Immunosuppressive Gene Therapy for Ocular Graft vs Host Disease

眼移植物抗宿主病的免疫抑制基因治疗

• 批准号: 10326039
• 负责人: BRIAN C GILGER
• 金额: $ 32.82万
• 依托单位: BEDROCK THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326039
• 关键词: Adrenal Cortex Hormones; Age related macular degeneration; AlamarBlue; Allogenic; Apoptosis; Autologous; Bandage; Biodistribution; Calcineurin inhibitor; Cells; Cellular Infiltration; Characteristics; Chronic Disease; Clinical Research; Codon Nucleotides; Complementary DNA; Complex; Contact Lenses; Cornea; Cyclosporine; DNA cassette; Dependovirus; Development; Diabetic Retinopathy; Disease; Disease model; Dose; Drug Formulations; Dry Eye Syndromes; Ductal Epithelium; Engineering; Evaluation; Eye Development; Fetal Development; Fibrosis; GTP-Binding Proteins; Genome; Goals; HLA Antigens; HLA-G1; HLA-G5; Hematological Disease; Hematopoietic Stem Cell Transplantation; Human; Human Activities; Immune; Immune response; Immunomodulators; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Infiltration; Inflammation; Injections; Integral Membrane Protein; Keratitis; Laboratories; Lacrimal gland structure; Lubricants; Mediating; Membrane; Methodology; Methods; Modeling; Molecular Conformation; Mus; Myofibroblast; New Zealand; Oryctolagus cuniculus; Pain; Patients; Pharmaceutical Preparations; Phase; Photophobia; Prevention; Production; Protein Isoforms; Proteins; Quality of life; Rattus; Redness; Safety; Saline; Serum; Symptoms; T-Cell Proliferation; T-Lymphocyte; Technology; Therapeutic; Tissues; Topical application; Toxic effect; Transplant Recipients; Transplantation; Tumor-infiltrating immune cells; Up-Regulation; Uvea; Vascularization; Viral Genome; Virion; Vision; Visual; Visual Acuity; Work; adeno-associated viral vector; amnion; autoimmune uveitis; base; chronic graft versus host disease; clinical development; conjunctiva; corneal scar; cytotoxicity; dimer; disorder prevention; effective therapy; efficacy evaluation; experience; eye dryness; gene therapy; graft vs host disease; immunoregulation; improved; innovation; intravitreal injection; irritation; lacrimal; limbal; meibomian gland; mouse model; neovascularization; novel; ocular surface; preclinical study; prevent; reduce symptoms; response; transduction efficiency; treatment response; treatment strategy; vector

Abstract Bedrock Therapeutics, Inc., is developing a method of controlling the immunologic response to allogenic hematopoietic stem cell transplants (HSCT) with the aim of preventing ocular manifestations of graft vs host disease (OGvHD), which significantly lower the quality of life of afflicted patients. Over 20,000 patients receive allogenic HSCTs per year in the US to treat hematological disorders. Of these, an estimated 35-54%, or approximately 7,000-11,000 patients annually, develop OGvHD. OGvHD is a manifestation of chronic graft vs host disease. The most common clinical development of OGvHD is dry eye, or keratoconjunctivitis sicca, which leads to symptoms such as ocular irritation, pain, conjunctival redness, photophobia, and reduced visual acuity. The dry eye of OGvHD significantly reduces quality of life of HSCT patients and limits their daily activities. Therapies for OGvHD are largely ineffective (response rate of only 23% at 6 months) and are directed at reducing symptoms, control of chronic disease, and prevention of tissue damage. Treatments include the use of multiple daily applications of topical lubricants, calcineurin inhibitors, corticosteroids, autologous serum, in addition to the use of bandage contact lenses, limbal or amnion membrane transplantation, and/or systemic immunosuppressants. Despite these treatments the therapeutic response is poor resulting in significantly reduced visual function and thus a large unmet need for effective treatment of OGvHD. Given the considerable number of HSCT performed annually in the US and the high incidence of OGvHD there is a critical need for an effective and practical means of treatment of OGvHD. Bedrock Therapeutics’ strategy for treatment of OGvHD is based on the immunomodulatory activities of Human Leukocyte Antigen G (HLA-G) proteins, which are natural proteins that act to prevent maternal rejection of the developing fetus. Our innovative optimized gene therapy methodology relies on use of adeno-associated virus (AAV) to deliver a novel engineered, HLA-G based, single chain immunomodulatory (scIM) protein to modulate the immunologic response following HSCT. To develop a single drug to ease regulatory development, Bedrock has engineered a functional scIM protein (BDRK#004) whose conformation mimics a beta2-microglubulin (B2M) bound HLA-G dimer complex whose cDNA can be packaged and delivered using a single AAV8 vector packaged with a self-complementary genome, which are enhanced >10-fold in transduction efficiency compared to single-strand AAV genomes. This innovative therapeutic will fulfill the unmet need for a safe and effective single dose drug for OGvHD and possibly other immune-mediated ocular diseases, such as keratitis, diabetic retinopathy, and age-related macular degeneration. Bedrock Therapeutics proposes in this phase I application to evaluate its single dose scIM drug formulation for tolerability and function on primary human T cells (Aim 1) and its efficacy, safety, and biodistribution in our murine model of OGvHD (Aim 2).

摘要 Bedrock Therapeutics，Inc.正在开发一种方法， 造血干细胞移植（HSCT），目的是预防移植物抗宿主的眼部表现 疾病（OGvHD），其显著降低患病患者的生活质量。超过20，000名患者接受 每年在美国进行同种异体HSCT治疗血液系统疾病。其中，估计有35- 54%，或 每年约有7，000 - 11，000名患者发生OGvHD。OGvHD是慢性移植物抗 宿主疾病OGvHD最常见的临床发展是干眼或干燥性角膜结膜炎， 导致诸如眼部刺激、疼痛、结膜发红、眼恐怖症和视力下降的症状。 OGvHD的干眼症显著降低了HSCT患者的生活质量并限制了他们的日常活动。 OGvHD的治疗在很大程度上是无效的（6个月时的应答率仅为23%），并且旨在减少 症状、控制慢性疾病和预防组织损伤。治疗方法包括使用多种 除了局部润滑剂、钙调神经磷酸酶抑制剂、皮质类固醇、自体血清外，每日应用 使用绷带隐形眼镜、角膜缘或羊膜移植和/或全身性 免疫抑制剂尽管有这些治疗，但治疗反应很差，导致显著的 降低的视觉功能，因此对OGvHD的有效治疗的大量未满足的需求。鉴于相当大的 美国每年进行的HSCT数量和OGvHD的高发病率是迫切需要的 为治疗OGvHD提供了一种有效和实用的手段。基岩疗法的治疗策略 OGvHD的发生是基于人类白细胞抗原G（HLA-G）蛋白的免疫调节活性， 是天然蛋白质，可防止母体对发育中的胎儿产生排斥反应。我们的创新优化基因 一种治疗方法依赖于使用腺相关病毒（AAV）来递送新的工程化HLA-G 基于单链免疫调节（scIM）蛋白，以调节以下免疫应答 HSCT。为了开发一种单一的药物，以减轻监管的发展，基岩已经设计了一个功能scIM 蛋白质（BDRK#004），其构象模拟β 2-微球蛋白（B2 M）结合的HLA-G二聚体复合物 其cDNA可以使用包装有自身互补的 在一些实施方案中，AAV基因组的转导效率比单链AAV基因组的转导效率提高>10倍。这 创新的治疗方法将满足对OGvHD安全有效的单剂量药物的未满足需求， 可能是其他免疫介导的眼部疾病，如角膜炎、糖尿病视网膜病变和年龄相关性黄斑变性。 退化基岩治疗公司在第一阶段申请中提出评估其单剂量scIM药物 本发明涉及一种用于对原代人T细胞的耐受性和功能的制剂（目的1）及其功效、安全性和生物相容性。 在我们的OGvHD鼠模型中的生物分布（目的2）。