FETAL STEM CELL TRANSPLANTATION FOR ALPHA THALASSEMIA

胎儿干细胞移植治疗α地中海贫血

• 批准号: 2230672
• 负责人: Anthony R. Hayward
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2230672
• 关键词: blood disorder diagnosis; bone marrow transplantation; disease /disorder proneness /risk; embryo /fetus surgery; embryonic stem cell; hemoglobin H; homologous transplantation; human fetus tissue; human pregnant subject; major histocompatibility complex; mixed lymphocyte reaction test; newborn human (0-6 weeks); polymerase chain reaction; pregnancy circulation; prenatal diagnosis; thalassemia; tissue mosaicism

Humans grafted with allogeneic bone marrows stem cells at 12-13 weeks of age will develop stable and long lasting chimerism. This hypothesis derives from the observation that T cells do not peripheralize from the human fetal thymus until 14 weeks of gestation, together with the finding that animals grafted with stem cells, before they have T cells develop specific immunologic tolerance. Thus, it may be possible to correct a range of congenital disorders by stem cell transplant prior to irreversible damage. Our response to the RFA focuses on humans because this is the area in which we have specific strengths. Fetuses homozygous for alpha thalassemia (a hemoglobinopathy causing fetal hydrops) will be identified by the Genetics service in Hawaii using an Hba chain specific PCR applied to chorionic villous biopsies obtained at 8-10 weeks gestation. Families with affected fetuses will be offered entry subject to specific criteria and admitted to the CRC at UCHSC by the 12th week of gestation. Marrow will be drawn from an appropriate donor, processed to deplete T cells and enrich for stem cells and then injected into the umbilical vein of affected fetuses at 12-13 weeks. Pregnancies will be monitored every 7 days through week 26 by ECHO. A fetal blood sample (FBS) will be obtained at 19-20 weeks and tested for Hb type and for chimerism by PCR. Fetuses with <10 g/dL of Hb will be transfused with packed red cells. A fetal blood sample will be obtained at 26-28 weeks from surviving fetuses and tested for Hb type, chimerism and alloantigen- specific tolerance. No further treatment will be attempted for fetuses who are not chimeric at this point. Chimeric fetuses will be supported as required through 34-36 weeks and then delivered. Surviving newborns will be retested for chimerism in the erythroid and white cell series, along with the degree of tolerance or alloreactivity. Fetuses who were transfusion dependent at 36-34 weeks will be retransplanted in the newborn period. Our studies will test our underlying hypothesis and will therefore generate data on which fetal grafts of genetically engineered cells might be based.

在移植后12-13周时移植同种异体骨髓干细胞的人 年龄将发展稳定和持久的嵌合体。 这一假设 来源于观察到T细胞不从外周血淋巴细胞中外周化。 人胎儿胸腺，直至妊娠14周，连同发现 移植了干细胞的动物在T细胞发育之前 特异性免疫耐受。 因此，可以校正 干细胞移植前先天性疾病的范围 不可逆转的伤害 我们对RFA的反应集中在人类身上，因为 这是我们的强项。 纯合子胎仔 对于α地中海贫血（一种导致胎儿水肿的血红蛋白病）， 由夏威夷的遗传学服务机构使用Hba链特异性 PCR应用于8-10周时获得的绒毛膜绒毛活检 怀孕 有受影响胎儿的家庭将被提供入学科目 符合特定标准，并在第12周之前进入UCHSC的CRC 妊娠期。 骨髓将从合适的供体中抽取， 耗尽T细胞并富集干细胞，然后注射到 12-13周时受影响胎儿的脐静脉。 怀孕将是 由ECHO每7天监测一次，直至第26周。 一个胎儿的血液样本 (FBS)将在19-20周时获得，并检测Hb类型和 PCR检测嵌合体。 Hb <10 g/dL的胎儿将输注 浓缩红细胞 将在26-28周时采集胎儿血样 从存活的胎儿和测试血红蛋白类型，嵌合体和同种异体抗原- 具体宽容。 不会尝试对胎仔进行进一步治疗 他们现在还不是嵌合体 将支持嵌合体胎儿 根据需要通过34-36周，然后交付。 存活新生儿 将在红系和白色细胞系列中重新检测嵌合体， 沿着耐受性或同种异体反应性的程度。 那些 在36-34周时依赖输血的患者将在 新生儿时期 我们的研究将检验我们的基本假设， 因此可以得出基因工程的胎儿移植物 细胞可能是基础。