Setting Standards for Preclinical Research in Rett Syndrome

In September of 2011, a workshop focused on the state of the art in animal studies of Rett syndrome (RTT) was convened by the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT). A broad cross-section of basic scientists, clinicians, and representatives from the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the pharmaceutical industry and private foundations attended the workshop in order to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. On October 31, the outcomes of this workshop, as well as extensive subsequent discussions among the participants, were published as an Open Access review article in Disease Models & Mechanisms (DMM). Several workshop participants contributed to the article, and the corresponding authors are Dr. David Katz (Case Western Reserve University School of Medicine), Dr. Laura Mamounas (National Institute of Neurological Diseases and Stroke) and Dr. Huda Zoghbi (Baylor College of Medicine).

In line with the aims of the workshop, the article comprehensively summarizes the phenotypes of currently available mouse models of RTT, and identifies areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies. The discussion highlights the impact of genetic differences among the models, and methodological differences among laboratories on the expression and analysis of phenotypic traits. Importantly, the authors end with a set of recommended guidelines that the RTT research community can implement for rigorous preclinical study design and transparent reporting. It is hoped that the authors’ recommendations will help to optimize the ability of the RTT research community to translate basic findings into new therapeutic approaches.

It is imperative that we as a community take the complexity of RTT pathophysiology into account in the design of preclinical studies. In particular, loss of MeCP2 function can have both direct effects on neuronal function and development, as well as indirect and cumulative effects on long-term neuronal maturation, leading to various distinct phenotypic consequences: thus, a combination of treatment strategies might be required. It will also be important to determine which features of RTT might be reversible with pharmacologic treatment alone (and at what developmental age) and which might require more complex interventions (e.g., pharmacotherapy combined with behavioral, cognitive and/or speech therapies). A better understanding of this complexity is essential to selecting therapeutic endpoints and to developing strategies that achieve them.

As new compounds approach testing, it is increasingly important that the recommendations made by the participants of the September 2011 workshop are incorporated into the design of preclinical studies involving mouse models of RTT. Given the high financial costs and expectations of clinical trials, it is essential that the RTT research community rigorously validates models, outcome measures and study designs to generate robust and reproducible preclinical findings with clear relevance to the human disease. Funding agencies recognize the added demands that such rigor places on investigators – especially in requesting independent replication of promising therapeutic leads before moving forward – but are willing to support such research, with the ultimate goal of shortening the time to effective treatments.