SBIR Phase I: Regulation of Hyperinflammation and Cell Survival Under Hypoxia with NELL1/NV1: A Therapy for Severe Lung Tissue Damage in Viral Infections (COVID-19)

SBIR 第一阶段：用 NELL1/NV1 调节缺氧下的过度炎症和细胞存活：病毒感染 (COVID-19) 严重肺组织损伤的治疗方法

• 批准号: 2045393
• 负责人: Cymbeline Culiat
• 金额: $ 24.23万
• 依托单位: NELLONE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2045393&HistoricalAwards=false
• 关键词: SBIR; Phase; Regulation; Hyperinflammation; Cell

The broader impact of this Small Business Innovation Research (SBIR) project is the development of a first-in-class therapeutic that minimizes lung damage and promotes tissue healing under the adverse environment of viral infection. The current standard of care for COVID-19 patients battling SARS-CoV-2 infection is limited to supportive care, long hospitalization, and re-purposed anti-inflammatory or anti-viral drugs. Many survivors suffer long-term lung scarring that reduces respiratory function. There remains a need for effective therapeutics that prevent or reduce virus-induced lung damage and/or promote tissue healing. Recombinant human NELL1 protein has an excellent safety profile in healing tissue injuries and a virus-agnostic mode of action. NELL1 is strongly differentiated from COVID-19 therapeutics in clinical development because it can be manufactured large-scale, cost-effectively, and has broad utility in treating future viral outbreaks independent of causative virus, strain, or variant. The proposed studies will rapidly advance NELL1 towards preclinical and clinical studies using COVID-19 expedited path(s). This Small Business Innovation Research (SBIR) Phase I project will demonstrate the scientific and technical feasibility of advancing NELL1 as a protein therapeutic for the treatment of viral-based respiratory damage, including damage caused by SARS-CoV-2. The first technical objective is to demonstrate NELL1 potential in promoting cell survival under hypoxic conditions and reducing inflammation in epithelial cell cultures. After NELL1 treatment and exposure to hypoxic growth conditions, the survival of bronchial epithelial cells and accumulation of reactive oxygen species will be monitored relative to no treatment controls. Similarly, inflammation will be induced in primary epithelial cells treated with NELL1 and inflammatory marker abundance and cell survival will be compared to no treatment control cells. Success is demonstrated by ≥30% cell survival under each condition and a concordant reduction in reactive oxygen species and markers of inflammation in cells treated with NELL1. The second technical objective is to demonstrate in vivo efficacy of NELL1 in modulating SARS-Co-V-2 induced cytokine storm. These studies will be performed in a validated hACE2 transgenic mouse model and it is expected that the abundance of at least three cytokines will be reduced by ≥30% in treated animals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个小企业创新研究（SBIR）项目的更广泛的影响是开发一种一流的治疗方法，最大限度地减少肺损伤，并在病毒感染的不利环境下促进组织愈合。目前对与SARS-CoV-2感染作斗争的COVID-19患者的护理标准仅限于支持性护理、长期住院和重新使用抗炎或抗病毒药物。许多幸存者遭受长期的肺疤痕，降低呼吸功能。仍然需要预防或减少病毒诱导的肺损伤和/或促进组织愈合的有效治疗剂。重组人NELL 1蛋白在愈合组织损伤和病毒不可知的作用模式方面具有优异的安全性。NELL 1在临床开发中与COVID-19治疗药物有很大区别，因为它可以大规模生产，具有成本效益，并且在治疗未来的病毒爆发中具有广泛的用途，而不依赖于致病病毒，毒株或变体。拟议的研究将使用COVID-19加速路径快速推进NELL 1的临床前和临床研究。这项小型企业创新研究（SBIR）第一阶段项目将证明推进NELL 1作为治疗病毒性呼吸道损伤（包括SARS-CoV-2引起的损伤）的蛋白质治疗的科学和技术可行性。第一个技术目的是证明NELL 1在缺氧条件下促进细胞存活和减少上皮细胞培养物中炎症的潜力。在NELL 1处理和暴露于缺氧生长条件后，相对于无处理对照，监测支气管上皮细胞的存活和活性氧物质的积累。类似地，将在用NELL 1处理的原代上皮细胞中诱导炎症，并且将炎症标志物丰度和细胞存活与无处理对照细胞进行比较。在每种条件下细胞存活率≥30%，以及用NELL 1处理的细胞中活性氧和炎症标志物的一致减少证明了成功。第二个技术目的是证明NELL 1在调节SARS-Co-V-2诱导的细胞因子风暴中的体内功效。这些研究将在经过验证的hACE 2转基因小鼠模型中进行，预计治疗动物中至少三种细胞因子的丰度将降低≥30%。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。