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dc.contributor.authorKhwaja, O. S.
dc.contributor.authorHo, E.
dc.contributor.authorBarnes, K. V.
dc.contributor.authorO, H. M.
dc.contributor.authorPereira, Luis Marcelo
dc.contributor.authorFinkelstein, Y.
dc.contributor.authorNelson, Charles A.
dc.contributor.authorVogel-Farley, V.
dc.contributor.authorDeGregorio, G.
dc.contributor.authorHolm, Ingrid Adele
dc.contributor.authorKhatwa, Umakanth A.
dc.contributor.authorKapur, Kush
dc.contributor.authorAlexander, Mark Edward
dc.contributor.authorFinnegan, D. M.
dc.contributor.authorCantwell, N. G.
dc.contributor.authorWalco, A. C.
dc.contributor.authorRappaport, Leonard Allan
dc.contributor.authorGregas, M.
dc.contributor.authorFichorova, Raina Nakova
dc.contributor.authorShannon, M. W.
dc.contributor.authorSur, M.
dc.contributor.authorKaufmann, Walter E
dc.date.accessioned2014-12-17T19:50:30Z
dc.date.issued2014
dc.identifier.citationKhwaja, O. S., E. Ho, K. V. Barnes, H. M. O’Leary, L. M. Pereira, Y. Finkelstein, C. A. Nelson, et al. 2014. “Safety, Pharmacokinetics, and Preliminary Assessment of Efficacy of Mecasermin (recombinant Human IGF-1) for the Treatment of Rett Syndrome.” Proceedings of the National Academy of Sciences 111 (12) (March 12): 4596–4601. doi:10.1073/pnas.1311141111.en_US
dc.identifier.issn1662-5161en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13548951
dc.description.abstractRett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.en_US
dc.language.isoen_USen_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isversionofdoi:10.3389/fnhum.2013.00444en_US
dash.licenseLAA
dc.titleSafety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndromeen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dash.depositing.authorNelson, Charles A.
dc.date.available2014-12-17T19:50:30Z
dc.identifier.doi10.3389/fnhum.2013.00444*
dash.authorsorderedfalse
dash.contributor.affiliatedKhatwa, Umakanth
dash.contributor.affiliatedKapur, Kush
dash.contributor.affiliatedKaufmann, Walter E
dash.contributor.affiliatedAlexander, Mark
dash.contributor.affiliatedRappaport, Leonard
dash.contributor.affiliatedHolm, Ingrid
dash.contributor.affiliatedNelson, Charles
dash.contributor.affiliatedFichorova, Raina
dash.contributor.affiliatedPereira, Luis


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