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).

抽象的 BedRock Therapeutics，Inc。正在开发一种控制对同种原理的免疫反应的方法 造血干细胞移植（HSCT），目的是预防移植物与宿主的眼部表现 疾病（OGVHD），大大降低了受苦患者的生活质量。超过20,000名患者接受 美国每年的Altegonic HSCTS治疗血液学疾病。其中估计为35-54％或 每年约有7,000-11,000名患者，开发OGVHD。 OGVHD是慢性移植与 宿主病。 OGVHD最常见的临床发育是干眼症或角膜结膜炎Sicca，它 导致诸如眼部刺激，疼痛，结膜发红，恐惧症和视力降低等症状。 OGVHD的干眼大大降低了HSCT患者的生活质量，并限制了他们的日常活动。 OGVHD的疗法在很大程度上无效（6个月时的响应率仅为23％），并致力于减少 症状，慢性病的控制以及预防组织损伤。治疗包括多次使用 局部润滑剂，钙调蛋白抑制剂，皮质类固醇，自体血清的每日应用 使用绷带隐形眼镜，边缘或羊膜膜移植和/或全身性 免疫抑制剂。尽管有这些治疗，但治疗反应较差，导致显着 视觉功能降低，因此对OGVHD有效治疗的巨大未满足。考虑到这一点 每年在美国执行的HSCT数量和OGVHD的高事件有关键的需求 用于有效且实用的OGVHD治疗方法。基岩治疗策略的治疗策略 OGVHD的基于人白细胞抗原G（HLA-G）蛋白的免疫调节活性，该活性 是天然蛋白质，可防止孕产妇对发育中的胎儿的排斥。我们创新的优化基因 治疗方法依赖于使用腺相关病毒（AAV）提供新型工程HLA-G 基于单链免疫调节（SICIM）蛋白调节免疫反应之后的免疫反应 HSCT。为了开发一种减轻监管开发的一种药物，基岩已经设计了功能性的障碍物 蛋白质（BDRK＃004）的构象模仿beta2-microglububulin（B2M）结合HLA-G二聚体复合物 可以使用单个AAV8矢量包装的cDNA包装和交付 与单链AAV基因组相比，基因组的翻译效率> 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的需求 其他免疫介导的眼部疾病，例如角膜炎，糖尿病性视网膜病和与年龄有关的黄斑 退化。 I阶段I申请中的基岩治疗疗法提案评估其单剂量cim药物 对原代人T细胞的耐受性和功能的公式（AIM 1）及其效率，安全性和 在我们的OGVHD鼠模型中生物分布（AIM 2）。