Targeting Galectin-3 with novel drugs for treatment of eczema

以 Galectin-3 为靶点治疗湿疹的新药

• 批准号: 7748108
• 负责人: Swey-Shen Chen
• 金额: $ 40.16万
• 依托单位: IGE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748108
• 关键词: Acute; Affect; Affinity; Allergic; Amino Acid Sequence; Animal Lectins; Atopic Dermatitis; Binding; C-terminal; Calcineurin inhibitor; Carbohydrates; Cell Nucleus; Cell physiology; Cell surface; Cells; Child; Chronic; Complex; Consensus; Cytosol; Data; Dendritic Cells; Developed Countries; Development; Disease; Drug Delivery Systems; Drug or chemical Tissue Distribution; Eczema; Epithelium; Exhibits; Extracellular Space; Family; Galactose Binding Lectin; Galactosides; Galectin 3; Glucocorticoids; Health; Human; Immune; Immunologics; Immunomodulators; Immunosuppressive Agents; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Lead; Mammals; Mediating; Modeling; Molecular Weight; Mus; N-terminal; Nematoda; Oligonucleotides; Pathway interactions; Patients; Peptide Signal Sequences; Pharmaceutical Preparations; Phase; Play; Polysaccharides; Population; Prevalence; Proline; Protein Secretion; Proteins; RNA; Regulation; Role; Safety; Signal Transduction; Skin; Specificity; Structure; T-Lymphocyte; Technology; Tissues; Topical application; Transgenic Mice; Transmembrane Domain; age group; aptamer; beta-galactoside; cell type; crosslink; eosinophil; extracellular; human tissue; improved; in vivo; inhibitor/antagonist; keratinocyte; mast cell; member; mouse model; novel; protein protein interaction; public health relevance; response; selective expression; skin disorder; traditional therapy

DESCRIPTION (provided by applicant): Eczema affects a wide population age group, and prevalence of the disease has increased two- to three-fold during the past three decades in industrialized countries, where the current incidence in children is estimated to be 15-20%. Studies suggest that eczema is a complex disease, involving multiple immunologic and inflammatory pathways that include T cells, dendritic cells, mast cells and eosinophils, as well as keratinocytes. Treatment of eczema continues to be a challenge, especially in patients with severe disease. Current therapies include topical application of glucocorticoids and calcineurin inhibitors (immunomodulators), and systemic treatment with glucocorticoids, immunosuppressants and calcineurin inhibitors. Due to significant health concerns of long-term use of glucocorticoids and immunosuppressants, topical immunomodulators gained wide acceptance. However, safety issues raised by the FDA may limit use of these immunomodulators. A family of animal lectins, called galectins, is beta-galactoside-binding animal lectins with conserved carbohydrate-recognition domains. They are evolutionarily highly conserved (found in nematodes and mammals), and some show wide tissue distribution, while others are more selectively expressed by tissue. Galectins have no signal sequence and no transmembrane domain and are found in the cytosol and nucleus, but also in extracellular spaces. Galectins function intracellularly by binding to other proteins through protein-protein interactions. Typical expression of galectin- 3 includes epithelia and immune and inflammatory cells. Galectin-3 is unique among others in possessing chimeric structure consisting of an N-terminal region that contains proline-rich repeats and a C-terminal carbohydrate-recognition domain. Galectin-3 forms oligomers through its N-terminal domain upon binding to multivalent saccharides. Through extensive studies of transgenic mice and human tissues, we have identified galectin-3 as a key molecule involved in skin inflammation. We have begun to characterize drugs targeting galectin-3 for treatment of eczema. These molecules are a newly-established, but growing class of drugs called aptamers (RNA oligonucleotides), and may offer improved safety and specificity over traditional therapies. PUBLIC HEALTH RELEVANCE: Atopic dermatitis is a common chronic inflammatory skin disease. In the US, 15-20% of the population born after 1980 is affected by this disease. Treatment of atopic dermatitis continues to be a challenge and new therapies are clearly needed. The current model suggests that atopic dermatitis is attributable to a Th2-mediated inflammatory response in the acute phase, and both T cells and dendritic cells play important roles. Galectin-3 is a member of a family of animal lectins defined by their affinity for 2-galactosides and consensus amino acid sequences. It is expressed by a number of cell types, including T cells and dendritic cells. Like other galectins, galectin-3 does not have a classical signal sequence and is present inside the cells, but it can be secreted. A number of extracellular functions have been demonstrated by using exogenously added galectin-3, which can induce transmembrane signal transduction by crosslinking cell surface glycans. In addition, a great deal of evidence implicates endogenous galectin-3 in the regulation of various cellular functions through intracellular actions (in the absence of protein secretion). We have obtained important information on the functions of endogenous galectin-3 by studying galectin-3-deficient (gal3-/-) mice, and demonstrated that galectin-3 promotes allergic inflammation. In particular, we have data demonstrating a critical role for galectin-3 in a mouse model of human atopic dermatitis: Gal3-/- mice exhibit Th1-polarized responses and significantly reduced disease Thus, we believe that galectin-3 is a target for treatment of atopic dermatitis, as well as other allergic diseases. Here we propose developing galectin-3 specific RNA aptamers as novel drugs for treatment of atopic dermatitis. We have chosen this technology, because RNA aptamers are more likely to have higher affinity for galectin-3 and more specific for galectin-3 over other galectins than low molecular weight compounds. Moreover, RNA aptamers can be used to target either extracellular or intracellular galectin-3 and may be applied topically. Specific Aim 1: Develop galectin-3-specific RNA aptamers as potent inhibitors Specific Aim 2: Demonstrate the potency of galectin-3 aptamers in suppressing galectin-3 functions in vitro 1. Selection of galectin-3 RNA aptamers that can inhibit galectin-3 functions in vitro 2. Determine the potency of galectin-3 RNA aptamers in inhibition of human Th2 responses in vitro Specific Aim 3: Determine the efficacy of galectin-3 aptamers for treatment of allergic skin inflammation by using a mouse model of human atopic dermatitis 1. Determine whether targeting extracellular galectin-3 is effective in suppressing allergic dermatitis 2. Evaluate the in vivo effects of galectin-3 RNA aptamers in a mouse model. We hope the proposed studies will definitively validate galectin-3 as a target for treating atopic dermatitis and lead to the development of a novel therapy for this disease.

描述(由申请人提供)：湿疹影响着广泛的人口年龄组，在过去30年里，这种疾病在工业化国家的流行率增加了两到三倍，那里目前的儿童发病率估计为15%-20%。研究表明，湿疹是一种复杂的疾病，涉及多种免疫和炎症途径，包括T细胞、树突状细胞、肥大细胞和嗜酸性粒细胞以及角质形成细胞。湿疹的治疗仍然是一个挑战，特别是在患有严重疾病的患者中。目前的治疗方法包括局部应用糖皮质激素和钙调神经磷酸酶抑制剂(免疫调节剂)，以及全身应用糖皮质激素、免疫抑制剂和钙调神经磷酸酶抑制剂。由于长期使用糖皮质激素和免疫抑制剂引起的重大健康问题，局部免疫调节剂得到了广泛的接受。然而，FDA提出的安全问题可能会限制这些免疫调节剂的使用。动物凝集素家族称为Galectins，是与β-半乳糖苷结合的动物凝集素，具有保守的碳水化合物识别结构域。它们在进化上高度保守(在线虫和哺乳动物中发现)，一些显示出广泛的组织分布，而另一些则更有选择性地在组织中表达。Galectins没有信号序列，也没有跨膜区，存在于胞浆和胞核，也存在于细胞外间隙。Galectins通过蛋白质-蛋白质相互作用与其他蛋白质结合，从而在细胞内发挥作用。Galectin-3的典型表达包括上皮细胞、免疫细胞和炎症细胞。Galectin-3是独一无二的，因为它具有嵌合结构，该结构由一个含有富含脯氨酸重复序列的N-末端区域和一个C-末端碳水化合物识别结构域组成。Galectin-3与多价糖结合后，通过N-末端结构域形成低聚体。通过对转基因小鼠和人类组织的广泛研究，我们已经确定Galectin-3是参与皮肤炎症的关键分子。我们已经开始针对Galectin-3治疗湿疹的药物进行表征。这些分子是一种新建立的、但正在增长的称为适体(RNA寡核苷酸)的药物类别，与传统疗法相比，它们可能提供更好的安全性和特异性。公共卫生相关性：特应性皮炎是一种常见的慢性炎症性皮肤病。在美国，1980年后出生的人口中有15%-20%受到这种疾病的影响。特应性皮炎的治疗仍然是一个挑战，显然需要新的治疗方法。目前的模型表明，特应性皮炎可归因于急性期Th2介导的炎症反应，T细胞和树突状细胞都发挥着重要作用。Galectin-3是动物凝集素家族中的一员，由其对2-半乳糖苷和共同氨基酸序列的亲和力所定义。它由多种细胞类型表达，包括T细胞和树突状细胞。与其他Galectin一样，Galectin-3没有经典的信号序列，存在于细胞内，但可以分泌。外源添加的Galectin-3可以通过交联细胞表面的糖链来诱导跨膜信号转导，从而证明了许多细胞外功能。此外，大量证据表明，内源性Galectin-3通过细胞内活动(在没有蛋白质分泌的情况下)调节各种细胞功能。我们通过对Galectin-3缺陷(Gal3-/-)小鼠的研究，获得了关于内源性Galectin-3功能的重要信息，并证明Galectin-3促进变态反应性炎症。特别是，我们有数据表明Galectin-3在人类特应性皮炎小鼠模型中发挥关键作用：Gal3-/-小鼠表现出Th1极化反应并显著减少疾病，因此，我们认为Galectin-3是治疗特应性皮炎和其他过敏性疾病的靶点。在这里，我们建议开发Galectin-3特异性RNA适配子作为治疗特应性皮炎的新药。我们之所以选择这项技术，是因为与低分子化合物相比，RNA适配子对Galectin-3的亲和力更高，对Galectin-3的特异性更强。此外，RNA适配子可用于靶向细胞外或细胞内Galectin-3，并可用于局部应用。特定目的1：开发Galectin-3特异性RNA适配子作为有效的抑制物特定目的2：证明Galectin-3适配子在体外抑制Galectin-3功能的有效性1.筛选可在体外抑制Galectin-3功能的Galectin-3 RNA适配子2.确定Galectin-3 RNA适配子在体外抑制人Th2反应的效力特殊目的3：通过建立人类特应性皮炎1的小鼠模型，确定Galectin-3适配子治疗过敏性皮炎的疗效。确定靶向Galectin-3是否有效抑制过敏性皮炎2。在小鼠模型中评价Galectin-3 RNA适配子的体内效应。我们希望拟议的研究将明确验证Galectin-3作为治疗特应性皮炎的靶点，并导致这种疾病的新疗法的开发。