Elizabeth Berry-Kravis, MD, PhD—Rush University Medical College
Clinical Trials in Fragile X Syndrome

Elizabeth Berry-Kravis, MD, PhD, Principal Investigator

FRAXA Awards:

$43,824 in 2011
$5,000 in 2010
$5,000 in 2009
$19,000 in 2007
$15,000 in 2007
$35,000 in 2006
$15,000 in 2006
$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.
Development of a Markerless Motion Analysis System to Quantify Hyperkinesis as an Outcome Measure for Clinical Trials in Fragile X Syndrome

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., all 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 (see below), 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
Aidan Silverton Student Fellowship, 2009

Dr. Berry-Kravis will direct The Aidan Silverton Student Fellowship at Rush each summer for four years. This research fund, established by Aidan's uncle, Dr. Craig Silverton, will support student-conducted research directly relevant to development of treatments for Fragile X.

by Elizabeth Berry-Kravis, 5/1/2010

The 2009 Aidan Silverton Student Fellowship was used for funding for several students to work on projects involving development of outcome measures and biomarkers to evaluate response in clinical trials of new medications targeted at underlying brain mechanisms in fragile X syndrome. Potential biomarkers studied in blood included amount and activity of mGluR5 receptors on T-lymphocytes obtained from patients with fragile X syndrome and controls, which proved very difficult due to low expression of these receptors in T cells. In order to study additional cell types from patients with fragile X syndrome, a collection of fibroblast (skin cell) cultures from different individuals with fragile X syndrome of varied levels of function, was also initiated as part of the summer projects. It was felt that this collection of cells might be used to identify molecular predictors of phenotype and/or treatment response in ongoing projects. Additional work involved validation of an eye tracker protocol to quantify eye gaze aversion in a group of patients with fragile X syndrome and age-matched control individuals. The eye tracker results were highly reproducible in a test-retest protocol and this should be an excellent outcome measure for a core fragile X phenotype for clinical trials in the future if it can be shown to be responsive to medications.
Study of Fenobam in Fragile X

by Elizabeth Berry-Kravis, 1/1/2008

January 2008: This single-dose clinical trial investigated the effects of the experimental new drug fenobam. Fenobam is an mGluR5 antagonist -- a compound which blocks a specific metabotropic glutamate receptor (mGluR5). mGluR5 is known to be overactive in the fragile X brain. FRAXA provided funds to purchase equipment for this study as well as future clinical trials. 
Add-On Pilot Trial of Lithium in Fragile X

by Elizabeth Berry-Kravis, 3/1/2007

The lithium trial has been completed and results published. (J Dev Behav Pediatr. 2008 Aug;29(4):293-302. "Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome." In general results were encouraging. Sixteen individuals with FXS were enrolled, ranging from age 6 to young adulthood. One child dropped out after the first few weeks due to issues probably unrelated to lithium. Of the 15 who completed two months treatment, some form of improvement in language was noted by 12 families. Twelve families chose to continue treatment for a year. Of those who discontinued lithium, one child showed worse behavior, one showed mild improvements but had an intolerable increase in thirst and urination, and one showed mild improvements but stopped due to difficulty with administering the capsules. Of the 12 continuing treatment for one year, 11 were improved in some area and one was unchanged but did not have side effects. Side effects were mild for most participants, with increased thirst and urination (3 participants) and mild changes in thyroid function (4 participants) being the most common problems. No kidney problems or tremor have been seen. There was improvement in at least 3 behavioral measures and at least 1 cognitive measure: a verbal memory test. For all participants continuing treatment past 5 months so far, improvements on behavior measures have persisted. The study appears to provide an early suggestion that lithium may be useful for treatment of FXS and are expected to provide support for a placebo-controlled trial to further evaluate the potential and safety of lithium in FXS.
Clinical Trial of Ampakine CX516 in Adults with Fragile X

by Elizabeth Berry-Kravis, 6/1/2006

The Ampakine trial with AMPA receptor activator CX516 has now been completed. This trial was initiated because of findings of reduced AMPA receptors and AMPA-mediated LTP (long term potentiation; a form of memory) in cerebral cortex of the fragile knockout mouse. The trial consisted of a Phase II 4-week randomized double-blind placebo-controlled clinical trial which was conducted to evaluate the safety and efficacy of the Ampakine CX516 as a potential treatment to correct the deficient AMPA activity as a means of treating the underlying brain disorder in fragile X syndrome (FXS). After baseline screening, 49 subjects with FXS underwent a one-week placebo lead-in, then were treated with study drug or placebo for 4 weeks. There were minimal side effects in the subjects with FXS who were treated with CX516, no significant changes in safety parameters, and no serious adverse events. There was a 12.5% frequency of allergic rash in the CX516 group and one subject developed a substantial rash. There was also no significant improvement in memory, the primary outcome measure, or in secondary measures of language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo. This study did demonstrate that many outcome measures were reproducible in this test-retest setting for the FXS population, yet some were too difficult or variable. Outcome measures (tests that measure improvement due to medication effect) that were shown to be reproducible will now be able to be used for future clinical trials of new medications in FXS. The study also showed that adult subjects with FXS were able to complete an intensive clinical trial with an excellent completion rate for all the tests required by the trial. Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect. In fact, when only subjects treated with an antipsychotic upon entering the CX516 study were analyzed, there appeared to be improvement in global cognitive and behavioral functioning in the CX516-treated group relative to the placebo group. Given the known ability of antipsychotics to potentiate the effect of CX516 in animal models, this would suggest that the CX516 was likely insufficiently potent. Thus it remains unclear whether modulation of AMPA-mediated neurotransmission is a viable therapeutic strategy for the treatment of FXS, but given the lack of major safety problems with CX516, and suggestion of effectiveness when combined with antipsychotics, it would be reasonable to propose further trials with more potent Ampakine molecules in the future. New, more potent ampakines which last longer in the body are being tested in the mouse model of fragile X (see FRAXA research projects of Dr. Julie Lauterborn). The outcome of this and other studies will help determine whether stronger ampakines may be effective in treating fragile X; new trials will be planned if stonger ampakines seem likely to help. We are grateful to the wonderful families and adult Fragile X subjects who have made the considerable effort required to participate in this study. They are helping lay the groundwork for future treatment of cognition in Fragile X syndrome.