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

干细胞体内扩增的刺激物，可加速化疗和干细胞移植继发的中性粒细胞减少症的恢复

• 批准号: 10324724
• 负责人: Jeremy A Elser
• 金额: $ 29.31万
• 依托单位: SHIP OF THESEUS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2023-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324724
• 关键词: Adult; Adverse effects; Adverse event; Allogenic; Anemia; Autologous; Blood; Blood Cell Count; Bone Marrow; Bone Marrow Diseases; CD34 gene; Cell Transplantation; Cells; Chimerism; Clinic; Clinical; Clinical Trials; Complex; Consumption; Data; Development; Donor person; Engraftment; Ensure; Erythrocytes; Excision; Exposure to; Flow Cytometry; Goals; Half-Life; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Research; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeodomain Proteins; Hospitalization; Human; Immune system; Immunodeficient Mouse; In Vitro; Infection; Inflammatory; Inpatients; Intravenous infusion procedures; Kinetics; Legal patent; Life; Maintenance; Malignant Bone Neoplasm; Marrow; Measures; Methods; Modeling; Monitor; Mononuclear; Mucositis; Mus; Myelogenous; Myeloproliferative disease; Neutropenia; Oncologist; PTPRC gene; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Phase; Phenotype; Platelet Transfusion; Proliferating; Proteins; Radiation therapy; Recovery; Reproducibility; Resistance; Risk; Safety; Secondary to; Ships; Small Business Innovation Research Grant; Source; Speed; Stains; Stem cell transplant; System; Testing; Therapeutic; Thrombocytopenia; Time; Toxic effect; Transplant Recipients; Transplantation; Transplantation Conditioning; Umbilical Cord Blood; Work; cell type; chemotherapy; clinical investigation; cohort; conditioning; congenic; cost; efficacy study; experience; experimental group; genetic manipulation; hematopoietic engraftment; hematopoietic stem cell expansion; high risk; improved; in vivo; infection risk; innovation; interest; man; mutant; novel; novel therapeutics; overexpression; peripheral blood; post-transplant; pre-clinical; progenitor; programs; prospective; reconstitution; safety study; stem cell expansion; stem cell function; success; transcription factor; uptake

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.

项目摘要 造血干细胞（HSC）移植（HSCT）被认为是一种潜在的治疗选择， 在美国每年进行超过20，000例造血干细胞移植。 然而，HSCT与高风险相关，因为在移植前需要去除患病的骨髓。 移植直到移植的细胞植入并增殖到足以重建患者的免疫力 系统中，患者被认为是贫血，在此期间，他们非常容易受到感染。除了 对患者潜在的危及生命的身体风险，中性粒细胞减少症需要长的住院时间， 在美国，HSCT的成本从20万美元到40万美元不等，具体取决于捐赠者 细胞类型。目前临床试验的策略是移植更大的供体HSC库，以缩短造血干细胞的存活时间。 相位然而，这些方法都依赖于供体细胞的离体培养，所述供体细胞依赖于不完美的人源化。 制造的培养系统可能会破坏干细胞的正常功能，并且可能非常昂贵。 Theseus的创新解决方案是一种药物，将用于短暂，一次性暴露于供体细胞之前， 涉及改善体内扩增的移植。我们的药物是一种专利的同源异型盒蛋白B4突变体 （HOXB 4（m））。HOXB 4是公认的促进HSC扩增而不改变分化。但其 停止了向临床的进展，因为HOXB 4蛋白的半衰期太短， 临床应用和遗传上过表达HOXB 4导致骨髓增生性疾病。我们的专利变种人 具有改善的抗降解性，延长其细胞内半衰期，足以实际用于临床使用 同时潜在地避免由组成型过表达诱导的副作用。有早期的临床前数据 表明用HOXB 4（m）处理细胞可以扩增HSC的所有主要谱系，同时保持多能性。 该I期SBIR提案的目标是对HOXB 4（m）的体内安全性和有效性进行概念验证。 这将通过执行两个目标来实现。在目标1中，我们将证明HOXB 4（m）-处理 细胞可以在短时间内减少小鼠间HSCT后的血小板减少期， 长期模型在目标2中，我们证明了长期的造血重建而没有不良反应或GVHD。 我们将在长期模型中用HOXB 4（m）或溶剂处理的人HSC在小鼠中进行HSCT。 该I期项目的成功完成将证明HOXB 4（m）作为HSC药物的可行性 在体内扩增，并提供必要的数据，以支持广泛的体内疗效和安全性研究， IND提交所需的II期项目。有了HOXB 4（m），我们可以绕过最初的障碍， HOXB 4和改善体内扩增，通过缩短血供期， 感染、住院时间和费用。