Most people are born with two functioning copies of each gene-one inherited from each parent. In many cases, having just one working copy is enough for the body to function normally. But for certain critical genes, a single copy simply cannot produce the amount of protein needed to keep cells healthy. This condition, known as haploinsufficiency, can disrupt normal cellular activity and lead to serious neurodevelopmental disorders, including severe, intractable epilepsy.
Scripps Research associate professor Giordano Lippi has been awarded a $4 million grant from the California Institute for Regenerative Medicine (CIRM) to develop a novel platform that could restore healthy gene function in neurodevelopmental disorders caused by haploinsufficiency. Over the next three years, Lippi will collaborate with co-investigators Gene Yao and Olivia Kim McManus from UC San Diego to build a system that identifies and corrects this faulty gene expression in brain cells.
We are developing a technology that can effectively 'turn the volume back up' on genes in which one copy has been silenced. By understanding how these genes are regulated and learning how to restore their protein levels, we hope to uncover new paths for treating complex neurodevelopmental disorders. We are deeply grateful to CIRM for supporting this early-stage work, which allows us to take bold steps toward future therapeutic solutions."
Giordano Lippi, project's principal investigator, associate professor, Scripps Research
To accomplish this, Lippi and his team will use induced pluripotent stem cell (iPSC)-derived neurons and cortical organoids-lab-grown models made from human cells that mimic key aspects of brain development and function. This approach will help reveal how to reactivate genes that have been silenced by the body's natural regulatory systems. Until now, scientists have lacked high-throughput tools to study and reverse these gene expression defects. The new platform aims to fill that gap, providing a powerful discovery engine for uncovering potential therapeutic targets.
The project is supported through CIRM's DISC0 Foundation Awards, which fund early-stage research intended to spark the new ideas and tools that are the first step in developing novel disease therapies. In addition to Lippi's award, this year's funded projects include efforts to better understand how stem cells and genetics influence human biology and disease, create stem cell-based models for biomedical discovery and identify new therapeutic opportunities.
"Discovery research is critical for uncovering novel disease targets and biomarkers that we can translate into therapies for clinical use," says Kelly Shepard, director of Discovery & Education programs at CIRM. "The DISC0 projects have the potential to address gaps in our current knowledge, advance our understanding of the origins and mechanisms of disease, and expand existing applications of stem cell and gene therapy-based treatments."
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