Scientists Discover Potential Treatment Path for ‘Smooth Brain’ Disorders

Yale researchers have identified a previously unknown molecular mechanism behind some forms of lissencephaly – rare genetic disorders where the brain develops without its characteristic folds – and successfully tested a drug that could potentially prevent and even reverse some brain malformations in laboratory models.

The breakthrough finding, published January 1 in Nature, offers the first glimpse of hope for treating these devastating neurological conditions, which currently have no available treatments and often result in severe seizures and intellectual disabilities.

“Lissencephaly belongs to a group of disorders we call malformations of cortical development, meaning the normal development and structure of the brain is disrupted,” explains Dr. Angeliki Louvi, professor of neurosurgery and neuroscience at Yale School of Medicine and co-senior author of the study. “They come about because certain genes that are very important for brain development are affected by rare mutations.”

A 17-Year Journey

The research represents the culmination of nearly two decades of work by Yale’s Program in Neurogenetics, pioneered by co-senior author Dr. Murat Gunel. “It has been 17 years since the first family enrolled in our research, and they happen to be one of the families in the study,” notes Dr. Kaya Bilguvar, associate professor adjunct of neurosurgery and genetics and co-senior author. “This level of collective commitment, including by patients and families, is inspiring.”

Using advanced laboratory techniques, the team created three-dimensional “mini-brains” called organoids from patients’ cells, allowing them to study how different types of lissencephaly develop. These organoids revealed a surprising finding: both types of lissencephaly they studied shared a common problem – reduced activity in a fundamental cellular pathway called mTOR.

An Unexpected Discovery

“This is a fundamental pathway that governs many different aspects of cellular metabolism to maintain cellular homeostasis,” Louvi explains. “And we know of many disorders in which the mTOR pathway is overactive, but here we found that in lissencephaly it’s actually underperforming.”

The team then tested a drug that boosts mTOR pathway activity. Remarkably, it prevented and even reversed the thickening of brain tissue characteristic of lissencephaly in their laboratory models, depending on when the treatment was started.

Hope for Future Treatments

“Right now, in medicine we have no way to slow or reverse these structural brain malformations in lissencephaly either during pregnancy or after,” says lead author Ce Zhang, who conducted the research as an M.D.-Ph.D. student and will soon begin neurology residency at Cedars-Sinai in Los Angeles. “That limits us to treating the symptoms, but even that can be difficult, as lissencephaly seizures may not be well-controlled using typical anti-epileptic drugs.”

The discovery that reduced mTOR activity plays a role in multiple types of lissencephaly suggests this pathway might be involved across the entire spectrum of these disorders. This raises the possibility that a single treatment approach could help patients with different genetic causes of lissencephaly.

“If there’s a converging pathway shared between these disorders, regardless of the genetic cause, it could mean one treatment, such as a mTOR activator like the one we tested in the study, might be beneficial to patients across the lissencephaly spectrum,” Zhang explains.

Next Steps

The research team is now working to determine whether the mTOR pathway is involved in other genetic types of lissencephaly and to better understand exactly how an underactive mTOR pathway leads to the condition.

“These findings extend our knowledge of this pathway, highlighting the fine balance that has to be met for healthy brain development,” says Louvi. “Now we want to understand what exactly happens molecularly when mTOR is underactivated.”

Bilguvar emphasizes that exploring potential clinical applications of mTOR activators in this spectrum of disorders will be crucial, as benefiting patients through basic discoveries remains the program’s ongoing motivation.

The research was published in Nature on January 1, 2025. The study was conducted by researchers at Yale School of Medicine’s Program in Neurogenetics.