Novel hematopoietic stem cell engineering and transplantation approaches for HIV cure

用于治疗艾滋病毒的新型造血干细胞工程和移植方法

• 批准号: 10163906
• 负责人: Paula M Cannon
• 金额: $ 265.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10163906
• 关键词: AIDS/HIV problem; Allogenic; Animal Model; Antibody-drug conjugates; Antiviral Agents; Autologous; Behavior Therapy; Berlin; Biomimetics; Biotechnology; Bone Marrow; CCR5 gene; Cell Compartmentation; Cell Transplantation; Cells; Clinical; Combined Modality Therapy; Communicable Diseases; DNA; DNA Repair; Data; Defect; Defense Mechanisms; Dose; Elements; Engineered Gene; Engineering; Engraftment; Environment; Frequencies; Gene Combinations; Genes; Genetic Engineering; Goals; HIV; HIV Infections; HIV Seropositivity; HIV resistance; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune; Immune response; Immunity; Immunoglobulin G; Immunotherapy; Individual; Infection; Lead; Lymphoma; Macaca; Malignant Neoplasms; Mediating; Methods; Modeling; Mutation; Nonhomologous DNA End Joining; Outcome; Pathway interactions; Patients; Production; Property; Protocols documentation; Regimen; Research Personnel; Resistance; Rosaniline Dyes; Safety; Series; Site; Stem cell transplant; T cell reconstitution; T cell response; T-Cell Development; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic immunosuppression; Toxic effect; Translating; Transplantation; Work; antiretroviral therapy; arm; base; cancer therapy; cell regeneration; chimeric antigen receptor T cells; combinatorial; comparative efficacy; conditioning; cryogel; engineered T cells; engineered stem cells; gain of function mutation; gene therapy; genome editing; graft vs host disease; humanized mouse; immune reconstitution; immune resistance; immunoreaction; improved; inhibitor/antagonist; leukemia; mouse model; nanobodies; neutralizing antibody; nonhuman primate; novel; novel strategies; post-transplant; preservation; programs; repaired; side effect; simian human immunodeficiency virus; targeted nucleases

Gene editing holds the promise of enhancing the precision and safety of anti-HIV gene therapies based on engineering hematopoietic stem and progenitor cells (HSPC), in order to recreate elements of the Berlin Patient cure. Targeted nuclease technology is already being used to exploit NHEJ-mediated repair of DNA breaks and thereby disrupt the CCR5 gene, which mimics one aspect of his cure. However, extending this treatment to noncancer patients, receiving engineered autologous HSPC, will likely need to include other approaches. To do this, we are exploiting the alternate pathway of DNA break repair based on homology-directed repair (HDR). This can be used to introduce gain-of-function mutations into cellular restriction factors, or to direct the controlled secretion of soluble anti-viral factors, including the broad entry inhibitor eCD4-Ig. Moreover, the site-specific insertion at eCD4-Ig at the CCR5 locus would combine HIV-resistance with systemic protection and thereby provide a combinatorial anti-HIV approach. In the current proposal we aim to continue to improve the safety and efficacy of gene editing in HSPC, and to apply the technology to provide both local and systemic HIV resistance. We will combine our established anti-HIV approaches with a new direction to engineer production of broadly neutralizing antibodies, and thereby provide a novel synthetic immune capability. Individual strategies and combination approaches will be evaluated in appropriate mouse models, to evaluate their impact on HIV infection and the latent reservoir.

基因编辑有望提高基于工程造血干细胞和祖细胞（HSPC）的抗HIV基因疗法的精确性和安全性，以重现柏林患者治愈的要素。靶向核酸酶技术已经被用于利用NHEJ介导的DNA断裂修复，从而破坏CCR 5基因，这模拟了他治愈的一个方面。然而，将这种治疗扩展到接受工程化自体HSPC的非癌症患者，可能需要包括其他方法。为了做到这一点，我们正在开发基于同源性定向修复（HDR）的DNA断裂修复的替代途径。这可用于将功能获得性突变引入细胞限制因子，或指导可溶性抗病毒因子（包括广泛进入抑制剂eCD 4-IG）的受控分泌。此外，在CCR 5基因座处的eCD 4-IG的位点特异性插入将联合收割机HIV抗性与系统性保护结合，从而提供组合抗HIV方法。在目前的提案中，我们的目标是继续提高基因编辑在HSPC中的安全性和有效性，并应用该技术提供局部和全身的HIV抗性。我们将联合收割机将我们已建立的抗艾滋病毒方法与设计广泛中和抗体生产的新方向相结合，从而提供一种新型的合成免疫能力。将在适当的小鼠模型中评价单个策略和组合方法，以评价其对HIV感染和潜伏储库的影响。