Gene Therapy Reduces Seizures, Extends Survival in Mouse Models

Novel treatment builds off previous Alzheimer's disease studies

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A mouse is held in a hand, as test tubes of blood sit nearby.

A novel gene therapy that works to increase the levels of an enzyme called p38-gamma extended survival and reduced seizure activity in a mouse model of Dravet syndrome, a new study reports.

“We have tested this therapy extensively, and rigorous assessment by independent labs has confirmed our results,” said Lars Ittner, MD, the study’s co-senior author and  director of Macquarie University’s Dementia Research Center, in Australia, in a university press release.

“Our next step is to conduct more detailed pre-clinical evaluation in preparation for clinical trials,” Ittner said, adding that they “hope to be able to offer it, initially to patients with uncontrolled epilepsy, within the next five to seven years.”

The study, “Treatment of epilepsy using a targeted p38γ kinase gene therapy,” was published in Science Advances.

The new research builds off previous studies conducted by Ittner’s team in a mouse model of Alzheimer’s disease, a neurodegenerative disease characterized by the accumulation of toxic clumps of the tau protein.

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Disease features lessened in mouse model

The researchers found that the p38-gamma, an enzyme of the p38 mitogen-activated protein kinase family, can make a chemical modification, called phosphorylation, in a specific region of tau that reduces the protein’s ability to induce neuronal hyperexcitation. This lessened disease features in the mouse model.

Neuronal hyperexcitation is a state when nerve cells fire excessive electric signals, which disrupt normal nerve circuitry and, in the long term, leads to nerve cell dysfunction and death.

Besides Alzheimer’s and other neurological disorders, neuronal hyperexcitation is key feature of seizure-causing disorders like Dravet syndrome.

As such, a team of researchers led by Ittner and Janet van Eersel, PhD, a senior researcher at Macquarie University, hypothesized that increasing the activity of p38-gamma could be beneficial also in epileptic disorders.

To test this idea, the researchers created a gene therapy that uses a modified and harmless adeno-associated virus to deliver to nerve cells a gene providing the instructions for making p38-gamma. The virus used is prone to enter the brain and spinal cord, and the delivered gene was modified to promote p38-gamma production only in nerve cells.

“By introducing our new therapy to the brains of mice via this [modified virus], we have been able to show we can increase production of [p38-gamma] only where it is needed,” Ittner said.

The team tested the gene therapy, administered directly in the bloodstream, in a mouse model of Dravet syndrome before seizure onset. Results showed treatment normalized electrical activity in the mouse’s brain, lessened behavioral abnormalities, and significantly reduced seizure-induced mortality.

These results “suggest that enhancing [p38-gamma] kinase activity holds promise for attenuating the severity and/or frequency of seizure episodes responsible for SUDEP [sudden unexpected death in epilepsy] in patients with [Dravet syndrome],” the researchers wrote.

The gene therapy also reduced seizure severity and seizure-related mortality in a separate mouse model where seizures were induced by administering a chemical called pilocarpine.

Anti-seizure effects were seen when the therapy was given both before and after pilocarpine administration, suggesting it may have protective effects even after seizure onset.

Additional experiments confirmed the anti-seizure effects of p38-gamma were mediated through its targeted phosphorylation of the tau protein. In mice genetically engineered so that p38-gamma could not modify tau, the gene therapy was ineffective at reducing seizures and related mortality.

The p38-gamma “appears to disengage tau from its epilepsy-associated pathway … alleviating downstream clinical outcomes,” the researchers wrote. “We propose increasing [p38-gamma] activity as a multiuse therapeutic target both in preventing and in treating diseases characterized by network dysfunction and [nerve cell dysfunction caused by hyperexcitation].”

Earlier this year, the Macquarie University created Celosia Therapeutics, a company designed to turn this type of groundbreaking research into commercially available treatments, the release stated.