[New perspectives on molecular and genic therapies in Down syndrome].
Trisomy 21 was first described as a syndrome in the middle of the nineteenth century and associated to a chromosomic anomaly one hundred years later: the most salient feature of this syndrome is a mental retardation of variable intensity. Molecular mapping and DNA sequencing have allowed identifying the gene content of chromosome 21. Molecular quantitative analyses indicated that trisomy is inducing an overexpression for a large part of the triplicated genes and deregulates also pathways involving non HSA21 genes. Together with the physiological description of murine models overexpressing orthologous genes, these data have allowed to elaborate hypotheses on the cause of cognitive impairment. From these hypotheses and using murine models it is now possible to assess the efficiency of various therapeutic strategies. This paper reviews these new perspectives starting from the strategies targeting the level of HSA21 RNAs or HSA21 proteins; then it describes methods targeting activities either of proteins involved in cell cycle pathways or of proteins controlling the synaptic plasticity. It is promising that strategies targeting specific genes or specific pathways are already giving positive results.
Delabar
Jean Maurice
JM
Unité de biologie fonctionnelle et adaptative (BFA), EAC CNRS 4413, Université Paris Diderot, Marie-Andrée Lagroua-Weill-Hallé, bâtiment Lamarck, 75205 Paris, France. delabar@univ-paris-diderot.fr
D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy / Q000628:therapy*; D015103:Droxidopa / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D005544:Forecasting; D005786:Gene Expression Regulation / Q000187:drug effects; D056726:Genetic Association Studies; D015316:Genetic Therapy; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D018377:Neurotransmitter Agents / Q000502:physiology; D010433:Pentylenetetrazole / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects
D053823:Hedgehog Proteins; D018377:Neurotransmitter Agents; D005473:Fluoxetine; D002392:Catechin; C045651:epigallocatechin gallate; D015103:Droxidopa; D008559:Memantine; D010433:Pentylenetetrazole