Kustova Angelina O, Gavrish Maria S, Sergeeva Marina A, Avlasenko Daria A, Kiseleva Anna O, Epifanova Ekaterina A, Babaev Alexey A, Mishchenko Tatiana A, Vedunova Maria V
Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia.
Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Brain Sci. 2022 Aug 4;12(8):1039. doi: 10.3390/brainsci12081039.
The high prevalence of diagnosed cases of severe neurological disorders, a significant proportion of which are epilepsy, contributes to a high level of mortality and disability in the population. Neurotrophic factors BDNF and GNDF are considered promising agents aimed at increasing the central nervous system's adaptive potential for the development of the epileptiform activity. Despite the pronounced neuroprotective and anticonvulsant potential, an appropriate way to stimulate these endogenous signaling molecules with minimal risk of side effects remains an open question. Herein, we assessed the safety of gene therapy using original adeno-associated viral constructs carrying the genes of neurotrophic factors BDNF and GDNF in the early postnatal period of development of experimental animals. The intraventricular injection of AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs into newborn mice was found to provide persistent overexpression of target genes in the hippocampus and cerebral cortex in vivo for four weeks after injection. The application of viral constructs has a multidirectional effect on the weight and body length characteristics of mice in the early postnatal period; however, it ensures the animals' resistance to the development of seizure activity under audiogenic stimulation in the late postnatal period and preserves basic behavioral reactions, emotional status, as well as the mnestic and cognitive abilities of mice after simulated stress. Our results demonstrated the safety of using the AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs in vivo, which indicates the expediency of further testing the constructs as therapeutic anticonvulsants.
严重神经疾病确诊病例的高患病率，其中很大一部分是癫痫，导致了人群中的高死亡率和残疾率。神经营养因子BDNF和GNDF被认为是有前景的药物，旨在提高中枢神经系统对癫痫样活动发展的适应潜力。尽管具有显著的神经保护和抗惊厥潜力，但以最小副作用风险刺激这些内源性信号分子的合适方法仍然是一个悬而未决的问题。在此，我们评估了在实验动物发育的出生后早期使用携带神经营养因子BDNF和GDNF基因的原始腺相关病毒构建体进行基因治疗的安全性。发现向新生小鼠脑室内注射AAV-Syn-BDNF-eGFP和AAV-Syn-GDNF-eGFP病毒构建体可在注射后四周内在体内使海马体和大脑皮层中的靶基因持续过表达。病毒构建体的应用对出生后早期小鼠的体重和体长特征有多向性影响；然而，它可确保动物在出生后晚期接受听源性刺激时对癫痫发作活动的发展具有抵抗力，并在模拟应激后保留小鼠的基本行为反应、情绪状态以及记忆和认知能力。我们的结果证明了在体内使用AAV-Syn-BDNF-eGFP和AAV-Syn-GDNF-eGFP病毒构建体的安全性，这表明进一步将这些构建体作为治疗性抗惊厥药物进行测试是可行的。
