combining lovastatin and a parent-implemented language intervention for fragile x syndrome

Conditions: Fragile X Syndrome; Genetic Diseases

Summary: the purpose of the study is to test the efficacy of a 20 week multi-modal treatment comprised of lovastatin or placebo, and the parent-implemented language intervention (pili) in children with fragile x syndrome (fxs). children will be randomized to drug or placebo in a double-blind design with all participating in the pili. the primary endpoint will be to measure improvements in spoken language and behavior among lovastatin-treated than placebo treated participants.

this is the first multi-modal treatment to combine a targeted treatment for fxs, lovastatin, with an innovative parent-implemented intervention (pili) targeting language and challenging behavior delivered through telehealth technology.the hypothesis is that targeted treatments will be more effective when applied in combination with pili. examination of whether changes in the activity of key pathways/proteins influenced by fragile x mental retardation protein (fmrp) (the mitogen-activated protein kinase (erk) and mmp-9) are biomarkers of treatment responsiveness. because lovastatin is also an anti-inflammatory, characterization of mek/erk signaling in peripheral immune cells both pre- and post- treatment will be carried out to determine whether levels of these signaling molecules are predictive biomarkers of treatment response. it is hypothesized that those individuals with elevated inflammatory cytokine profiles will be most responsive to lovastatin treatment. once modeled in fxs, results from these studies can then be applied to other neurodevelopmental disorders including rasopathies. the behavioral component of the proposed multi-modal treatment will be a parent-implemented intervention (pili) that targets improvements in spoken language and challenging behavior for 10- to 17-year-olds with fxs by increasing parental verbal responsiveness (pvr) within picture-book based story-telling episodes. parents will be encouraged to use the targeted strategies in other everyday interactions with their child. the intervention will be delivered to parents in their homes by way of video teleconferencing (vtc). participants will be randomly assigned to receive the behavioral intervention alone or in combination with lovastatin.

Eligibility criteria:
inclusion criteria: * documentation of a full mutation with absence or deficient fmrp levels. * males and females ages 10 through 17 years * willingness of potential study participant as well as a parent or caretaker to participate in the protocol. * speech is the primary means of communication with three-word or longer utterances used on a daily basis. * intelligence quotient (iq) ≤70 as measured by the leiter- r. * sexually active women of childbearing potential (wcbp) must be using a medically acceptable method of birth control and have a negative qualitative serum β-human chorionic growth hormone (β-hcg) or urine pregnancy test collected at the initial screening visit. exclusion criteria: * persons who do not speak english. * changes in any medications (including investigational medications) within the last month (4 weeks). all concomitant medications must have been on a stable course for at least 4 weeks prior to enrollment into the study and maintain stability throughout the course of the study. * changes in behavioral therapy or educational programming during the study. this does not include scheduled school holidays. * have any disease or condition (medical or surgical) at screening that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or would place the subject at increased risk. * patients who, in the opinion of the investigator, are unsuitable in any other way to participate in this study, including being unable to comply with the requirements of the study or displaying clinically significant abnormalities in safety assessments at screening. * patients on prohibited medications * history of recurrent status epilepticus. * inability to withhold grapefruit and grapefruit juice from diet during the entire clinical trial. * subjects unwilling to abstain from alcoholic beverages during the trial. * subjects who are actively suicidal.

Keywords: fra(x) syndrome trinucleotide repeat expansion fragile x syndrome fragile x mental retardation syndrome intellectual disability parent implemented language intervention (pili) fxs mental retardation, x-linked genetic diseases, x-linked neurobehavioral manifestations chromosome disorders