Postnatal Cell-Based Therapies for Hemophilia A

A 型血友病的产后细胞疗法

• 批准号: 9186030
• 负责人: Graca Duarte Almeida-Porada
• 金额: $ 69.86万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186030
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Autologous; Biological Models; Birth; Blood Circulation; Bone Marrow; Cell Therapy; Cells; Childhood; Clinical; Clinical Management; Coagulation Process; Collection; Complication; Development; Disease; Dose; Engraftment; F8 gene; Goals; Healthcare Systems; Hemarthrosis; Hematopoietic; Hemophilia A; Human; Immune; Immune Tolerance; Immune response; Immune system; In Vitro; Incidence; Infusion procedures; Knowledge; Life; Marrow; Mediating; Methods; Modeling; Organ; Patient Care; Patients; Physical activity; Population; Property; Proteins; Protocols documentation; Quality of life; Recombinants; Recurrence; Risk; Sheep; Site; Stem cells; Stromal Cells; Symptoms; System; Testing; Therapeutic; Time; Transgenes; Transplantation; Treatment Efficacy; Viral; Work; base; boys; cellular engineering; clinical application; cost; early childhood; genetic inhibitor; head-to-head comparison; inhibitor/antagonist; intraperitoneal; novel; novel strategies; novel therapeutics; patient population; postnatal; pre-clinical; preconditioning; prophylactic; success; vector

PROJECT SUMMARY Despite great developments in treatment care for patients with Hemophilia A (HA), still none is curative, and all depend upon lifelong, recurrent, prohibitively expensive, FVIII infusions (≥$600,000/year/patient). In addition, >30% of patients with severe HA develop inhibitory antibodies to FVIII, which is the most serious challenge in the clinical management of HA. There is thus a critical need to develop novel therapies that can offer a longer- lasting/permanent improvement, and/or can defeat the immune hurdles that currently thwart treatment. The delivery of FVIII through a cellular platform, such as marrow stromal cells (MSC), is an appealing approach, since following viral transduction, MSC secrete high levels of vector-encoded FVIII that is indistinguishable from the native protein, and do not transform or progress to clonal dominance. In addition, upon infusion, MSC can lodge long-term in multiple organs within both the parenchyma and the perivascular zones, placing them ideally for delivering FVIII into the circulation. MSC have immunomodulatory/anti-inflammatory properties and, if autologous MSC are used, it may enable FVIII delivery in a tolerogenic fashion. We recently tested the therapeutic potential of FVIII-expressing MSC utilizing a line of sheep that emulates the genetics, inhibitor formation (to administered FVIII protein), and clinical symptoms of the severe form of human HA, and showed that, without recipient preconditioning, the postnatal administration of haploidentical MSC engineered to express high levels of FVIII led to complete phenotypic correction of two pediatric HA sheep, reversal of existing hemarthroses, and return to normal physical activity. Remarkably, this phenotypic correction was long lasting despite the presence of high-titer inhibitors in these sheep, and the engrafted MSC were not cleared by the recipient's immune system, enabling them to persist long-term in multiple sites. This prior work leads us to hypothesize that the delivery of FVIII-expressing MSC results in perivascular engraftment and release of FVIII protein into the circulation at levels that could be curative for HA, and that using MSC to stably deliver high levels of FVIII into the circulation may represent a novel means of clinically correcting HA patients with pre- existing inhibitors. Therefore we propose to: 1) Determine the sites and duration of engraftment of FVIII- producing autologous MSC, and test the ability of this therapy to mediate clinical/phenotypic improvement in sheep recipients with and without pre-existing inhibitors; 2) Test whether the immunomodulatory properties of MSC will enable autologous cells to present FVIII to the FVIII-naïve recipient in a tolerogenic fashion, such that these animals will be inhibitor-free for life; and 3) Investigate whether the continued delivery of FVIII through this MSC-based approach can be used as a novel means of inducing immune tolerance in animals with pre- existing inhibitors, and compare this method with current immune tolerance induction protocols. We hope that these studies will provide the necessary knowledge for the development of a clinically viable therapeutic strategy to treat/cure severe HA and overcome immunological hurdles in patients beset with FVIII inhibitors.

项目摘要 尽管针对血友病A（HA）患者的治疗护理有很大的发展，但仍然没有治疗，所有 取决于终身，经常性，禁止的昂贵的FVIII输注（≥60万美元/年/患者）。此外， > 30％的严重HA发育抑制性抗体的患者对FVIII，这是最严重的挑战 HA的临床管理。因此，迫切需要开发可提供更长的新型疗法 持久/永久改进和/或可以击败当前阻碍治疗的免疫力。这 通过细胞平台（例如骨髓基质细胞（MSC））将FVIII传递是一种外观方法， 自从病毒翻译之后，MSC分泌了无法区分的高水平矢量编码的FVIII 从天然蛋白质，不要转化或发展为克隆优势。另外，输注后，MSC 可以长期在实质和血管周围的多个器官中长期放置，并将其放置 理想情况下，将FVIII输送到循环中。 MSC具有免疫调节/抗炎特性， 如果使用自体MSC，它可能会以耐受性方式实现FVIII。我们最近测试了 使用模拟遗传学，抑制剂的一系列绵羊表达FVIII的治疗潜力 形成（用于施用FVIII蛋白）和严重形式的人HA的临床症状，并显示 在没有接受者预处理的情况下，单倍型MSC的产后管理设计为 表达高水平的FVIII导致两只小儿HA绵羊的完全表型矫正，逆转 现有的呼吸道，并恢复正常的体育锻炼。值得注意的是，这种表型校正很长 持久的任务是这些绵羊中的高晶月抑制剂以及植入的MSC的存在。 接收者的免疫系统使他们能够在多个站点长期持续。这项先前的工作使我们进入 假设表达FVIII的MSC的递送导致血管周围植入和释放FVIII 蛋白质以可以治愈HA的水平进入循环，并使用MSC稳定提供高 FVIII水平进入循环可能代表了一种新的临床纠正HA患者的新方法 现有的抑制剂。因此，我们建议：1）确定fviii-植入的位置和持续时间 产生自体MSC，并测试该疗法介导临床/表型改进的能力 绵羊的接受者有或没有预先存在的抑制剂； 2）测试是否的免疫调节特性是否 MSC将使自体细胞能够以耐受性的方式将FVIII呈现给FVIII-NOI-NOI-NOTH受体 这些动物将无抑制剂生命； 3）调查FVIII是否继续通过 这种基于MSC的方法可以用作具有预先诱发的动物的新型免疫耐受性的方法 现有抑制剂，并将这种方法与当前的免疫耐受诱导方案进行比较。我们希望那样 这些研究将为开发临床可行的治疗提供必要的知识 治疗/治愈严重的HA并克服患有FVIII抑制剂患者的免疫障碍的策略。