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

HTRA1 特异性小分子抑制剂的验证和开发

• 批准号: 7910760
• 负责人: BIN ZHANG
• 金额: $ 24.94万
• 依托单位: CALCYTE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910760
• 关键词: Age related macular degeneration; Alleles; Animal Model; Antibodies; Applications Grants; Biological Assay; Blood Vessels; Chemicals; Choroidal Neovascularization; Developed Countries; Development; Disease; Elderly; Endothelium; Etiology; Eye diseases; Family; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Haplotypes; Human; Human Genetics; In Vitro; Libraries; Modeling; Monoclonal Antibodies; Mus; Pathogenesis; Pathologic; Pathologic Neovascularization; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Prevalence; Principal Investigator; Protease Inhibitor; Reporting; Retina; Retinal; Risk; Role; Serine Protease; Serine Proteinase Inhibitors; Small Business Innovation Research Grant; Structure; Structure of retinal pigment epithelium; Structure-Activity Relationship; Testing; Therapeutic; Transcription Initiation Site; Validation; Vascular Diseases; Visual impairment; aging population; analog; base; cost; design; human disease; improved; in vivo; inhibitor/antagonist; novel; novel therapeutic intervention; polyclonal antibody; programs; promoter; public health relevance; research study; retina blood vessel structure; small molecule

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.

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是发达国家老年人视力损害的最常见原因。尽管它的患病率随着人口老龄化，其病因和发病机制知之甚少，治疗选择有限。CalCyte的科学联合创始人Kang Zhang报道说，编码HTRA 1的基因启动子的多态性在AMD的遗传易感性中起着重要作用。多态性（SNP rs 11200638）位于HTRA 1转录起始位点上游512处，A风险等位基因仅与主要疾病单倍型相关，其使HTRA 1表达增加约3倍。这项人类基因发现表明，阻断HTRA 1活性可能是治疗AMD的重要策略。 HTRA 1属于丝氨酸蛋白酶家族，在视网膜、视网膜色素上皮和病理性视网膜血管内皮中表达。张康博士实验室已经产生了针对人HTRA 1的多克隆和单克隆抗体。在初步实验中，HTRA 1的单克隆和多克隆抗体可以有效地抑制高氧诱导的视网膜血管疾病和脉络膜新生血管的小鼠模型中的病理性血管生成。这些研究首次证明了阻断HTRA 1是一种有效的治疗策略。 小分子是抑制HTRA 1的另一种方法。与抗体相比，小分子药物在易于生产、更经济、易于储存、分配和给药等方面具有显著的优势。基于小分子的丝氨酸蛋白酶抑制剂早已被报道并开发为治疗特定人类疾病的药物。这项SBIR资助申请的中心目标是证明HTRA 1小分子抑制剂将作为治疗年龄相关性黄斑变性的新治疗方法，并开发新的/改进的HTRA 1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损害的最常见原因。尽管它的患病率随着人口老龄化，其病因和发病机制知之甚少，治疗选择有限。CalCyte的科学联合创始人Kang Zhang报道说，编码HTRA 1的基因启动子的多态性在AMD的遗传易感性中起着重要作用。HTRA 1属于丝氨酸蛋白酶家族，在视网膜、视网膜色素上皮和病理性视网膜血管内皮中表达。张康博士实验室已经产生了针对人HTRA 1的多克隆和单克隆抗体。在初步实验中，HTRA 1的单克隆和多克隆抗体可以有效地抑制高氧诱导的视网膜血管疾病和脉络膜新生血管的小鼠模型中的病理性血管生成。这些研究首次证明了阻断HTRA 1是一种有效的治疗策略。SBIR资助申请中描述的特异性HTRA 1小分子抑制剂的开发将为治疗年龄相关性黄斑变性提供新的治疗方法。