Validation and development of specific small molecule inhibitors of HTRA1 for tre

描述(申请人提供)：老年性黄斑变性(AMD)是发达国家老年人视力障碍的最常见原因。尽管它随着人口老龄化而流行，但其病因和发病机制尚不清楚，治疗选择有限。CalCyte的科学联合创始人张康报告说，编码HTRA1的基因启动子的多态在AMD的遗传易感性中起着重要作用。该多态性(SNP Rs11200638)位于HTRA1转录起始点上游的512处，A风险等位基因仅与一种重大疾病单倍型相关，该单倍型使HTRA1的表达增加约三倍。这一人类基因发现表明，阻断HTRA1活性可能是治疗AMD的重要策略。HTRA1属于丝氨酸蛋白酶家族，表达于视网膜、视网膜色素上皮和病理性视网膜血管内皮细胞。张康博士实验室研制出了抗人HTRA1的多克隆和单克隆抗体。在初步实验中，抗HTRA1的单抗和多克隆抗体可以有效地抑制高氧性视网膜血管疾病和脉络膜新生血管模型小鼠的病理性血管生成。这些研究首次证明了阻断HTRA1是一种有效的治疗策略。小分子是另一种抑制HTRA1的方法。与抗体相比，小分子药物在制造、储存、分配和给药等方面具有显著的优势。长期以来，小分子丝氨酸蛋白酶抑制剂一直被报道和开发为治疗特定人类疾病的药物。这项SBIR赠款申请的中心目标是证明HTRA1小分子抑制剂将作为治疗老年性黄斑变性的新方法，并开发新的/改进的HTRA1小分子抑制剂。 公共卫生相关性：老年性黄斑变性(AMD)是发达国家老年人视力受损的最常见原因。尽管它随着人口老龄化而流行，但其病因和发病机制尚不清楚，治疗选择有限。CalCyte的科学联合创始人张康报告说，编码HTRA1的基因启动子的多态在AMD的遗传易感性中起着重要作用。HTRA1属于丝氨酸蛋白酶家族，表达于视网膜、视网膜色素上皮和病理性视网膜血管内皮细胞。张康博士实验室研制出了抗人HTRA1的多克隆和单克隆抗体。在初步实验中，抗HTRA1的单抗和多克隆抗体可以有效地抑制高氧性视网膜血管疾病和脉络膜新生血管模型小鼠的病理性血管生成。这些研究首次证明了阻断HTRA1是一种有效的治疗策略。在这项SBIR拨款申请中描述的特定HTRA1小分子抑制剂的开发将为治疗老年性黄斑变性提供一种新的治疗方法。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of visual impairment of the elderly in developed countries. Despite its prevalence with the aging population, its etiology and pathogenesis are poorly understood and the treatment options are limited. CalCyte's scientific co-founder, Kang Zhang, reported that polymorphisms in the promoter of the gene encoding HTRA1 plays a major role in genetic susceptibility to AMD. The polymorphism (SNP rs11200638) is located 512 by upstream of the HTRA1 transcription start site and the A risk allele is exclusively associated with a major disease haplotype which increases HTRA1 expression by approximately three fold. This human genetic discovery suggests that blocking HTRA1 activity may be an important strategy for treating AMD. HTRA1 belongs to a family of serine proteases and is expressed in the retina, retinal pigment epithelium and in the endothelium of pathologic retinal vessels. Dr. Kang Zhang Lab has generated polyclonal and monoclonal antibodies against human HTRA1. In preliminary experiments, monoclonal and polyclonal antibodies to HTRA1 can effectively inhibit pathologic angiogenesis in murine models of hyperoxic induced retinal vascular disease and choroidal neovascularization. These studies provide the first proof of concept that blocking HTRA1 is an effective therapeutic strategy. Small molecule is another approach to inhibit HTRA1. Comparing with antibody, small molecule drugs have significant advantages in ease of manufacturing more cost-effectively, storing, distributing and administering. Small molecule based serine proteases inhibitors have been long reported and developed as drugs for treating specific human diseases. The central goal of this SBIR grant application is to demonstrate the HTRA1 small molecule inhibitor would serve as a new therapeutic approach for treating age-related macular degeneration and develop new/improved HTRA1 small molecule inhibitors. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the most common cause of visual impairment of the elderly in developed countries. Despite its prevalence with the aging population, its etiology and pathogenesis are poorly understood and the treatment options are limited. CalCyte's scientific co-founder, Kang Zhang, reported that polymorphisms in the promoter of the gene encoding HTRA1 plays a major role in genetic susceptibility to AMD. HTRA1 belongs to a family of serine proteases and is expressed in the retina, retinal pigment epithelium and in the endothelium of pathologic retinal vessels. Dr. Kang Zhang Lab has generated polyclonal and monoclonal antibodies against human HTRA1. In preliminary experiments, monoclonal and polyclonal antibodies to HTRA1 can effectively inhibit pathologic angiogenesis in murine models of hyperoxic induced retinal vascular disease and choroidal neovascularization. These studies provide the first proof of concept that blocking HTRA1 is an effective therapeutic strategy. Development of specific HTRA1 small molecule inhibitors as described in this SBIR grant application will provide a new therapeutic approach for treating age-related macular degeneration.