Elizabeth Berry-Kravis, MD, PhD, fragile X researcherClinical Trials Outcome Measures / Lithium Pilot Trial

FRAXA Awards:
$43,824 in 2011
$10,000 in 2009-2010
$34,000 in 2007
$35,000 in 2006
$15,000 in 2005
$48,000 in 2004
$48,000 in 2003
$48,000 in 2002

Objective outcome measures for clinical trials are essential for investigation of new treatments, and this is an area of great need in fragile X research. Dr. Berry-Kravis’ 2011 FRAXA project is to validate a new automated video tracking system for quantifying physical activity as an outcome measure for fragile X clinical trials.

Project: Markerless Motion Analysis System to Quantify Hyperkinesis as an Outcome Measure for Clinical Trials in Fragile X

The team conducting this project are Elizabeth Berry Kravis, MD, PhD; Markus Wimmer, PhD, Deborah A. Hall, MD, PhD and Joan A. O’Keefe, PT, PhD., at Rush University Medical Center

by Elizabeth Berry-Kravis, 4/11/2011

Excessive motor activity (hyperkinesis), including hyperactivity and repetitive movements, called stereotypies, is a core behavioral phenotype in both the fragile X mouse model and humans with fragile X syndrome (FXS), affecting 90% of boys with FXS and 35-50% of girls, and frequently requiring treatment intervention. These aberrant motor behaviors and hyperactivity interfere with functioning, including social interactions and learning. Given that motor hyperactivity is such a strong aspect of the FXS phenotype, a methodology to accurately quantify this would serve as an excellent outcome measure for clinical trials of new pharmacotherapy targeted to the underlying disorder. Indeed open field hyperactivity in the fragile X mouse model has been one of the few behavioral phenotypes in the mouse that has been shown to be abnormal in multiple laboratories and reversed by mGluR5 blockers.

There currently are no adequate quantitative systems designed to accurately measure hyperkinesis or repetitive movements in individuals with FXS. Current outcome tools used when investigating pharmaceutical effects on hyperkinesis consist of rating scales or checklists. The limitations with using these scales for clinical trials research include lack of objectivity, variation between raters, inability to detect small increments of change, lack of specificity to FXS symptoms and floor and/or ceiling effects within the spectrum of hyperkinetic behaviors seen in persons with FXS.

This study is a unique collaboration between investigators with expertise in FXS, movement disorders, neuroscience of gait and movement, and computer engineering and will evaluate the use of a novel markerless motion analysis system to quantify hyperkinesis in a small group of children, teenagers and young adults (ages 5-30) with FXS. The study will utilize a commercially available multiple camera-based 3-dimensional motion analysis system developed by Organic Motion (www.organicmotion.com), which won “The Wall Street Journal 2009 Technology Innovation Award for Computing Systems” to quantify hyperkinesis in FXS. Our motion analysis system is analogous to the open field hyperactivity measure used in the fragile X mouse and will allow us to design analyses to quantify the amount of hyperactive movement of all types (eg. both from walking around or from moving the hands and arms about) for an individual with FXS doing a standardized set of activities within the motion analysis space. The measure does not require the individual with FXS to wear anything, is not invasive, and does not put demands on the participant, and thus should be very easy for children and young adults with FXS to do. In this study we will pilot and develop the analyses for the motion analysis measure. These pilot data will be used to obtain further funding through NIH and/or industry, so that we can extend studies to more extensive validation and tests of pharmaceutical effects on the motion analysis measurements.

It is expected that this project will lead to development of the motion analysis system as a prototype to quantify hyperkinesis that would be included in a “toolkit” of validated outcome measures for use in proof-of-concept and early phase clinical trials of new medications targeting the underlying disorder in FXS. Given the findings using the analogous measure in the fragile X mouse, development of this outcome measure will assist with direct translation of research findings in the FXS animal model to clinical trials in humans with FXS.


Trial of Lithium in 15 individuals with Fragile X

by Elizabeth Berry-Kravis, 2/26/2011

Fifteen subjects with fragile X will be treated with lithium to get pilot data to justify a larger trial of lithium. The lithium treatment will be added on to other medications the individuals enrolled are already taking, and treatment will be for at least two months and up to a year if the lithium is helpful. Tests will be given at the beginning of the study, after two months of treatment, and after a year of treatment for those who are treated a full year. Side effects will be monitored closely to make sure that lithium is safe in the fragile X population. We will use a battery of behavioral and thinking tests which we are validating specifically for use in medication trials in fragile X. We will try new physiological tests to measure overstimulation and eye aversion, a special blood test that may serve as a biomarker for improvement in the cellular defect in fragile X, and some new tests of associative learning. These new tests, in combination with some of the tests that worked best in our previous Ampakine study, should allow us to know if lithium is improving some of the behaviors and learning deficits seen in fragile X syndrome. If the new tests are able to measure a medication response in this study, we can then use them for other future studies.

Results of the pilot trial:

https://www.researchgate.net/publication/23166017_Open-Label_Treatment_Trial_of_Lithium_to_Target_the_Underlying_Defect_in_Fragile_X_Syndrome

2014 Review:
Lithium: A Promising Treatment for Fragile X Syndrome

Zhonghua Liu and Carolyn Beebe Smith*
National Institute of Mental Health
ACS Chem. Neurosci.

http://pubs.acs.org/doi/abs/10.1021/cn500077p