Preclinical research in Rett syndrome: setting the foundation for translational success

Author:

Katz David M.1,Berger-Sweeney Joanne E.2,Eubanks James H.3,Justice Monica J.4,Neul Jeffrey L.45,Pozzo-Miller Lucas6,Blue Mary E.7,Christian Diana1,Crawley Jacqueline N.8,Giustetto Maurizio9,Guy Jacky10,Howell C. James1,Kron Miriam1,Nelson Sacha B.11,Samaco Rodney C.5,Schaevitz Laura R.2,St. Hillaire-Clarke Coryse12,Young Juan L.13,Zoghbi Huda Y.514,Mamounas Laura A.12

Affiliation:

1. Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44120, USA

2. Department of Biology, Tufts University, 165 Packard Avenue, Medford, MA 02155, USA

3. Toronto Western Research Institute, 399 Bathurst Street, Mac 11-408, Toronto, ON M5T 2S8, Canada

4. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS227, R804, Houston, TX 77030, USA

5. Departments of Pediatrics, Neurology, and Neuroscience, Baylor College of Medicine, and Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, 1250 Moursund Street, Houston, TX 77030, USA

6. Department of Neurobiology, The University of Alabama at Birmingham, 1825 University Boulevard, SHEL-1002, Birmingham, AL 35294, USA

7. Hugo W. Moser Research Institute at Kennedy Krieger, 707 North Broadway, Room 400R, Baltimore, MD 21209, USA

8. Department of Psychiatry and Behavioral Sciences, UC Davis, 2825 50th Street, Sacramento, CA 95817, USA

9. Department of Neuroscience and National Institute of Neuroscience-Italy, University of Torino, Corso M. D’Azeglio 52, Torino 10126, Italy

10. University of Edinburgh, Michael Swann Building, Mayfield Road, Edinburgh, EH9 3JR, UK

11. Shapiro Science Center, Room 1-15, Brandeis University, 415 South Street, Waltham, MA 02454, USA

12. National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Boulevard, Bethesda, MD 20892, USA

13. Hussman Institute for Human Genomics, 1501 Northwest 10th Avenue, BRB-524 (M-860), Miami, FL 33136, USA

14. Howard Hughes Medical Institute, Houston, TX 77030, USA

Abstract

In September of 2011, 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) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was 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. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotypes of RTT mouse models to date, and areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies; (2) discussion of the impact of genetic differences among mouse models, and methodological differences among laboratories, on the expression and analysis, respectively, of phenotypic traits; and (3) definitions of the standards that the community of RTT researchers can implement for rigorous preclinical study design and transparent reporting to ensure that decisions to initiate costly clinical trials are grounded in reliable preclinical data.

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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