Development of attenuated herpes simplex virus vector for analysis of neurological functions.

开发用于分析神经功能的减毒单纯疱疹病毒载体。

• 批准号: 13558094
• 负责人: SHIRAKI Kimiyasu
• 金额: $ 8.38万
• 依托单位: Toyama Medical and Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13558094/
• 关键词: Herpes simplex virus; Viral vector; attenuated vector; neurological function; gene therapy; anterior horn motor neuron; ウイルスベクター; 中枢神経系; 潜伏感染; 単純ヘルペスウイルスベクター; 脊髄前角運動細胞; 神経親和性; 弱毒ウイルス; 遺伝子発現ベクター

We have developed a live attenuated HSV-1 vector, βH1, expressing β-galactosidase (β-gal) in the nervous system. Its subcutaneous inoculation led the expression of β-gal activity in neurons of the sensory ganglia innervating the inoculation site for at least 45 days. βH1 was also sufficient to deliver the foreign gene into motor neurons in the bilateral anterior horn of the spinal cord of rats by an intramuscular inoculation and β-gal expression continued for at least 182 days in 90% of motor neurons in the bilateral anterior horn of spinal cord in a wide range. The presence of immunity to HSV was not an obstacle to deliver the transgene in anterior horn motor neurons in the intramuscularly inoculated rats. Furthermore, βH1 inoculation into the right caudate putamen of rats was efficient in expressing β-gal activity not only in the neurons of the inoculation site but also in the area projecting to the inoculation site, where this spread of area was regulated by an anti-HSV agent, ganciclovir. βH1 is originated from HSV-1 HF strain that is attenuated to mice, and expresses β-gal activity in the central nervous system (CNS), especially motor neurons in spinal cord without causing tissue destruction or inflammation. It would be a broad potential vector for gene therapy for familial amyotrophic lateral sclerosis and CNS diseases

我们已经开发了一种在神经系统中表达β-半乳糖苷酶（β-gal）的HSV-1减毒活载体βH1。其皮下接种导致在支配接种部位的感觉神经节的神经元中表达β-gal活性至少45天。βH1也足以通过肌肉注射将外源基因递送到大鼠脊髓双侧前角运动神经元中，并且在脊髓双侧前角运动神经元中90%的运动神经元中β-gal表达持续至少182天。对HSV免疫的存在并不妨碍转基因在肌内接种大鼠的前角运动神经元中的传递。此外，将βH1接种到大鼠的右侧尾壳核中，不仅在接种部位的神经元中，而且在投射到接种部位的区域中表达β-gal活性，其中该区域的扩散由抗HSV剂更昔洛韦调节。βH1来源于HSV-1 HF株，经小鼠减毒后，在中枢神经系统（CNS），尤其是脊髓运动神经元表达β-gal活性，不引起组织破坏或炎症。该载体有望成为家族性肌萎缩侧索硬化症和中枢神经系统疾病基因治疗的载体

项目成果

Kurokawa, M., Brown, J., Kagawa, Y., Shiraki, K.: "Cytokine-regulatory activity and therapeutic efficacy of cinnamyl derivatives in endotoxin shock"Eur.J.Pharm.. 474. 283-293 (2003)

Kurokawa, M.、Brown, J.、Kakawa, Y.、Shiraki, K.：“肉桂基衍生物在内毒素休克中的细胞因子调节活性和治疗功效”Eur.J.Pharm.. 474. 283-293 (2003)

Kurokawa et al.: "Biological characterization of eugeniin as an anti-herpes simplex virus type 1 compound in vitro and in vivo."Journal of Pharmcology and Experimental Therapeutics. 297. 372-379 (2001)

Kurokawa 等人：“丁子香素作为抗 1 型单纯疱疹病毒化合物的体外和体内生物学特征。”药理学和实验治疗学杂志。

Tropism of varicella-zoster virus to hepatocytes in its pathogenesis and tropism of Oka varicella vaccine to dermal fibroblasts in its attenuation.

水痘带状疱疹病毒的发病机制向肝细胞趋向，Oka水痘疫苗的减毒作用向真皮成纤维细胞趋向。

• 发表时间: 2003
• 期刊: Journal of Infectious Diseases 188
• 作者: Shiraki K;Yoshida Y;Asano Y;Yamanishi K;Takahashi M.
• 通讯作者: Takahashi M.

Phumiamorn S et al.: "Induction of cell-mediated and humoral immunity to hepatitis B surface antigen by a novel adjuvant activity of Oka varicella vaccine"Journal of General Virology. 84. 287-291 (2003)

Phumiamorn S 等人：“通过 Oka 水痘疫苗的新型佐剂活性诱导对乙型肝炎表面抗原的细胞介导和体液免疫”普通病毒学杂志。

Suppression of generation and replication of acyclovir-resistant herpes simplex virus by its sensitive virus.

其敏感病毒抑制阿昔洛韦耐药的单纯疱疹病毒的产生和复制。

• 发表时间: 2004
• 期刊: Journal of Medical Virology 72
• 作者: Okuda T;Kurokawa K;Matsuo K;Honda M;Niimura M;Shiraki;K.
• 通讯作者: K.