Abstract
Gene therapy to treat pharmacoresistant temporal lobe epilepsy in humans is now being developed using an AAV vector (CG01) that encodes the combination of neuropeptide Y and its antiepileptic receptor Y2. With this in mind, the present study aimed to provide important preclinical data on the effects of CG01 on the duration of transgene expression, cellular tropism, and potential side effects on body weight and cognitive function. The CG01 vector was administered unilaterally into the dorsal and ventral hippocampus of adult male rats and expression of both transgenes was found to remain elevated without a sign of decline at 6 months post-injection. CG01 appeared to mediate expression selectively in hippocampal neurons, without expression in astrocytes or oligodendrocytes. No effects were seen on body weight as well as on short- or long-term memory as revealed by testing in the Y-maze or Morris water maze tests. Thus these data show that unilateral CG01 vector treatment as future gene therapy in pharmacoresistant temporal lobe epilepsy patients should result in stable and long-term expression predominantly in neurons and be well tolerated without side effects on body weight and cognitive function.
Highlights
Epilepsy is the fourth most common disorder of the central nervous system, affecting up to 1% of the world population (Fiest et al, 2017)
Gene therapy is being developed for pharmacoresistant temporal lobe epilepsy using unilateral intrahippocampal gene therapy with CG01, an associated viral (AAV) vector mediating overexpression of neuropeptide Y (NPY) and Y2 (Drew, 2018)
Our groups have explored the effects of unilateral NPY/Y2 gene therapy and shown that hippocampal overexpression of both transgenes induces significant seizuresuppressant effect in a chronic rat temporal lobe epilepsy model (Ledri et al, 2016; Melin et al, 2019)
Summary
Epilepsy is the fourth most common disorder of the central nervous system, affecting up to 1% of the world population (Fiest et al, 2017). Many studies have established the seizure-suppressant effects of NPY against seizures in the hippocampus both in rodents (Woldbye et al, 1996, 1997, 2005; Vezzani et al, 1999; Klemp and Woldbye, 2001) and hippocampal slices from pharmacoresistant human epilepsy patients (Patrylo et al, 1999; Ledri et al, 2015; Wickham et al, 2019). The seizure-suppressant effects of NPY appear to be mediated primarily via activation of Y2 receptors (El Bahh et al, 2005) while Y5 receptors may play a role outside the hippocampus (Woldbye et al, 1997, 2005; Marsh et al, 1999). Y1 receptors appear to act in an opposite manner (Benmaamar et al, 2003; Lin et al, 2006; Olesen et al, 2012)
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