This is the first in a series of webinars focused on current topics in Fragile X research. Hosted by FRAXA and organized by Patricia Cogram, PhD, and Michael Tranfaglia, MD, this series will feature outstanding speakers on current frontiers.

Details of future webinars will be posted asap. Confirmed sessions include:
- Drug Repurposing, by Dr. David Brown and colleagues at Healx Pharmaceuticals
- Sound Processing, by Dr. Devin Binder and Dr. Khaleel Razak at UC Riverside
- Biomarkers, by Dr. Charles Nelson and Dr. Carol Wilkinson at Harvard Medical School
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Alysson R. Muotri, PhD
Professor, University of California San Diego Stem Cell Program
Presentation Abstract - Modeling Neurological Conditions with Brain Organoids

Human brain organoids generated from induced pluripotent stem cells (iPSCs) are emerging as a scaled-down, three-dimensional model of the human brain, mimicking various developmental features at the cellular and molecular levels. Human brain organoids became an essential tool in research, advancing discoveries regarding the development, diseases, and evolution of the human brain. We developed cortical organoids that spontaneously display periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our approach provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex. Applications for neurodevelopmental disorders, including Fragile X syndrome will be discussed.
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Fabio C. Tucci, PhD
Chief Operating Officer and co-founder, Epigen Biosciences, Inc.
Presentation Abstract - Therapeutic Development for Fragile X and Other Rare Diseases

Fragile X syndrome (FXS) is the most common inheritable form of cognitive impairment and the leading known genetic cause of autism. Dysregulated protein synthesis is widely accepted as a core molecular abnormality associated with FXS. Because neuronal protein synthesis is critical for learning and memory, altered synaptic translation is considered a major contributor to the intellectual deficits seen in FXS. Currently available pharmacological intervention strategies for FXS primarily treat behavioral problems and have focused largely on targets upstream of translational control to normalize FXS-related phenotypes.

We have identified a specific target that is a common downstream effector of both mTORC1 and ERK signaling and plays a direct role in regulating translation. Genetic deletion of the target in an animal model of FXS corrected exaggerated protein synthesis and other biochemical, neuroanatomical and behavioral abnormalities associated with FXS. These results suggest a strategy for developing a disease modifying therapeutic for FXS. By using a rational design approach that combines structural protein information and optimal ADME properties, we have discovered a novel series of potent, selective and brain-penetrant inhibitors. Lead optimization efforts identified EPGN2036 as a candidate for pharmacological evaluation. This compound dose-dependently corrected deficits in FMR1 KO2 mice after oral administration. Moreover, EPGN2036 demonstrated target engagement in hippocampal lysates of FMR1 KO mice treated with the compound.

In collaboration with Dr. Alysson Muotri at UCSD, we have started evaluation of EPGN2036 and analogs in FXS brain organoids. Preliminary safety studies in rats indicate that EPGN2036 has sufficient safety margin to warrant further investigation. This talk will describe the rationale and Epigen’s efforts in developing a disease-modifying therapy for FXS.
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Timestamps
0:00 Intro with Dr. Michael Tranfaglia
1:06 Modeling Neurological Conditions with Brain Organoids
24:29 Therapeutic Development for Fragile X
56:54 Questions and Answers
1:22:00 Closing remarks

FRAXA’s mission is to find effective treatments and ultimately a cure for Fragile X syndrome. We directly fund research grants and fellowships at top universities around the world. We partner with biomedical and pharmaceutical companies, large and small, to bridge the gap between research discoveries and actual treatments.

Treatments for Fragile X are likely to help people affected by autism, Alzheimer’s, and other brain disorders.

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• Brain Organoids and Therapeutic Development for Fragile X and Other Rare Diseases ( Download)
• Towards Understanding the Role of FMRP in Human Brain Development Using Brain Organoids ( Download)
• Rett Syndrome Patient-Derived Brain Organoids with Robert T. Fremeau, Jr. ( Download)
• Pioneering Community-Based Drug Development for Fragile X - FRAXA Research Foundation ( Download)
• Elizabeth Berry-Kravis - Clinical Trials and Cyclic AMP in Fragile X Syndrome (February 24, 2021) ( Download)
• Healx Drug Repurposing Programme for Fragile X Syndrome ( Download)
• Fragile X Research: Current Treatment Trials and Progress Towards a Cure - Q&A Webinar (Nov 2023) ( Download)
• Brain organoids mouse models and GRIN; with English Captions: Third GRIN European Conference ( Download)
• Rare genetic neurodevelopmental disorders: from basic science to precision medicine ( Download)
• Using Genetic Maps of the Brain to Understand Autism & Related Psychiatric Illnesses ( Download)
• Accelerating cures for rare childhood diseases using iPSC models ( Download)
• Fragile X Syndrome (FXS) Medical Animation by Geometric Medical ( Download)
• Taking Root: Growing a Community for LGS Research ( Download)
• Gene-Based Therapies for Neurodevelopmental Disorders (Yael Weiss, MD, PhD) ( Download)
• Biofutures Brain Organoids from the Lab With Alysson Muotri ( Download)