Postnatal Cell-Based Therapies for Hemophilia A

A 型血友病的产后细胞疗法

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管 A 型血友病 (HA) 患者的治疗护理取得了巨大进展，但仍然没有一种药物能够治愈，并且所有依赖于终身、反复、昂贵的 FVIII 输注（≥600,000 美元/年/患者）。 >30% 的严重 HA 患者会产生 FVIII 抑制性抗体，这是最严重的挑战因此，迫切需要开发能够提供更长期治疗的新疗法。持久/永久的改善，和/或可以克服目前阻碍治疗的免疫障碍。通过骨髓基质细胞 (MSC) 等细胞平台递送 FVIII 是一种颇具吸引力的方法，由于病毒转导后，MSC 会分泌高水平的载体编码的 FVIII，且无法区分来自天然蛋白质，并且不会转化或进展为克隆优势。此外，在输注后，MSC。可以长期停留在实质和血管周围区域内的多个器官中，将它们放置在 MSC 具有免疫调节/抗炎特性，非常适合将 FVIII 输送到循环系统中。如果使用自体 MSC，它可能会以耐受性方式递送 FVIII。我们最近测试了该方法。利用模仿遗传、抑制剂的绵羊品系表达 FVIII 的 MSC 的治疗潜力人类 HA 严重形式的形成（施用 FVIII 蛋白）和临床症状，并显示在没有接受者预处理的情况下，半相合 MSC 的出生后施用被设计为表达高水平的 FVIII 导致两只儿科 HA 羊的表型完全纠正，逆转值得注意的是，这种表型纠正持续了很长时间。尽管这些羊体内存在高滴度抑制剂，但移植的 MSC 并未被清除接受者的免疫系统，使它们能够长期存在于多个位点。研究表明，表达 FVIII 的 MSC 的递送会导致 FVIII 的血管周围植入和释放蛋白质进入循环系统的水平可以对 HA 起到治疗作用，并且使用 MSC 可以稳定地提供高水平进入循环系统的 FVIII 水平可能代表一种临床纠正 HA 患者预因此，我们建议： 1) 确定 FVIII- 的植入位点和持续时间。产生自体 MSC，并测试该疗法介导临床/表型改善的能力具有或不具有预先存在的抑制剂的绵羊受体；2) 测试是否具有免疫调节特性 MSC 将使自体细胞能够以耐受方式将 FVIII 呈递给未接触过 FVIII 的接受者，从而这些动物将终生不受抑制剂的影响；以及 3) 研究是否通过持续递送 FVIII 这种基于间充质干细胞的方法可以用作诱导动物免疫耐受的新方法。现有的抑制剂，并将该方法与当前的免疫耐受诱导方案进行比较。这些研究将为开发临床上可行的治疗方法提供必要的知识治疗/治愈严重 HA 并克服受 FVIII 抑制剂困扰的患者的免疫障碍的策略。