Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation
Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation
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DOI：
10.1073/pnas.0607012103
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发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Reisner, Yair
中科院分区：
文献类型：
--
作者：
Aronovich, Anna;Tchorsh, Dalit;Reisner, Yair
先前通过移植同种异体脾来纠正遗传缺陷如血友病或戈谢病的临床尝试与由来自供体脾的成熟T细胞介导的侵袭性移植物抗宿主病相关。我们发现，胎猪脾脏收获在胚胎第42天阶段，T细胞出现之前，移植到SCID小鼠后表现出最佳的生长潜力，和生长组织表达因子VIII。将胚胎第42天的脾组织移植到血友病SCID小鼠中导致在移植后2-3个月内血友病完全缓解，如尾部出血和因子VIII血液水平测定所证明的。这些结果为以下概念提供了原理证明：从T细胞出现之前的发育阶段获得的胎儿脾脏的移植可以为可以被生长的脾脏组织替代的酶或因子的遗传缺陷提供新的治疗方式。
Previous clinical attempts to correct genetic deficiencies such as hemophilia or Gaucher disease by transplantation of allogeneic spleen were associated with aggressive graft versus host disease, mediated by mature T cells derived from the donor spleen. We show that a fetal pig spleen harvested at the embryonic day 42 stage, before the appearance of T cells, exhibited optimal growth potential upon transplantation into SCID mice, and the growing tissue expressed factor VIII. Transplantation of embryonic day 42 spleen tissue into hemophilic SCID mice led to complete alleviation of hemophilia within 2-3 months after transplant, as demonstrated by tail bleeding and by assays for factor VIII blood levels. These results provide a proof of principle to the concept that transplantation of a fetal spleen, obtained from a developmental stage before the appearance of T cells, could provide a novel treatment modality for genetic deficiencies of an enzyme or a factor that can be replaced by the growing spleen tissue.