Establishment of the gene therapy model for protecting retroviral infection

保护逆转录病毒感染的基因治疗模型的建立

• 批准号: 11670206
• 负责人: KITAGAWA Masanobu
• 金额: $ 1.6万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670206/
• 关键词: retrovirus; Friend leukemia virus; gene therapy; レトロウィルス; フレンド白血病ウィルス; Fv-4

To establish the gene therapy model for retrovirus-induced disease, experiments using murine Friend leukemia virus (FLV) system were performed. We transduced the Fv-4^r gene that was the host resistant gene against ecotropic murine leukemia virus found in wild mouse. This gene encodes a truncated form of ENV protein which would bind to the receptor of the virus to block viral infection of the same receptor-specificity.First of all, we searched for the condition to produce gene transfer system with good expression efficacy. Transduced Fv-4^r gene was well expressed in the hematopoietic cells and thus we could generate the bone marrow chimera mice by transplantation of Fv-4^r transduced bone marrow cells. Mice transduced with Fv-4^r gene were resistant to FLV-infection.Next, mechanisms for the resistance by transduced Fv-4^r gene in bone marrow chimera mice were examined. By using FLV-ENV-GFP system, we clarified the receptor interference effect of Fv-4^r gene product in bone marrow chimera mice.Finally, we analyzed the Fv-4^r gene therapy effect in immunosuppressed hosts. Fv-4^r gene therapy was also effective in thymectomized mice.In summary, our gene therapy model was effective for resisting FLV-induced disease and the efficacy was transferred through receptor interference mechanism by the gene product. Because the therapy was effective even under the immunosuppressed condition of the hosts, human diseases by retrovirus such as AIDS would also be the target of this kind of gene therapy.

为建立逆转录病毒诱导疾病的基因治疗模型，利用小鼠Friend白血病病毒(Flv)系统进行了实验。我们将野生型小鼠白血病病毒的宿主抗性基因Fv-4^r基因导入野鼠体内。该基因编码截短形式的ENV蛋白，可与病毒的受体结合，阻断同一受体特异性的病毒感染。首先，我们寻找了产生良好表达效果的基因转移系统的条件。转导的FV-4^r基因在造血细胞中表达良好，可通过移植FV-4^r转导的骨髓细胞产生骨髓嵌合体小鼠。转导FV-4^r基因的小鼠对流感病毒感染具有抵抗力。其次，探讨了转导FV-4^r基因的骨髓嵌合体小鼠产生抵抗力的机制。利用FLV-ENV-GFP系统，阐明FV-4^R基因产物在骨髓嵌合体小鼠体内的受体干扰作用，并对FV-4^R基因在免疫抑制宿主中的治疗作用进行分析。Fv-4^r基因治疗对去胸腺小鼠同样有效。综上所述，我们的基因治疗模型是有效的，其作用是通过基因产物通过受体干扰机制来实现的。由于这种治疗即使在宿主免疫抑制的情况下也是有效的，因此逆转录病毒感染的人类疾病，如艾滋病，也将成为这种基因治疗的靶点。

项目成果

Kitagawa M, et al.: "A gene therapy model for retrovirus-iudutced disease with a vival env gene expression-dependent resistance in immunosuppressed hosts"Leukemia. 15. 1779-1784 (2001)

Kitakawa M等人：“一种用于逆转录病毒引起的疾病的基因治疗模型，在免疫抑制的宿主中具有活的env基因表达依赖性抵抗力”白血病。

Yamaguchi S,Kitagawa M, et al.: "Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia."Mechanisms of Ageing and Development. (in press).

Yamaguchi S，Kitakawa M，等人：“淋巴细胞在对弗兰德白血病病毒诱发的白血病易感性的年龄相关变化中的作用。”衰老和发育的机制。

Kitagawa M,et al.: "Protection of retrovirus-induced disease by transplantation of bone marrow cells transduced with MuLV env via retrovirus vector"Experimental Hematology. 27. 234-241 (1999)

Kitakawa M,et al.：“通过逆转录病毒载体转导 MuLV env 的骨髓细胞移植来保护逆转录病毒诱导的疾病”实验血液学。

Kitagawa. M. et al.: "A gene therapy model for retrovirus-induced disease with a viral env gene ; expression-dependent resistance in immunosuppressed hosts"Leukemia. Vol. 15. 1779-1784 (2001)

北川。

Kitagawa M, et al.: "A gene therapy model for retrovirus-infuced disease with a viral env gene : expression-dependent resistance in immunosuppressed hosts"Leukemia. 15. 1779-1784 (2001)

Kitakawa M 等人：“用病毒 env 基因治疗逆转录病毒感染疾病的基因治疗模型：免疫抑制宿主中的表达依赖性耐药性”白血病。