FMR1 Gene Therapy for Fragile X Syndrome
Principle Investigators: Christina Gross, PhD, & Ernest Pedapati, MD
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and monogenic autism. Individuals with FXS cannot live independent lives, and there is currently no treatment or cure available.
Transcriptional silencing of the FMR1 gene causes FXS and leads to loss of the Fragile X Mental Retardation Protein (FMRP). FMRP associates with hundreds of mRNAs, regulating their translation and stability, but also can directly affect neuronal excitability by binding ion channels at synapses. Consequently, loss of FMRP leads to many molecular and structural alterations that are difficult to correct with single drug strategies in humans.
Our research will address this issue by preclinically testing a highly translatable AAV-based gene replacement strategy in mice that will restore FMRP expression in the brain and is expected to rescue all neuropsychiatric FXS-associated symptoms. To do this, we will use the viral vectors, delivery and outcome measures, such as novel quantitative EEG biomarkers detectable in mice and humans, that are most likely to be successful in humans. We have designed this research project for seamless transition into clinical trials and will generate essential support for extramural funding and to conduct the first clinical gene therapy trial for FXS at Cincinnati Children’s.