Gene therapy for canine alpha-L-iduronidase deficiency: in utero adoptive transfer of genetically corrected hematopoietic progenitors results in engraftment but not amelioration of disease.
Gene therapy for canine alpha-L-iduronidase deficiency: in utero adoptive transfer of genetically corrected hematopoietic progenitors results in engraftment but not amelioration of disease.
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犬α-L-艾杜糖酸酶缺乏症的基因治疗：基因校正的造血祖细胞在子宫内过继转移导致植入，但不能改善疾病。
DOI：
10.1089/10430349950017851
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发表时间：
1999
影响因子：
4.2
通讯作者：
Ian D. Dubé
中科院分区：
文献类型：
--
作者：
Carolyn Lutzko;Fusayuki Omori;A. Abrams;Robert M. Shull;Liheng Li;K. Lau;Christine Ruedy;S. Nanji;Cathy Gartley;H. Dobson;Robert A. Foster;Stephen A. Kruth;Ian D. Dubé
犬α - l -伊杜糖醛酸酶（伊杜糖醛酸酶）缺乏症是人类溶酶体储存障碍粘多糖病I型（MPS I）的一个模型。我们用这个犬模型来评估造血干细胞（HSC）基因治疗酶缺乏症的治疗潜力。在之前的研究中，伊杜糖醛酸酶缺乏的狗注入基因修饰的表达伊杜糖醛酸酶的自体骨髓细胞，长期植入原病毒标记的细胞，但没有证据表明原病毒伊杜糖醛酸酶的表达或临床改善。在这些实验中，针对伊杜糖醛酸酶的体液和细胞免疫反应的存在显然取消了HSC基因治疗的治疗潜力。为了评估HSC基因治疗在没有混淆免疫反应的情况下对犬MPS I的治疗效果，我们现在已经在子宫内将伊杜脲酶转导的MPS I骨髓细胞过继移植到免疫前的胎仔体内。在三个独立的实验中，17只妊娠中期胎仔注射了0.5-1.5 × 10(7)个正常或MPS I异体长期骨髓培养（LTMC）细胞，这些细胞被neo(r)-或含有伊杜糖醛酸酶的逆转录病毒载体转导。9只正常和3只MPS I幼崽在新生儿期存活下来，并在长达12个月的时间里，以高达12%的水平植入了当地标记的祖细胞。然而，原标记循环白细胞的比例约为1%。在任何MPSⅰ型犬的血液或骨髓白细胞中均未检测到伊杜糖醛酸酶或前病毒特异性转录物。在新生儿中未检测到对伊杜糖醛酸酶的体液免疫反应，即使在自体伊杜糖醛酸酶转导的LTMC细胞“增强”后也是如此。所有MPS I型犬在8-11月龄时死于MPS I型疾病的并发症，没有证据表明MPS I型疾病有所改善。我们的研究结果表明，伊杜糖醛酸酶转导的原始造血祖细胞可以移植到胎儿受体中，促进造血，并诱导MPS I犬对伊杜糖醛酸酶的免疫无反应。然而，在这种伊杜糖醛酸酶缺乏症模型中，HSC基因转移的治疗潜力似乎受到前病毒伊杜糖醛酸酶基因表达维持不良和基因校正循环白细胞水平相对较低的限制。
Canine alpha-L-iduronidase (iduronidase) deficiency is a model of the human lysosomal storage disorder mucopolysaccharidosis type I (MPS I). We used this canine model to evaluate the therapeutic potential of hematopoietic stem cell (HSC) gene therapy for enzyme deficiencies. In previous studies, iduronidase-deficient dogs infused with autologous marrow cells genetically modified to express iduronidase had long-term engraftment with provirally marked cells, but there was no evidence of proviral iduronidase expression or clinical improvement. The presence of humoral and cellular immune responses against iduronidase apparently abrogated the therapeutic potential of HSC gene therapy in these experiments. To evaluate HSC gene therapy for canine MPS I in the absence of a confounding immune response, we have now performed in utero adoptive transfer of iduronidase-transduced MPS I marrow cells into preimmune fetal pups. In three separate experiments, 17 midgestation fetal pups were injected with 0.5-1.5 x 10(7) normal or MPS I allogeneic long-term marrow culture (LTMC) cells transduced with neo(r)- or iduronidase-containing retroviral vectors. Nine normal and three MPS I pups survived the neonatal period and demonstrated engraftment of provirally marked progenitors at levels of up to 12% for up to 12 months. However, the proportion of provirally marked circulating leukocytes was approximately 1%. Neither iduronidase enzyme nor proviral-specific transcripts were detected in blood or marrow leukocytes of any MPS I dog. Humoral immune responses to iduronidase were not detected in neonates, even after "boosting" with autologous iduronidase-transduced LTMC cells. All MPS I dogs died at 8-11 months of age from complications of MPS I disease with no evidence of amelioration of MPS I disease. Our results suggest that iduronidase-transduced primitive hematopoietic progenitors can engraft in fetal recipients, contribute to hematopoiesis, and induce immunologic nonresponsiveness to iduronidase in MPS I dogs. However, the therapeutic potential of HSC gene transfer in this model of iduronidase deficiency appears to be limited by poor maintenance of proviral iduronidase gene expression and relatively low levels of genetically corrected circulating leukocytes.
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1992
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