Neuroscience

Gene therapy of neurodegenerative diseases

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Group Leader

Michele Simonato

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Epilepsy is one of the most common severe brain disorders, with an estimated 50-60 million patients worldwide. Systemic drug therapy is not effective in controlling seizures for more than 30% of the patients, and drug-resistant epilepsy is associated with high rates of depression, suicide, accidents, and social exclusion, thus bearing huge socio-economic tolls to individuals and society. Very few patients are suitable for epilepsy surgery to remove the abnormal part of the brain, often because of overlap with cortex that serves critical functions such as language or movement. Alternative therapeutic approaches, such as electrical stimulation of the brain and or the vagus nerve, are poorly effective.

Nearly half of the epilepsies, and most of those occurring in adults, are acquired following trauma, tumors, strokes or other pathogenic noxae capable of inducing damage to brain tissue. Over time, an epileptogenic tissue could develop around this area of damage in 10-20% of cases. To date, we do not have any preventive therapy to prevent the development of epilepsy in subjects at risk. Identification of biomarkers that predict who will actually develop epilepsy after an epileptogenic event would greatly facilitate development of such preventive therapies. Unfortunately, such biomarkers do not yet exist.

Research activity

The Research Unit pursues three broad goals:

  1. To identify biomarkers of epileptogenesis in peripheral blood;

  2. To develop treatments for preventing epilepsy development in at-risk individuals;

  3. To develop gene or cell therapy approaches for drug-resistant epilepsies.

Currently, the main active projects focus on gene therapy (goal 3). By using different viral vector platforms (based on herpes-, lenti- and adeno-associated virus), we are developing completely new therapeutic approaches to control epileptic hyperexcitability. One strategy focuses on NPY, a neuropeptide that inhibits neuronal activity by activation of its receptors Y2 and Y5, but exerts pro-epileptic actions through its Y1 receptor. Therefore, we designed a vector expressing NPY and Y2 under the CamKII promoter, to bias expression in (and thereby selectively inhibit) excitatory cells. The second strategy uses an innovative chemogenetic approach. Current chemogenetic approaches use modified receptors that do not respond to endogenous ligands but only to an otherwise inert drug. A problem with this approach is that the mutant receptor is potentially immunogenic. Therefore, we thought to overexpress endogenous (rather than exogenous) receptors that mediate the response to drugs already in clinical use, i.e., benzodiazepine- and barbiturate-sensitive GABA-A. We designed vectors expressing a combination of specific GABA-A subunits under control of the CaMKII promoter. Not only these are expected to increase endogenous GABA-mediated inhibition on excitatory neurons, but also to increase the responsiveness to benzodiazepines and barbiturates exclusively by transduced neurons of the epileptogenic region.

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