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Edited* by Michael Merzenich, Brain Plasticity Institute, San Francisco, CA, and approved February 13, 2014 (received for review June 24, 2013)
Significance
This paper provides unique insights into mechanism-based therapeutics for Rett syndrome (RTT), a devastating neurodevelopmental disorder. This clinical trial was based on pioneer preclinical work from the laboratory of M.S. Outcome measures include clinical instruments, standardized behavioral measures, and biomarkers, the latter being not only objective but also applicable to experimental studies. We believe this work will a have major impact on the understanding and treatment of RTT, as well as other neurodevelopmental disorders.
Abstract
Rett 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.
Footnotes
↵1O.S.K. and E.H. contributed equally to this work.
↵2Deceased March 10, 2009.
- ↵3To whom correspondence should be addressed. E-mail: walter.kaufmann{at}childrens.harvard.edu.
Author contributions: O.S.K., C.A.N., M.W.S., M.S., and W.E.K. designed research; O.S.K., E.H., K.V.B., H.M.O., V.V.-F., G.D., I.A.H., M.E.A., D.M.F., N.G.C., A.C.W., L.R., R.N.F., and W.E.K. performed research; R.N.F. contributed new reagents/analytic tools; K.V.B., H.M.O., L.M.P., Y.F., C.A.N., U.K., K.K., N.G.C., A.C.W., M.G., R.N.F., and W.E.K. analyzed data; and W.E.K. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1311141111/-/DCSupplemental.
Treatment of Rett syndrome with rhIGF1
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