Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency.
Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency.
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DOI：
10.1038/sj.mt.6300393
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发表时间：
2008-03
期刊：
影响因子：
--
通讯作者：
Thrasher AJ
中科院分区：
文献类型：
--
作者：
Thornhill SI;Schambach A;Howe SJ;Ulaganathan M;Grassman E;Williams D;Schiedlmeier B;Sebire NJ;Gaspar HB;Kinnon C;Baum C;Thrasher AJ
X连锁严重联合免疫缺陷症（SCID-X1）的基因治疗已被证明对于长期恢复人类受试者的免疫力非常有效。然而，由于原癌基因表达失调而导致的淋巴增殖并发症的发生强调了开发更安全的载体系统的必要性。为了减少插入突变的可能性，我们评估了自失活（SIN）γ逆转录病毒载体在 SCID-X1 细胞和体内模型中的功效。包含内部人延伸因子-1α调节元件的载体能够完全恢复γc缺陷谱系阴性细胞的淋巴分化潜力。小鼠模型的多系淋巴重建达到了与先前临床试验中使用的传统长末端重复（LTR）调节载体相似的水平。对促有丝分裂刺激的功能性增殖反应也得到恢复，血清免疫球蛋白水平也恢复正常。 SIN 载体配置和替代的非 LTR 调控元件所带来的诱变潜力降低，加上已证实的纠正细胞缺陷的功效，为 SCID-X1 下一阶段临床试验的开发提供了重要平台。
Gene therapy for X-linked severe combined immunodeficiency (SCID-X1) has proven highly effective for long-term restoration of immunity in human subjects. However, the development of lymphoproliferative complications due to dysregulated proto-oncogene expression has underlined the necessity for developing safer vector systems. To reduce the potential for insertional mutagenesis, we have evaluated the efficacy of self-inactivating (SIN) gammaretroviral vectors in cellular and in vivo models of SCID-X1. Vectors incorporating an internal human elongation factor-1α regulatory element were capable of fully restoring the lymphoid differentiation potential of γc-deficient lineage negative cells. Multilineage lymphoid reconstitution of a murine model was achieved at a similar level to that achieved by a conventional long-terminal repeat (LTR)-regulated vector used in previous clinical trials. Functional proliferative responses to mitogenic stimuli were also restored, and serum immunoglobulin levels were normalized. The reduced mutagenic potential conferred by SIN vector configurations and alternative non-LTR-based regulatory elements, together with proven efficacy in correction of cellular defects provides an important platform for development of the next phase of clinical trials for SCID-X1.
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影响因子：
5.1
作者：
Kraunus, J;Schaumann, DHS;Baum, C
通讯作者：
Baum, C
影响因子：
158.5
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
通讯作者：
Leiva, L
影响因子：
20.3
作者：
Modlich, Ute;Bohne, Jens;Baum, Christopher
通讯作者：
Baum, Christopher
影响因子：
15.9
作者：
Deichmann, Annette;Hacein-Bey-Abina, Salima;Cavazzana-Calvo, Marina
通讯作者：
Cavazzana-Calvo, Marina
影响因子：
168.9
作者：
Antoine, C;Müller, S;Fischer, A
通讯作者：
Fischer, A