Developmental Acoustic Exposure as a Novel Approach to Treat Fragile X Syndrome
Abstract
Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability affecting 1 in 4,000 boys and 1 in 8,000 girls. FXS is also the leading known genetic cause of autism spectrum disorders. Disabilities ranging from mild to severe include behavioral effects such as excitability, hyperactivity, anxiety, abnormal social interactions, and increased sensitivity to sounds. Some of the same symptoms are also present in conditions such as post-traumatic stress disorder that affect military personnel. Because FXS is the result of cells failing to produce a protein called FMRP, research has focused on testing drugs that compensate for the absence of this protein in mice that have a similar inherited condition. But beneficial effects of drugs at the cellular level and on complex cognitive behaviors in mice are difficult to measure in people with FXS. There is an immediate need to identify robust outcome measures in FXS given that two recent clinical trials failed to produce the effects in humans that were predicted based on strong preclinical outcomes in mice. One of the many reasons for such failure is the choice of treatment windows. FXS is a neurodevelopmental disorder, but most trials so far have targeted adolescents and young adults. This is because there is currently no data-driven guidance on whether early treatment is safe, efficient, and long-lasting. One of the primary goals of the proposed studies is to address this big gap in the field of neurodevelopmental disorders. Understanding the proper developmental windows to initiate treatment would have a major impact on future clinical trials. A second possible reason for failure to translate preclinical success to the clinic is the choice of outcome measures and biomarkers. It remains unclear to what extent complex social and cognitive behaviors and underlying circuits are conserved across rodents and humans. Sensory deficits in FXS may provide an opportunity to overcome this difficulty. Basic sensory responses, circuits, and plasticity mechanisms are more similar between animals and humans than complex cognitive behaviors. Identifying brain mechanisms underlying FXS symptoms may be easier for basic sensory deficits and early cortical processing compared to higher-level cognitive functions. Therefore, the proposed experiments uniquely bring together the expertise of an auditory electrophysiologist, a biochemist, an epilepsy specialist, and a hearing scientist from the Veterans Affairs Healthcare System to investigate whether a novel combination therapy with acoustic exposure and a drug that has shown potential in FXS (minocycline), given during early development to mice, will show long-lasting benefits. The proposed experiments will utilize a broad range of innovative approaches, including combination of two types of novel treatments and clinically relevant electroencephalography (EEG) studies. Discovery of auditory abnormalities and mechanisms in FXS mice has relevance for humans, especially when these “biomarkers” of disease (or its reversal) can be measured and compared. Therefore, identification of mechanisms of sensory deficits in the mouse brain will lead to understanding of abnormalities in the brain of people with FXS. The structural and functional mechanisms identified here will identify novel therapeutic targets for FXS, and autism in general. These studies will identify for the first time the long-term efficacy of treatment during specific developmental windows in FXS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910521
Entities
People
- Khaleel Razak
Organizations
- United States Army
- University of California, Riverside