Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States.
Special Hematology Laboratory, Wake Forest School of Medicine, Winston-Salem, NC, United States.
Front Immunol. 2022 Dec 2;13:1070476. doi: 10.3389/fimmu.2022.1070476. eCollection 2022.
Hemophilia A (HA) is the most common X-linked bleeding disorder, occurring in 1 in 5,000 live male births and affecting >1 million individuals worldwide. Although advances in protein-based HA therapeutics have improved health outcomes, current standard-of-care requires infusion 2-3 times per week for life, and 30% of patients develop inhibitors, significantly increasing morbidity and mortality. There are thus unmet medical needs requiring novel approaches to treat HA.
We tested, in a highly translational large animal (sheep) model, whether the unique immunological and biological properties of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) could enable them to serve as cellular delivery vehicles to provide long-term expression of FVIII, avoiding the need for frequent infusions.
We show that autologous BM-MSCs can be isolated, transduced with a lentivector to produce high levels of ovine (o)FVIII, extensively expanded, and transplanted into adult animals safely. The transplanted cells engraft in multiple organs, and they stably produce and secrete sufficient quantities of FVIII to yield elevated plasma FVIII levels for at least 15 weeks.
These studies thus highlight the promise of cellular-based gene delivery approaches for treating HA.
血友病 A（HA）是最常见的 X 连锁出血性疾病，每 5000 例活产男婴中就有 1 例发病，影响全球超过 100 万人。尽管基于蛋白的 HA 治疗方法取得了进展，改善了健康结果，但目前的标准治疗需要终生每周输注 2-3 次，并且 30%的患者会产生抑制剂，显著增加发病率和死亡率。因此，需要新的方法来治疗 HA，以满足未满足的医疗需求。
我们在高度转化的大型动物（绵羊）模型中测试了，自体骨髓（BM）来源的间充质基质细胞（MSCs）独特的免疫和生物学特性是否可以使它们能够作为细胞输送载体，提供 FVIII 的长期表达，避免频繁输注的需要。
我们表明，可以分离自体 BM-MSCs，用慢病毒载体转导以产生高水平的绵羊（o）FVIII，进行广泛扩增，并安全地移植到成年动物体内。移植的细胞在多个器官中定植，并稳定地产生和分泌足够量的 FVIII，使血浆 FVIII 水平升高至少 15 周。
这些研究因此强调了细胞为基础的基因传递方法治疗 HA 的前景。
