Stimulant for stem cell expansion in vivo to speed recovery of neutropenia secondary to chemotherapy and stem cell transplant

项目总结 造血干细胞移植(HSCT)被认为是治疗慢性粒细胞白血病患者的一种潜在选择。 在美国，每年有超过20,000例血液和骨髓癌以及超过20,000例造血干细胞移植。 然而，造血干细胞移植的风险很高，因为在移植之前需要切除患病的骨髓。 移植。直到移植的细胞植入并增殖到足以重建患者的免疫系统 系统中，患者被认为是中性粒细胞减少症，在此期间他们极易受到感染。除了……之外 中性粒细胞减少症可能危及患者的生命，因此需要较长的住院时间。 Can在一定程度上推动了HSCT在美国的昂贵费用，根据捐赠者的不同，费用从200,000美元到400,000美元不等 单元类型。目前临床试验中的一种策略是移植更大的供者造血干细胞池以缩短中性粒细胞减少的时间 相位。然而，这些方法都依赖于供体细胞的体外培养，而供体细胞依赖于不完美的人- 制造的培养系统可能会扰乱干细胞的正常功能，而且可能昂贵得令人望而却步。 特修斯之船的创新解决方案是一种药物，将用于在供体细胞之前短暂的一次性接触 到促进体内扩张的移植。我们的药物是同源盒蛋白B4的专利突变体 (HOXB4(M))。HOXB4在不改变分化的情况下促进HSC的扩张是行之有效的。然而，它的 由于HOXB4蛋白的半衰期太短而不能用于临床，因此停止了临床应用 临床应用和HOXB4基因过表达导致骨髓增生性疾病。我们的专利突变体 提高了耐降解性，延长了其细胞内的半衰期，足以用于临床 同时潜在地避免了结构性过度表达所引起的不良影响。有早期的临床前数据 提示用HOXB4(M)处理细胞可以扩大所有主要的造血干细胞谱系，同时保持多能性。 该第一阶段SBIR建议的目标是在体内进行HOXB4(M)的安全性和有效性的概念验证。 这将通过执行两个目标来实现。在目标1中，我们将演示HOXB4(M)处理 与赋形剂处理相比，小鼠对小鼠HSCT后，细胞可以在短时间内减少中性粒细胞减少的阶段。 术语模型。在目标2中，我们展示了长期的造血重建，没有不良反应或GVHD。 我们将在长期模型中用HOXB4(M)或赋形剂处理人HSCs的小鼠进行HSCT。 这一第一阶段计划的成功完成将证明HOXB4(M)作为治疗HSC的药物的可行性 并提供必要的数据，以支持广泛的体内有效性和安全性研究 提交IND所需的第二阶段计划。使用HOXB4(M)，我们可以绕过最初的障碍 HOXB4和改善体内扩张通过缩短中性粒细胞减少减少中性粒细胞减少而造福HSCT患者 感染、住院时间和费用。

PROJECT SUMMARY Hematopoietic stem cell (HSC) transplants (HSCTs) are considered a potentially curative option for patients with certain cancers of the blood and bone marrow and over 20,000 HSCTs are performed in the US each year. However, HSCTs are associated with high risk due to the required removal of diseased bone marrow before transplantation. Until the transplanted cells engraft and proliferate enough to reconstitute the patient’s immune system, the patient is considered neutropenic during which they are highly susceptible to infection. In addition to the potentially life-threatening physical risk to the patient, neutropenia necessitates long hospitalization time that can in part drives the expensive cost of HSCTs ranging from $200,000-400,000 in the US depending on donor cell type. A current strategy in clinical trials is to transplant larger pools of donor HSCs to shorten the neutropenic phase. However, these approaches all rely on ex vivo culturing of donor cells that depend on imperfect man- made culture systems that may disrupt the proper function of the stem cells and can be prohibitively expensive. Ship of Theseus’ innovative solution is a drug that will be used for a brief, one-time exposure to donor cells prior to transplantation that improves expansion in vivo. Our drug is a patented mutant of Homeobox protein B4 (HOXB4(m)). HOXB4 is well-established to promote HSC expansion without altering differentiation. However, its progression to the clinic was stopped because the half-life of HOXB4 protein was too short to be practical for clinical use and genetically overexpressing HOXB4 resulted in myeloproliferative disorders. Our patented mutant has improved degradation resistance, elongating its intracellular half-life enough to be practical for clinical use while potentially avoiding adverse effects induced by constitutive overexpression. There is early preclinical data indicating treating cells with HOXB4(m) can expand all major lineages of HSCs while maintaining multipotency. The goal of this Phase I SBIR proposal is to perform proof-of-concept in vivo safety and efficacy of HOXB4(m). This will be accomplished through the execution of 2 aims. In Aim 1, we will demonstrate HOXB4(m)-treated cells can reduce the neutropenic phase compared to vehicle-treated after mouse-to-mouse HSCT in a short- term model. In Aim 2, we demonstrate long-term hematopoietic reconstitution without adverse effects or GVHD. We will perform HSCTs in mice with human HSCs treated with HOXB4(m) or vehicle in a long-term model. Successful completion of this Phase I program will demonstrate feasibility of HOXB4(m) as a drug for HSC expansion in vivo and provide the necessary data to support extensive in vivo efficacy and safety studies in a Phase II program necessary for an IND submission. With HOXB4(m), we can circumvent the original hurdles of HOXB4 and improve expansion in vivo to benefit HSCT patients by shortening the neutropenic phase to reduce infection, hospitalization time, and cost.