A Phase 2b placebo-controlled cross-over study of rh-IGF1 for treatment of Rett syndrome and development of Rett-specific novel biomarkers of cortical and autonomic function

We propose to evaluate the efficacy of IGF1 in reversing the autonomic and neuro-developmental features of RTT. In a randomized two-arm, double-blind, placebo-controlled cross-over clinical trial 30 patients with RTT, based on established clinical criteria and with known MECP2 mutations, will be enrolled. Subjects will be randomized to receive either IGF1 twice daily by subcutaneous injection for 5 months or subcutaneous saline. At the end of the first phase, and after a 6-week washout period, the initial treatment group will receive saline while the initial control group receives IGF1. The crossover design ensures all study patients will have access to the trial medication and allows for a secondary analysis of changes in the “off-treatment” group. Main outcome measures will be improvement in cardiorespiratory dysregulation and neurodevelopment. Cardiorespiratory dysregulation will be measured using the novel biomarker of autonomic/respiratory index as measured by non-invasive standardized respiratory inductance plethysmography. Neurodevelopment will be assessed using validated survey instruments: Clinical Global Impression Scale, Aberrant Behavior Checklist, Vineland Adaptive Behavior Scale, Rett Syndrome Behavioral Questionnaire, and the Motor-Behavioral Assessment for Rett Syndrome. Safety measures monitored during this trial will include alterations in growth velocity and glucose homeostasis. We hypothesize that subjects with RTT will have sustained improvements in cardiorespiratory regulation and neuro-developmental function during treatment with IGF1. This pilot study will provide critical data needed for a broader study of IGF1 treatment in children with MECP2-associated autism spectrum disorder (ASD). We expect that pharmacological therapy for RTT, that acts to stimulate synaptic maturation, will serve as a model for pharmacological treatment for other disorders. We are further assessing RNA expression and small molecule profiles prior to and during treatment with IGF1. We are developing novel quantitative markers of cortical function as well as collaborating to create new lines of induced pluripotential stem cells from patients with the most common MECP2 mutations with the prospect of creating rapid high throughput screening assays. We are further planning DNA studies to detect variants that may be up or downstream targets for MECP2 that act as modifiers.