A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome.

Alexander Kolevzon,William Chaplin,Robert Rapaport,Joseph D Buxbaum,Yitzchak Frank,David Grodberg,Lauren Bush,Danielle Halpern,A Wang,Latha Soorya,Teresa Tavassoli

doi:10.1186/2040-2392-5-54

Abstract

BackgroundAutism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.MethodsNine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.ResultsCompared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.ConclusionsThis study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.

Highlights

Autism spectrum disorder (ASD) is understood to have multiple genetic risk genes and one example is SHANK3
Autism spectrum disorder (ASD) is currently a diagnosis established by behavioral criteria but its etiology resides in complex genetics, and many distinct genetic risk genes have been identified as causal
insulin-like growth factor-1 (IGF-1) is effective in reversing phenotypic changes in human neuronal models of Rett syndrome [22], providing additional evidence that this pathway may be a target in diverse forms of ASD

Summary

Introduction

Autism spectrum disorder (ASD) is understood to have multiple genetic risk genes and one example is SHANK3. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. Autism spectrum disorder (ASD) is currently a diagnosis established by behavioral criteria but its etiology resides in complex genetics, and many distinct genetic risk genes have been identified as causal One such example is the SHANK3 gene located on the terminal end of chromosome 22q where loss of one copy (haploinsufficiency) of SHANK3 causes a monogenic form of ASD with a because different genetic causes of ASD converge on several common pathways, including SHANK3 [18,19]. IGF-1 is effective in reversing phenotypic changes in human neuronal models of Rett syndrome [22], providing additional evidence that this pathway may be a target in diverse forms of ASD. Recent evidence provides preliminary support of efficacy with IGF-1 in children with Rett syndrome [23]

Objectives

Methods

Results

Discussion

Conclusion