In this year alone, nearly 150,000 new cases of epilepsy will be diagnosed in the United States, adding to the estimated 2.5 million Americans (Hirtz, 2007) and 50 million people worldwide (Hauser and Hesdorffer, 1990) affected by the disease. Epilepsy is a chronic neurological condition characterized by recurrent seizures. Although current anti-epileptic medication effectively controls seizures in approximately 70% of people receiving optimal care, these medications are inadequate for the remaining 30% of patients (Cascino, 2008;Kwan, 2000). As both basic and applied neuroscientists, our primary goal is to generate and test novel therapeutics that will provide expanded and improved treatment options for treating epilepsy. Galanin is a small neuropeptide that exerts anticonvulsant, antiseizure, and neuroprotective effects (Mazarati, 2004;Elliott- Hunt et al., 2004). In addition, recent findings suggest that galanin may also be anti-inflammatory (Jonakait et al., 2008, Su et al., 2003). Our lab (e.g. Haberman et al., 2003;McCown, 2006) and others (Lin et al., 2003) provided proof-of-principle that galanin gene transfer can prevent seizures and / or prevent neuronal damage when administered prophylactically. However, it is still unknown whether galanin can prevent or treat epilepsy or seizure-related tissue pathology after an epileptogenic insult.
In Aim 1 of our proposal, we examine whether administering a rapidly-expressing self-complementary adeno-associated galanin vector to susceptible brain areas shortly following chemiconvulsant-induced status epilepticus can ameliorate the ensuing neurodegeneration and / or neuroinflammation following insult.
In Aim 2, we administer a regulatable galanin vector to these same brain areas after chemiconvulsive insult and through controlling expression of the therapeutic, determine whether galanin expression can prevent insult-driven epileptogenesis and / or treat epilepsy. Galanin is a leading candidate for gene therapy treatment of focal epilepsy. However, for it to be a viable therapeutic it must prove effective at treating the pathological state. Ideally, treatment of epilepsy will not only provide protection from seizures, but amelioration of seizure-induced pathology. Our studies examine both the efficacy of galanin to suppress insult-driven tissue pathology, including neurodegeneration and neuroinflammation, and whether galanin can prevent or treat the epileptic state. Thus the proposed studies seek to reduce the burden of neurological disease through discovery and testing of novel and efficacious therapies. The possibility that galanin serves as a neuroprotectant in the seizure-damaged brain opens the door to new therapeutic strategies in the treatment of intractable temporal lobe epilepsy and other neurodegenerative and neuroinflammatory disorders.
Epilepsy afflicts an estimated 2.5 million Americans and 1% of people worldwide, making it one of the most prevalent neurological disorders. Galanin is a promising neuropeptide candidate for treating intractable focal epilepsy based on prophylactic studies, but its ability to ameliorate seizure-induced neuropathology or treat epilepsy is unknown. Through post-insult administration of rapidly expressing or regulatable galanin vectors, we will directly test whether galanin can serve as a viable therapeutic option to prevent seizures and seizure- related pathology in the injured brain.
|Weinberg, Marc S; Nicolson, Sarah; Bhatt, Aadra P et al. (2014) Recombinant adeno-associated virus utilizes cell-specific infectious entry mechanisms. J Virol 88:12472-84|
|Bartus, Raymond T; Weinberg, Marc S; Samulski, R Jude (2014) Parkinson's disease gene therapy: success by design meets failure by efficacy. Mol Ther 22:487-497|
|Donegan, Jennifer J; Girotti, Milena; Weinberg, Marc S et al. (2014) A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex. J Neurosci 34:953-62|
|Weinberg, Marc S; Blake, Bonita L; McCown, Thomas J (2013) Opposing actions of hippocampus TNF? receptors on limbic seizure susceptibility. Exp Neurol 247:429-37|
|He, Yi; Weinberg, Marc S; Hirsch, Matt et al. (2013) Kinetics of adeno-associated virus serotype 2 (AAV2) and AAV8 capsid antigen presentation in vivo are identical. Hum Gene Ther 24:545-53|
|Weinberg, Marc S; McCown, Thomas J (2013) Current prospects and challenges for epilepsy gene therapy. Exp Neurol 244:27-35|
|Weinberg, Marc S; Samulski, R Jude; McCown, Thomas J (2013) Adeno-associated virus (AAV) gene therapy for neurological disease. Neuropharmacology 69:82-8|