Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome

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 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.

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.

- 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.