Immunosuppressive Gene Therapy for Ocular Graft vs Host Disease

摘要 基岩治疗公司正在开发一种控制同种异体免疫反应的方法 造血干细胞移植(HSCT)旨在预防移植物对宿主的眼部表现 疾病(OGvHD)，显著降低了患者的生活质量。超过20,000名患者接受 美国每年用于治疗血液病的异基因造血干细胞移植。其中，估计有35%-54%，或 每年大约有7,000-11,000名患者患上OGvHD。OGvHD是慢性移植物抗宿主病的一种表现 寄主疾病。OGvHD最常见的临床表现是干眼症或干燥性角结膜炎，它 会导致眼睛刺激、疼痛、结膜发红、畏光和视力下降等症状。 OGvHD的干眼症显著降低了HSCT患者的生活质量，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个月的应答率只有23%)，目的是减少 症状、慢性病的控制和组织损伤的预防。治疗方法包括使用多个 每日使用局部润滑剂、钙调神经磷酸酶抑制剂、皮质类固醇、自体血清 使用绷带隐形眼镜，角膜缘或羊膜移植，和/或全身 免疫抑制剂。尽管有这些治疗方法，但治疗反应很差，导致显着 视功能下降，因此对OGvHD的有效治疗有大量未得到满足的需求。考虑到相当大的 美国每年进行HSCT的数量和OGvHD的高发病率迫切需要 为治疗OGvHD提供一种有效、实用的手段。基岩治疗公司的治疗策略 OGvHD的基础是人类白细胞抗原G(人类白细胞抗原G)蛋白的免疫调节活性，它 是一种天然蛋白质，可以防止母体排斥发育中的胎儿。我们的创新优化基因 治疗方法依赖于使用腺相关病毒(AAV)来提供一种新型的工程化的人类白细胞抗原-G 基于单链免疫调节(SCIM)蛋白来调节下列免疫反应 HSCT。为了开发一种单一的药物来简化监管开发，基岩设计了一种功能强大的SCIM 蛋白质(BDRK#004)，其构象模拟β2-微球蛋白(B2M)结合的人类白细胞抗原-G二聚体复合体 其cDNA可以使用单个AAV8载体包装和递送，该载体带有自互补的 与单链AAV基因组相比，它们的转导效率提高了10倍。这 创新的治疗方法将满足对安全有效的OGvHD单剂量药物的未得到满足的需求 可能还有其他免疫介导的眼部疾病，如角膜炎、糖尿病视网膜病变和老年性黄斑 退化。基岩治疗公司建议在这一I期应用中评估其单剂SCIM药物 原代人类T细胞耐受性和功能的配方(目标1)及其有效性、安全性和安全性 OGvHD小鼠模型的生物分布(目标2)。

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).