The future of epilepsy treatment: focus on adeno-associated virus vector gene therapy.
ABSTRACT Adeno-associated virus (AAV) vectors support long-term, nontoxic gene expression in the central nervous system, and these AAV properties prove particularly applicable to the treatment of focal epilepsies, especially intractable temporal lobe epilepsy. A number of clinical studies have employed AAV vectors and to date, no known adverse effects have been directly associated with these treatments, particularly AAV serotype 2 (AAV2). Although other AAV serotypes may confer an advantage in the future, extensive studies on the inhibitory neuropeptides, galanin and neuropeptide Y, have generated enough preclinical evidence of efficacy to warrant AAV2-based clinical trials in the near future. Beyond these trials, emerging evidence suggests that AAV-mediated manipulation of adenosine can significantly impact limbic seizure activity. Thus, with appropriate nonhuman primate transduction patterns and favorable overall toxicology studies, AAV-based manipulation of adenosine could follow the AAV-neuropeptide clinical studies. Finally, recent findings using AAV capsid shuffling and directed evolution have identified a hybrid AAV vector that can selectively cross the seizure compromised blood-brain barrier and transduce cells after peripheral, intravenous administration. Thus, in the more distant future, AAV therapeutics for focal epilepsies may be delivered without any neurosurgical interventions.
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ABSTRACT: Neuropeptide Y (NPY) causes anxiolytic- and antidepressant-like effects after central administration in rodents. These effects could theoretically be utilized in future gene therapy for anxiety and depression using viral vectors for induction of overexpression of NPY in specific brain regions. Using a recombinant adeno-associated viral (rAAV) vector, we addressed this idea by testing effects on anxiolytic- and depression-like behaviours in adult mice after overexpression of NPY transgene in the amygdala and/or hippocampus, two brain regions implicated in emotional behaviours. In the amygdala, injections of rAAV-NPY caused significant anxiolytic-like effect in the open field, elevated plus maze, and light-dark transition tests. In the hippocampus, rAAV-NPY treatment was associated with anxiolytic-like effect only in the elevated plus maze. No additive effect was observed after combined rAAV-NPY injection into both the amygdala and hippocampus where anxiolytic-like effect was found in the elevated plus maze and light-dark transition tests. Antidepressant-like effects were not detected in any of the rAAV-NPY injected groups. Immobility was even increased in the tail suspension and forced swim tests after intra-amygdaloid rAAV-NPY. Taken together, the present data show that rAAV-NPY treatment may confer non-additive anxiolytic-like effect after injection into the amygdala or hippocampus, being most pronounced in the amygdala.Neuropeptides 09/2014; DOI:10.1016/j.npep.2014.09.004 · 2.55 Impact Factor
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ABSTRACT: Epilepsy is a common neurological disorder characterized by recurrent seizures. These seizures are due to abnormal excessive and synchronous neuronal activity in the brain caused by a disruption of the delicate balance between excitation and inhibition. Neuropeptides can contribute to such misbalance by modulating the effect of classical excitatory and inhibitory neurotransmitters. In this review, we discuss 21 different neuropeptides that have been linked to seizure disorders. These neuropeptides show an aberrant expression and/or release in animal seizure models and/or epilepsy patients. Many of these endogenous peptides, like adrenocorticotropic hormone, angiotensin, cholecystokinin, cortistatin, dynorphin, galanin, ghrelin, neuropeptide Y, neurotensin, somatostatin, and thyrotropin-releasing hormone, are able to suppress seizures in the brain. Other neuropeptides, such as arginine-vasopressine peptide, corticotropin-releasing hormone, enkephalin, β-endorphin, pituitary adenylate cyclase-activating polypeptide, and tachykinins have proconvulsive properties. For oxytocin and melanin-concentrating hormone both pro- and anticonvulsive effects have been reported, and this seems to be dose or time dependent. All these neuropeptides and their receptors are interesting targets for the development of new antiepileptic drugs. Other neuropeptides such as nesfatin-1 and vasoactive intestinal peptide have been less studied in this field; however, as nesfatin-1 levels change over the course of epilepsy, this can be considered as an interesting marker to diagnose patients who have suffered a recent epileptic seizure.Molecular Neurobiology 04/2014; DOI:10.1007/s12035-014-8669-x · 5.29 Impact Factor
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ABSTRACT: Epilepsy is one of the most common neurological diseases and it is characterized by the reoccurrence of seizures with variable severity and frequency. The burden of epilepsy, however, is more than having seizures as the disease is frequently associated with comorbid cognitive and behavioral disorders. Diagnosis as well as treatment suffers both from the inadequate understanding of the underlying epileptogenic molecular, cellular and network mechanisms and the related lack of reliable biomarkers for the development, progression, or even the presence and severity of the epileptic condition. Here we summarize the recent advances in both clinical and experimental approach regarding epilepsy, which may create the premise for identification of clinically useful, reliable biomarkers. Identification of the basic patomechanisms of epileptogenesis and epilepsy would potentially create new therapeutic approaches that could not only treat but also prevent and cure epilepsy. Current knowledge regarding the electrophysiological alterations as well as the underlying cellular and molecular mechanisms regarding temporal lobe epilepsy is also critically scrutinized.Brain Research Bulletin 10/2014; 109. DOI:10.1016/j.brainresbull.2014.08.004 · 2.97 Impact Factor