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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- "NPY application exerts prominent seizure-suppressant effects in rodents in vitro and in vivo (Baraban et al., 1997; Klapstein and Colmers, 1997; Vezzani et al., 1999; Woldbye et al., 1996, 1997, 2005) and recombinant adeno-associated viral (rAAV) vector-mediated overexpression of NPY also suppresses seizures in both acute and chronic models of epilepsy (Foti et al., 2007; Noe et al., 2008, 2010; Richichi et al., 2004; Sørensen et al., 2009). Consequently , rAAV-mediated NPY gene therapy has been proposed as an alternative treatment strategy for patients suffering from intractable TLE (McCown, 2010; Riban et al., 2009). "
ABSTRACT: We recently demonstrated that recombinant adeno-associated viral vector-induced hippocampal overexpression of neuropeptide Y receptor, Y2, exerts a seizure-suppressant effect in kindling and kainate-induced models of epilepsy in rats. Interestingly, additional overexpression of neuropeptide Y in the hippocampus strengthened the seizure-suppressant effect of transgene Y2 receptors. Here we show for the first time that another neuropeptide Y receptor, Y5, can also be overexpressed in the hippocampus. However, unlike Y2 receptor overexpression, transgene Y5 receptors in the hippocampus had no effect on kainate-induced motor seizures in rats. However, combined overexpression of Y5 receptors and neuropeptide Y exerted prominent suppression of seizures. This seizure-suppressant effect of combination gene therapy with Y5 receptors and neuropeptide Y was significantly stronger as compared to neuropeptide Y overexpression alone. These results suggest that overexpression of Y5 receptors in combination with neuropeptide Y could be an alternative approach for more effective suppression of hippocampal seizures.Neurobiology of Disease 08/2011; 45(1):288-96. DOI:10.1016/j.nbd.2011.08.012 · 5.20 Impact Factor
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ABSTRACT: Local delivery of compounds directly into the brain may become an attractive treatment option for several neurological diseases. Higher therapeutic drug levels may be reached at the targeted brain region and in this way systemic side effects avoided. This paper provides an overview of the currently investigated experimental and clinical local delivery strategies in the brain ranging from delivery via pump mechanisms to more advanced techniques with cell and gene therapy. The second part focuses on local brain delivery strategies for epilepsy with special attention to adenosine. Adenosine is a good candidate for local delivery techniques for epilepsy because of its proven anticonvulsive effect and it cannot be given systemically because of systemic side effects. An overview of the current published studies with local delivery of adenosine is given.Seizure 06/2011; 20(5):376-82. DOI:10.1016/j.seizure.2011.03.003 · 2.06 Impact Factor
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ABSTRACT: Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness.Methods in molecular biology (Clifton, N.J.) 01/2012; 829:3-30. DOI:10.1007/978-1-61779-458-2_1 · 1.29 Impact Factor