Fragile X targeted pharmacotherapy: lessons learned and future directions

Journal of Neurodevelopmental Disorders

Dejan Budimirovic¹  John A. Sweeney²  Elizabeth Berry-Kravis³  Tori L. Schaefer⁴  Ernest V. Pedapati⁴  Logan K. Wink⁴  Matthew H. Davenport⁴  Sarah E. Fitzpatrick⁴  Craig A. Erickson⁴  Walter E. Kaufmann⁵  W. Ted Brown⁶  Randi J. Hagerman⁷  David Hessl⁷ 

[1] Clinical Research Center, Clinical Trials Unit, Fragile X Clinic, Kennedy Krieger Institute, The Johns Hopkins Medical Institutions;Department of Psychiatry, College of Medicine, University of Cincinnati;Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center;Division of Child and Adolescent Psychiatry (MLC 4002), Cincinnati Children’s Hospital Medical Center;Greenwood Genetic Center;Institute for Basic Research in Developmental Disabilities;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Davis Medical Center, University of California;

关键词: Fragile X syndrome;    Translational treatment;    Targeted treatments;    Drug development;    Genetic disorder;   

DOI  :  10.1186/s11689-017-9186-9

来源: DOAJ

【 摘 要 】

Abstract Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

【 授权许可】

Unknown