Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats

Abstract

Somatostatin is expressed widely in the hippocampus and notably in hilar GABAergic neurons that are vulnerable to seizure neuropathology in chronic temporal lobe epilepsy. We previously demonstrated that sustained bilateral preprosomatostatin (preproSST) expression in the hippocampus prevents the development of generalized seizures in the amygdala kindling model of temporal lobe epilepsy. Here we tested whether sustained preproSST expression is anticonvulsant in rats already kindled to high-grade seizures. Rats were kindled until they exhibited 3 consecutive Racine Grade 5 seizures before adeno-associated virus serotype 5 (AAV5) vector driving either eGFP (AAV5-CBa-eGFP) or preproSST and eGFP (AAV5-CBa-preproSST-eGFP) expression was injected bilaterally into the hippocampal dentate gyrus and CA1 region. Retested 3 weeks later, rats that received control vector (AAV5-CBa-eGFP) continued to exhibit high-grade seizures whereas 6/13 rats that received preproSST vector (AAV5-CBa-preproSST-eGFP) were seizure-free. Of these rats, 5/6 remained seizure-free after repeated stimulation sessions and when the stimulation current was increased. These results suggest that vector-mediated expression of preproSST may be a viable therapeutic strategy for temporal lobe epilepsy.

Current Strategies for Brain Drug Delivery

“…Serious adverse effects were reported in the clinical trial, but it was not clear whether the adverse effects were directly attributed to the AAV2 CU hCLN2 vector 23 . Currently, new viral vectors have been developed to treat various brain diseases; however, most approaches still followed direct injection into the brain 24 , 25 . Thus, safe and systemic delivery is the key focus in the development of novel viral vectors for brain gene therapy.…”

Gene and Cell Therapy for Epilepsy: A Mini Review

“…For example, the introduction of AAV encoding the glial cell line-derived neurotrophic factor (GDNF) gene or the γ-aminobutyric acid decarboxylase 67 (GAD67) gene reduced the seizure frequency in the TLE model ( Kanter-Schlifke et al, 2007 ; Shimazaki et al, 2019 ). Moreover, promising results were demonstrated for AVVs encoding preprosomatostatin injected into the hippocampus ( Natarajan et al, 2017 ).…”

Hyperexcitability: From Normal Fear to Pathological Anxiety and Trauma

“…This is selective for somatostatinergic interneurons as there are small or no changes in the total number of GABAergic or parvalbumin-GABAergic neurons ( Botterill et al, 2017 ). Pharmacologically, somatostatin, somatostatin agonists, and sustained adeno-associated viral mediated somatostatin expression in the dentate gyrus suppress development and expression of kindling and kindling-induced neurogenesis of excitatory granule cells ( Vezzani and Hoyer, 1999 ; Zafar et al, 2012 ; Natarajan et al, 2017 ; Leibowitz et al, 2019 ). Endogenous somatostatin expression increases as kindling proceeds from partial to full kindling ( Shinoda et al, 1991 ) and both basal and stimulated somatostatin release in the dentate gyrus is enhanced following kindling ( Marti et al, 2000 ).…”