Yale researchers have discovered a new molecular mechanism behind certain forms of lissencephaly, a rare genetic disorder where the brain does not develop its typical folds. They have also successfully tested a drug that could potentially prevent and even reverse some brain malformations in laboratory models.
The groundbreaking study, published in Nature on January 1, provides hope for treating these devastating neurological conditions that currently have no available treatments. These conditions often lead to severe seizures and intellectual disabilities.
Dr. Angeliki Louvi, professor of neurosurgery and neuroscience at Yale School of Medicine and co-senior author of the study, explains, “Lissencephaly is part of a group of disorders known as malformations of cortical development, where the normal structure and development of the brain are disrupted due to rare mutations affecting crucial genes for brain development.”
A 17-Year Journey
This research is the result of nearly 17 years of work by Yale’s Program in Neurogenetics, led by co-senior author Dr. Murat Gunel. Dr. Kaya Bilguvar, associate professor adjunct of neurosurgery and genetics and co-senior author, highlights the collective commitment of patients and families who have been part of the research since the beginning.
Using advanced techniques, the team created 3D “mini-brains” called organoids from patients’ cells to study the development of different types of lissencephaly. They found that both types of lissencephaly they studied shared a common issue – reduced activity in a cellular pathway called mTOR.
An Unexpected Discovery
“The mTOR pathway is essential for maintaining cellular homeostasis, but we discovered that it is underperforming in lissencephaly, unlike other disorders where it is overactive,” Louvi explains. Testing a drug that boosts mTOR pathway activity prevented and even reversed brain tissue thickening in their laboratory models.
Hope for Future Treatments
Lead author Ce Zhang, an M.D.-Ph.D. student, emphasizes the lack of current treatments for lissencephaly and the potential of targeting the mTOR pathway for different genetic causes of the disorder. This suggests a single treatment approach could benefit patients across the lissencephaly spectrum.
Next Steps
The research team is exploring whether the mTOR pathway is involved in other genetic types of lissencephaly and aims to understand how an underactive mTOR pathway leads to the condition. They continue to investigate potential clinical applications of mTOR activators in these disorders.
This research, conducted by Yale School of Medicine’s Program in Neurogenetics, was published in Nature on January 1, 2025.
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