Tau reduction: A possible new therapeutic target for Dravet Syndrome patients

Rajalaxmi Natarajan, PhD
Fri, 11/14/2014

Dravet syndrome is a rare and catastrophic form of incurable epilepsy that begins in infancy. Initially, these children develop normally but by the second year of life, they exhibit a progressive decline. Typically, Dravet begins as seizures triggered by high fever that progress to severe spontaneous seizures. Thereafter, these children begin to exhibit behavior and developmental delays, movement and sensory integration issues, chronic infections and autistic traits. Moreover, incidences of SUDEP (sudden unexplained death in epilepsy) are high among these patients.

Dravet syndrome is one of the most drug-resistant forms of epilepsy. Most of the common anti-epileptic drugs are either ineffective or sometimes even harmful. So alternative lines of therapy are urgently needed for children suffering from Dravet syndrome.

Seizures are fairly common in Alzheimer’s patients. Typically, tau reduction is the therapeutic objective for Alzheimer’s patients. Interestingly, studies in rodent models of Alzheimer’s and epilepsy have shown a positive correlation between reducing microtubule-associated protein tau and fewer seizures Based on these observations, it has been proposed that tau reduction could also be a potential therapeutic option for intractable epilepsies. However, the effects of reducing tau in animal models of severe childhood epilepsy had never been tested.

A recent study published in the Annals of Neurology by Dr. Lennart Mucke’s team at the Gladstone Institute of Neurological Disease in the University of California at San Francisco¹ demonstrates that genetic ablation of tau in a mouse model of Dravet syndrome reverses most of the symptoms.

They used a transgenic Dravet mouse model in which the animals have the same mutation in SCN1A, the voltage-gated sodium channel gene as Dravet patients and also develop similar symptoms such as seizures, behavioral abnormalities and cognitive and social deficits. Reduction of tau in these Dravet mice not only significantly improved their survival but also reduced the frequency of spontaneous and heat-induced seizures.

Laboratory and wild mice engage in nesting and burrowing activities on a daily basis. This behavior serves as a sensitive indicator of good health and well-being, i.e., absence of stress, pain, illnesses such as brain or motor dysfunction or onset of neurodegenerative disease. While normal mice are able to form entire nests within 24 hours, Dravet mice exhibit a profound deficiency in these skills. Interestingly, when these transgenic mice also carried a deletion in tau, their nest-building performance was as good as regular mice, indicating that seizures may have interfered with their ability to perform daily tasks.

Researchers also reported that removal of tau in Dravet mice not only corrected hyperactivity and other behavioral abnormalities, it was also enough to overcome the cognitive defects in spatial and associative learning and memory.

This pioneering study demonstrates that endogenous tau plays a critical role in the onset and/or progression of Dravet syndrome and that its reduction can ameliorate most of the associated symptoms. Given the dearth of viable treatment options for Dravet syndrome, this study offers a promise of a novel and effective therapeutic strategy to these patients. Of course, extensive animal and clinical studies are needed to validate and establish the safety and efficacy of this approach in treating Dravet patients.

References:

1. Gheyara et al., Tau reduction Prevents Disease in a Mouse Model of Dravet Syndrome. Annals of Neurology, July 16 2014, doi: 10.1002/ana.24230. 
2. Learn More about Dravet syndrome and Dravet Foundation.