Initial Trials of Translational Medicine in Rett Syndrome

Background: Rett syndrome (RTT) is a neurodevelopmental disorder characterized by severe autistic behavior (autism spectrum disorder, ASD) during its regression period. It is linked to mutations of the transcriptional regulator MECP2, which has led to the development of mouse models of Mecp2 deficit that have increased our understanding of the neurobiology of RTT. During the last decade, multiple strategies for correcting the consequences of Mecp2 deficiency have been tested. Particularly promising have been growth factors that modulate synaptic plasticity, such as BDNF and IGF-1. The latter has the advantage of good central nervous system penetration when administered systemically and is clinically available as a treatment for growth deficiency.

Objectives: To determine the safety and tolerability of IGF-1 for the treatment of core manifestations of RTT through early phase clinical trials. Both trials were based on mouse model data showing that IGF-1 can reverse many RTT-relevant phenotypical features. 

Methods: A phase I trial involving 12 girls with MECP2 mutations, most of them with RTT, tested safety, tolerability, and potential efficacy (covering multiple neurobehavioral manifestations) of IGF-1. Encouraging results from the phase I study have led to an ongoing randomized, controlled, cross-over phase II trial including 30 girls with RTT, after the regression stage. The design, based on significant and trend-level improvements observed during a 20-week open label period, includes anxiety symptoms as the primary endpoint and a wide range of secondary and exploratory outcome measures. This trial is expected to be completed by early 2016.

Results: The phase I trial demonstrated that IGF-1 was safe and well tolerated in girls with RTT. It also showed that IGF-1 reached the CNS compartment and distributed following non-linear kinetics. As mentioned above, preliminary analyses of efficacy, including both clinical and automated biomarker-type outcome measures, demonstrated that IGF-1 improved anxiety and social avoidance behaviors as well as breath-holding. Consequently, the phase II trial measures breathing abnormalities using pletysmography, as in phase I. Multiple biomarkers are tested as exploratory outcome measures in the ongoing trial; among them are right frontal alpha band asymmetry on EEG, an index of anxiety and depression that correlated with behavioral ratings in phase I, and other electrophysiological and psychobiological measures.

Conclusions: We have entered a new era of targeted treatments in RTT, which target fundamental neurobiological processes disrupted as a consequence of Mecp2 deficit. Initial findings suggest that some but not all major symptoms could be improved. Because IGF-1 and other drugs under examination target major synaptic processes, underlying most genetic forms of ASD, there is hope that these treatments will be efficacious beyond RTT. An example of this are ongoing trials with a shorter (tripeptide) form of IGF-1 (vs. the full-length form we used in our studies) in RTT and fragile X syndrome. While this is an exciting time in ASD therapeutics, we should be cautious since the work in RTT and other monogenic causes of ASD focuses on mechanisms present in all affected individuals, not only in those with severe autistic behavior.