Emerging pharmacologic treatment options for fragile X syndrome

Tori L. Schaefer, Matthew H. Davenport, Craig A. Erickson

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Fragile X syndrome (FXS) is the most common single gene cause of intellectual disability and autism spectrum disorder. Caused by a silenced fragile X mental retardation 1 gene and the subsequent deficiency in fragile X mental retardation protein, patients with FXS experience a range of physical, behavioral, and intellectual debilitations. The FXS field, as a whole, has recently met with some challenges, as several targeted clinical trials with high expectations of success have failed to elucidate significant improvements in a variety of symptom domains. As new clinical trials in FXS are planned, there has been much discussion about the use of the commonly used clinical outcome measures, as well as study design considerations, patient stratification, and optimal age range for treatment. The evidence that modification of these drug targets and use of these failed compounds would prove to be efficacious in human clinical study were rooted in years of basic and translational research. There are questions arising as to the use of the mouse models for studying FXS treatment development. This issue is twofold: many of the symptom domains and molecular and biochemical changes assessed and indicative of efficacy in mouse model study are not easily amenable to clinical trials in people with FXS because of the intolerability of the testing paradigm or a lack of noninvasive techniques (prepulse inhibition, sensory hypersensitivity, startle reactivity, or electrophysiologic, biochemical, or structural changes in the brain); and capturing subtle yet meaningful changes in symptom domains such as sociability, anxiety, and hyperactivity in human FXS clinical trials is challenging with the currently used measures (typically parent/caregiver rating scales). Clinicians, researchers, and the pharmaceutical industry have all had to take a step back and critically evaluate the way we think about how to best optimize future investigations into pharmacologic FXS treatments. As new clinical trials are coming down the drug discovery pipeline, it is clear that the field is moving in a direction that values the development of molecular biomarkers, less subjective quantitative measures of symptom improvement, and rating scales developed specifically for use in FXS in conjunction with drug safety. While summarizing preclinical evidence, where applicable, and discussing challenges in FXS treatment development, this review details both completed clinical trials for the targeted and symptomatic treatment of FXS and introduces novel projects on the cusp of clinical trial investigation.

Original languageEnglish (US)
Pages (from-to)75-93
Number of pages19
JournalApplication of Clinical Genetics
Volume8
DOIs
StatePublished - Apr 7 2015
Externally publishedYes

Fingerprint

Fragile X Syndrome
Clinical Trials
Therapeutics
Intellectual Disability
Fragile X Mental Retardation Protein
Outcome Assessment (Health Care)
Translational Medical Research
Drug Industry
Drug Discovery
Pharmaceutical Preparations
Caregivers
Genes
Hypersensitivity
Anxiety
Biomarkers
Research Personnel

Keywords

  • Anxiety
  • Autism
  • Clinical trial
  • Fragile X syndrome
  • Intellectual disability

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Emerging pharmacologic treatment options for fragile X syndrome. / Schaefer, Tori L.; Davenport, Matthew H.; Erickson, Craig A.

In: Application of Clinical Genetics, Vol. 8, 07.04.2015, p. 75-93.

Research output: Contribution to journalArticle

Schaefer, Tori L. ; Davenport, Matthew H. ; Erickson, Craig A. / Emerging pharmacologic treatment options for fragile X syndrome. In: Application of Clinical Genetics. 2015 ; Vol. 8. pp. 75-93.
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