Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine (WFSOM), Winston Salem, NC, USA.
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, GA, USA.
Nat Commun. 2023 Jul 14;14(1):4206. doi: 10.1038/s41467-023-39986-1.
Hemophilia A is the most common X-linked bleeding disorder affecting more than half-a-million individuals worldwide. Persons with severe hemophilia A have coagulation FVIII levels <1% and experience spontaneous debilitating and life-threatening bleeds. Advances in hemophilia A therapeutics have significantly improved health outcomes, but development of FVIII inhibitory antibodies and breakthrough bleeds during therapy significantly increase patient morbidity and mortality. Here we use sheep fetuses at the human equivalent of 16-18 gestational weeks, and we show that prenatal transplantation of human placental cells (10-10/kg) bioengineered to produce an optimized FVIII protein, results in considerable elevation in plasma FVIII levels that persists for >3 years post-treatment. Cells engraft in major organs, and none of the recipients mount immune responses to either the cells or the FVIII they produce. Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating hemophilia A prior to birth.
血友病 A 是最常见的伴 X 染色体隐性遗传性出血性疾病，影响全球超过 50 万人。重度血友病 A 患者凝血因子 VIII 水平 <1%，会自发出现使人衰弱且危及生命的出血。血友病 A 治疗方法的进步显著改善了健康结果，但在治疗过程中产生 FVIII 抑制性抗体和突破性出血会显著增加患者的发病率和死亡率。在这里，我们使用相当于人类 16-18 孕周的绵羊胎儿，并表明对经过生物工程改造以产生优化的 FVIII 蛋白的人胎盘细胞（10-10/kg）进行产前移植，可使血浆 FVIII 水平显著升高，并在治疗后持续>3 年。细胞在主要器官中定植，且没有一个受者对细胞或其产生的 FVIII 产生免疫反应。因此，这些研究证明了在出生前治疗血友病 A 的可行性、免疫优势和安全性。
