Brain Organoids and Therapeutic Development for Fragile X and Other Rare Diseases

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
  

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.

Dr. Muotri earned a Ph.D. in Genetics in 2001 from University of Sao Paulo, in Brazil. He moved to the Salk Institute as Pew Latin America Fellow in 2002 for a postdoctoral training in the fields of neuroscience and stem cell biology. He has been a Professor at the School of Medicine, University of California in San Diego since late 2008. His research focuses on modeling neurological diseases, such as Autism Spectrum Disorders, using human pluripotent stem cells.

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.

Dr. Tucci has over 20 years of experience in drug discovery, medicinal chemistry and organic synthesis. In this role, Dr. Tucci is responsible for managing certain aspects of the company, including project management, medicinal chemistry design, investor relations, operations and administration functions. As the Director of Chemistry at Tanabe Research Laboratories, he led the Medicinal Chemistry Department and advanced several programs on inflammation and metabolic diseases to the pipeline of Mitsubishi Tanabe Pharma Corporation in Japan. While at Neurocrine Biosciences, Dr. Tucci served as Principal Scientist in the Medicinal Chemistry Department where he was part of the team that designed and optimized Elagolix (Orilissa), a potent small-molecule GnRH antagonist that has recently gained FDA approval. Dr. Tucci received a Ph.D. degree in organic chemistry from the Universidade de São Paulo, Brazil, and conducted postdoctoral studies at the University of Wisconsin, Madison and The Scripps Research Institute, La Jolla. He authored/co-authored 65 peer-reviewed publications and is an inventor in more than 20 patents and patent applications.