Friday, April 18, 2025
4/18/2025
Reelin and Fragile X Syndrome - This grant initiative undertakes an exploration of Reelin, an extracellular signaling protein, and its role in Fragile X syndrome (FXS). FXS is the most prevalent inherited form of intellectual disability, that manifests with a spectrum of clinical symptoms including impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS has an estimated prevalence of 1 in 7,000 males and 1 in 11,000 females (Centers for Disease Control). The core pathology of FXS stems from loss-of-function mutations in the X-chromosome gene FMR1, resulting in a lack of FMRP (Fragile X Messenger Ribonucleoprotein Protein) expression. FXS remains an enigmatic challenge, devoid of a cure, with available medications merely aimed at mitigating specific symptoms, such as anxiety, hyperactivity, aggression, and attention deficits. As a single-gene disorder, FXS stands out as a promising candidate for viral-vector-based gene therapy, however, the Fmr1 gene therapy approach has not resulted in the amelioration of phenotypical behaviors as anticipated. Many studies failed to report cognitive tasks or show cognitive recovery despite successful FMRP expression. Considering that the loss of FMRP function results in the disturbance of typical synaptic signaling, the goal of restoring synaptic function emerges as a compelling alternative therapeutic avenue for FXS—a terrain yet uncharted. Reelin offers a potential therapeutic target as it has emerged as a pivotal player in orchestrating synaptic dynamics. Our lab’s focus on neurodevelopmental disorders led us to identify 50% reduction in Reelin in the FXS mouse model. The tantalizing prospect that a decline in Reelin might underpin the synaptic dysregulation in FXS, we hypothesized that restoring Reelin signaling would improve synaptic signaling in FXS. Subsequently, we published that Reelin supplementation was able to fully rescue cognitive deficits in the FXS mouse model. As a follow up, we now demonstrate that an optimized minimal active Reelin fragment can also completely rescue cognitive deficits in the FXS mouse. More importantly, this construct can be expressed using a gene therapy approach, to amazingly completely restore the cognitive deficits in the FXS mouse model back to wild-type performance levels. In this proposal we further validate this gene therapy approach in Aim 1 with examination of new viral vectors that offers a less invasive gene delivery for the brain. We hypothesize that this will be as efficacious as our preliminary data, and could enhance the translatability towards a human therapeutic. In Aim 2 we will endeavor to determine the mechanism of action of Reelin in FXS. Currently there is no known direct interaction between Reelin and FMRP, but we hypothesize that Reelin indirectly rescues FMRP loss through the regulation of the synaptic proteins such as STEP and PSD-95. We will take an unbiased approach to examine the mechanism of increased Reelin signaling in Fmr1 KO mice using RNAseq and biochemical analysis of treated versus control mice.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).