Elizabeth Berry-Kravis, MD, PhD
Rush University Medical Center, Chicago

FRAXA Awards:
  $5,000 in 2010
  $5,000 in 2009
  $19,000 in 2007
  $35,000 in 2006
  $144,000 in 2002-4

by Elizabeth Berry-Kravis, 5/2010

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.

(2006-7) This clinical trial looked at the effects of lithium on behavior and thinking in Fragile X. Lithium partially blocks the mGluR pathway, which is overactive in the Fragile X brain. Lithium has been shown to reverse learning problems seen in Fragile X fruit flies and there is also data to suggest it reduces sound-induced seizures seen in Fragile X knockout mice.

by Elizabeth Berry-Kravis, updated March 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.

by Elizabeth Berry-Kravis, 2006

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.

2002-2004: This study, funded by FRAXA for a total of $144,000, was the first clinical trial of a specific treatment for learning and memory deficits in Fragile X and autism. Over the past decade, several pharmaceutical companies have been developing a new class of medications, Ampakines, which seem to enhance learning. The compound used in this trial, Ampakine CX516, is the first of a series of compounds developed by Cortex Pharmaceuticals.

by Elizabeth Berry-Kravis, 6/2006

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.