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编码神经肽Y及其Y2受体的基因治疗载体用于癫痫的未来治疗：大鼠的临床前数据

Gene Therapy Vector Encoding Neuropeptide Y and Its Receptor Y2 for Future Treatment of Epilepsy: Preclinical Data in Rats.

作者信息

Szczygieł Julia Alicja, Danielsen Kira Iben, Melin Esbjörn, Rosenkranz Søren Hofman, Pankratova Stanislava, Ericsson Annika, Agerman Karin, Kokaia Merab, Woldbye David Paul Drucker

机构信息

Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.

Experimental Epilepsy Group, Epilepsy Centre, Lund University Hospital, Lund, Sweden.

出版信息

Front Mol Neurosci. 2020 Dec 4;13:232. doi: 10.3389/fnmol.2020.603409. eCollection 2020.

DOI:10.3389/fnmol.2020.603409
PMID:33343295
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7746806/
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.

摘要

目前正在研发一种使用腺相关病毒载体（CG01）的基因疗法，用于治疗人类药物难治性颞叶癫痫，该载体编码神经肽Y及其抗癫痫受体Y2的组合。考虑到这一点，本研究旨在提供关于CG01对转基因表达持续时间、细胞嗜性以及对体重和认知功能潜在副作用影响的重要临床前数据。将CG01载体单侧注射到成年雄性大鼠的背侧和腹侧海马体中，发现两个转基因的表达在注射后6个月仍保持升高，没有下降的迹象。CG01似乎在海马神经元中选择性地介导表达，在星形胶质细胞或少突胶质细胞中不表达。在Y迷宫或莫里斯水迷宫测试中进行的测试表明，对体重以及短期或长期记忆均无影响。因此，这些数据表明，作为未来药物难治性颞叶癫痫患者基因疗法的单侧CG01载体治疗应能在神经元中实现稳定且长期的表达，并且耐受性良好，对体重和认知功能无副作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/96b374e74c33/fnmol-13-603409-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/b5bb65e4c819/fnmol-13-603409-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/6b22b74a5f47/fnmol-13-603409-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/b9f447e9ef56/fnmol-13-603409-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/808af9fab846/fnmol-13-603409-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/0efc8d915dd7/fnmol-13-603409-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/6c4424c01c64/fnmol-13-603409-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/bcc265a179d7/fnmol-13-603409-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/96b374e74c33/fnmol-13-603409-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/b5bb65e4c819/fnmol-13-603409-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/6b22b74a5f47/fnmol-13-603409-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/b9f447e9ef56/fnmol-13-603409-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/808af9fab846/fnmol-13-603409-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/0efc8d915dd7/fnmol-13-603409-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/6c4424c01c64/fnmol-13-603409-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/bcc265a179d7/fnmol-13-603409-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d9b/7746806/96b374e74c33/fnmol-13-603409-g0008.jpg

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