Validation of SPX-101 as a candidate for the treatment of cystic fibrosis

验证 SPX-101 作为治疗囊性纤维化的候选药物

• 批准号: 9347354
• 负责人: David W Scott
• 金额: $ 22.26万
• 依托单位: SPYRYX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2018-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347354
• 关键词: Address; Adult; Advanced Development; Adverse effects; Age-Years; Agreement; Air; Amiloride; Animal Model; Bacteria; Binding; Biological Assay; Biological Sciences; Blood Circulation; Canis familiaris; Cell membrane; Cells; Cessation of life; Chloride Ion; Chlorides; Chronic; Chronic lung disease; Climacteric; Clinic; Clinical; Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Sequence Alteration; Dehydration; Disease; Diuresis; Dose; Epithelial; Epithelial Cells; Epithelium; Exposure to; Functional disorder; Goals; Grant; Growth; Half-Life; Health; Height; Human; Hydration status; Hyperactive behavior; Incidence; Infection; Intravenous infusion procedures; Kidney; Lead; Leukocyte Elastase; Life Expectancy; Liquid substance; Lung; Measures; Microscopic; Modeling; Molecular Target; Mucolytics; Mucous body substance; Mutation; Nebulizer; Nutrient; Organ; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Plasma; Proteins; Proteomics; Pulmonary Cystic Fibrosis; Quality of life; Rattus; Regulation; Saline; Sheep; Small Business Innovation Research Grant; Sodium; Sodium Chloride; Source; Surface; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Transgenic Mice; Translating; Validation; Work; absorption; airway surface liquid; base; bronchial epithelium; clinical application; cost; cystic fibrosis airway; cystic fibrosis mouse; cystic fibrosis patients; disease-causing mutation; epithelial Na+ channel; extracellular; hyperkalemia; improved; inhibitor/antagonist; novel; novel strategies; novel therapeutics; overexpression; palliative; patient subsets; peptide drug; prevent; small molecule; success; translational study; water diffusion

The Epithelial Na+ Channel (ENaC) is the rate limiting step for Na+ absorption across many epithelia. In the airways of cystic fibrosis (CF) patients, ENaC is abnormally hyperactive leading to disproportionate Na+ absorption and a depletion of airway surface liquid (ASL) volume. ENaC hyperactivity contributes to mucus stasis and increased incidence of airway infections that frequently lead to the death of the patient. Despite previous efforts, there are no existing therapies to treat abnormal ENaC activity in the lung. Using a proteomic screen, we have identified the protein SPLUNC1 as a potent allosteric inhibitor of ENaC that binds extra-cellularly to ENaC, reducing the amount of ENaC in the plasma membrane and subsequently limiting ENaC activity. We have also identified the ENaC-inhibitory domain of SPLUNC1, and have synthesized small peptide that corresponds to this domain, called SPX-101. This peptide robustly inhibits ENaC and prevents ASL hyperabsorption in CF airway cultures for 24 h following a single dose. SPX-101 continues to function in the presence of neutrophil elastase, which is highly abundant in CF airways, suggesting that this peptide may be therapeutically beneficial in the treatment of CF lung disease. We have also demonstrated that SPX-101 improves survival in a transgenic mouse model of CF that specifically overexpresses ENaC in the lung epithelia (βENaC-Tg) and that SPX-101 can be effectively delivered to the lung via nebulization. Notably, SPX-101 does not induce diuresis or hyperkalemia when delivered by intravenous infusion in rats. Furthermore, nebulized SPX-101 remains sequestered within the lung and <1% of the dose administered to the lung reaches systemic circulation in rats. To advance the development of a SPX-101 for the treatment of CF we are seeking this Phase I SBIR grant to: (i) measure the effect of SPX-101 in rat, canine and ovine bronchial epithelial cells to demonstrate the relevance of these species for toxicological and translational studies, and (ii) define the maximal effective dose and fully power the dose dependent effects of SPX-101 in a CFTR inhibitor- induced inhibition of tracheal mucus velocity in sheep. Completion of the proposed work will lead to a Phase II application that will be aimed at completion of toxicology studies and human clinical trials of this novel therapy for CF.

上皮Na+通道（ENAC）是许多上皮的Na+抽象的速率限制步骤。在 囊性纤维化（CF）患者的气道实质上过度活跃，导致不成比例 NA+受损和气道表面液体（ASL）体积的部署。 ENAC多动症有助于 粘液停滞和增加的气道感染事件，这些事件经常导致死亡 病人。尽管以前的努力，但没有现有的疗法来治疗异常的ENAC活性 肺。使用蛋白质组学筛选，我们已将蛋白质Splunc1鉴定为潜在的变构抑制剂 eNAC外的ENAC与ENAC结合，减少了质膜中的ENAC量 随后限制ENAC活动。我们还确定了 Splunc1，并合成了与该域相对应的小胡椒，称为SPX-101。这 肽可靠地抑制ENAC并防止CF气道培养物中的ASL超吸附24小时 遵循单剂量。 SPX-101在存在中性粒细胞弹性酶的情况下继续起作用， 在CF气道中高度丰富，表明该肽可能对 治疗CF肺部疾病。我们还证明，SPX-101提高了A CF的转基因小鼠模型，该模型特异性地表达了肺上皮中的ENAC（βenac-TG） SPX-101可以通过雾化有效地传递到肺部。值得注意的是，SPX-101没有 当大鼠静脉输注递送时，会诱导利尿或高钾血症。此外，雾化 SPX-101在肺部保持隔离，<1％的剂量给肺部延伸 大鼠的全身圆圈。 为了促进SPX-101的开发用于治疗CF，我们正在寻求此阶段I SBIR 授予：（i）测量SPX-101在大鼠，犬和卵子支气管上皮细胞中的影响 证明这些物种与毒理学和翻译研究的相关性，以及（ii）定义 最大有效剂量并完全供应SPX-101在CFTR抑制剂中的剂量依赖性作用 诱导的绵羊气管粘液速度的抑制作用。拟议工作的完成将导致 第二阶段的应用将旨在完成毒理学研究和人类的临床试验 这种新颖的CF疗法。