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.

为了建立逆转录病毒诱导疾病的基因治疗模型，采用小鼠Friend白血病病毒（FLV）系统进行了实验。我们将野生小鼠中发现的抗嗜生态小鼠白血病病毒的宿主抗性基因Fv-4^r转导到宿主。该基因编码一种截断的ENV蛋白，这种蛋白可以与病毒的受体结合，从而阻断病毒对同一受体特异性的感染。首先，我们寻找产生具有良好表达效能的基因转移系统的条件。转导后的Fv-4^r基因在造血细胞中表达良好，因此可以通过移植Fv-4^r转导的骨髓细胞产生骨髓嵌合体小鼠。转染Fv-4^r基因的小鼠对flv感染具有抗性。接下来，研究了Fv-4^r基因在骨髓嵌合体小鼠体内的耐药性机制。利用FLV-ENV-GFP系统，阐明了Fv-4^r基因产物对骨髓嵌合体小鼠受体的干扰作用。最后，我们分析了Fv-4^r基因在免疫抑制宿主中的治疗效果。Fv-4^r基因治疗对去胸腺小鼠也有效。综上所述，我们的基因治疗模型对flv诱导的疾病是有效的，其疗效是通过基因产物的受体干扰机制转移的。由于这种疗法即使在宿主免疫抑制的情况下也是有效的，因此艾滋病等由逆转录病毒引起的人类疾病也将成为这种基因治疗的目标。

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。