Immunomodulatory Gene Therapy Prevents Antibody Formation and Lethal Hypersensitivity Reactions in Murine Pompe Disease
Immunomodulatory Gene Therapy Prevents Antibody Formation and Lethal Hypersensitivity Reactions in Murine Pompe Disease
复制标题
DOI：
10.1038/mt.2009.195
复制
发表时间：
2010-02-01
影响因子：
12.4
通讯作者：
Koeberl, Dwight D.
中科院分区：
文献类型：
--
作者：
Sun, Baodong;Kulis, Michael D.;Koeberl, Dwight D.
婴儿庞贝病在缺乏有效治疗的情况下会发展为一种致命的心肌病。重组人酸性α-葡萄糖苷酶(RhGAA)的酶替代疗法(ERT)对大多数Pompe病患者有效，但由于高滴度抗体应答而降低了疗效。与模型组小鼠相比，低剂量的腺相关病毒载体(2×10(10)个颗粒)免疫调节基因治疗显著降低了庞贝病小鼠的GAA免疫球蛋白G、IgG1和IgE抗体(P<；0.05)。AAV-LSPhGAApA对GAA抗体的产生有相同的影响，无论是在注射GAA之前、之后或与初始GAA注射同时注射。服用AAV-LSPhGAApA的小鼠在GAA攻击后体温下降(P<；0.001)和过敏评分(P<；0.01)显著降低。小鼠肥大细胞蛋白-1(MMCP-1)的表达模式与超敏反应相关(P<；0.05)。调节性T细胞(Treg)被证明在基因治疗诱导的耐受中起作用，因为Treg的缺失导致GAa特异性免疫球蛋白的增加(P<；0.001)。Treg耗竭的小鼠被GAA挑战，并且比接受基因治疗而没有随后Treg耗竭的小鼠有显著更强的过敏反应(温度：P<；0.01；症状：P<；0.05)。无处不在的GAA表达未能阻止抗体的形成。因此，免疫调节基因治疗可以为酶替代治疗溶酶体储存障碍提供辅助治疗。
Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 x 10(10) particles) containing a liver-specific regulatory cassette significantly lowered immuno-globin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement.