 28 weeks window to positively impact brain development and improve postnatal cognitive outcome in affected individuals. Only a few approaches (Epigallocatechine gallate, NAP/SAL, fluoxetine, and apigenin) have been used to treat mice in utero; these showed therapeutic effects that persisted to adulthood. SUMMARY: In this article, we discuss the challenges, recent progress, and lessons learned that pave the way for new therapeutic approaches in Down syndrome.
Authors: Faycal Guedj; Jeroen L A Pennings; Millie A Ferres; Leah C Graham; Heather C Wick; Klaus A Miczek; Donna K Slonim; Diana W Bianchi Journal: Am J Med Genet A Date: 2015-05-14 Impact factor: 2.802
Authors: Steven U Walkley; Leonard Abbeduto; Mark L Batshaw; Anita Bhattacharyya; Susan Y Bookheimer; Bradley T Christian; John N Constantino; Jean de Vellis; Daniel A Doherty; David L Nelson; Joseph Piven; Annapurna Poduri; Scott L Pomeroy; Rodney C Samaco; Huda Y Zoghbi; Michael J Guralnick Journal: Ann Neurol Date: 2019-07-27 Impact factor: 10.422
Authors: Jianling Ji; Hane Lee; Bob Argiropoulos; Naghmeh Dorrani; John Mann; Julian A Martinez-Agosto; Natalia Gomez-Ospina; Natalie Gallant; Jonathan A Bernstein; Louanne Hudgins; Leah Slattery; Bertrand Isidor; Cédric Le Caignec; Albert David; Ewa Obersztyn; Barbara Wiśniowiecka-Kowalnik; Michelle Fox; Joshua L Deignan; Eric Vilain; Emily Hendricks; Margaret Horton Harr; Sarah E Noon; Jessi R Jackson; Alisha Wilkens; Ghayda Mirzaa; Noriko Salamon; Jeff Abramson; Elaine H Zackai; Ian Krantz; A Micheil Innes; Stanley F Nelson; Wayne W Grody; Fabiola Quintero-Rivera Journal: Eur J Hum Genet Date: 2015-05-06 Impact factor: 4.246