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)

这个小型企业创新研究(SBIR)项目的更广泛影响是开发出一流的治疗方法，在病毒感染的不利环境下将肺损伤降至最低，并促进组织愈合。目前对正在与SARS-CoV-2感染作斗争的新冠肺炎患者的护理标准仅限于支持性护理、长期住院以及重新调整用途的抗炎或抗病毒药物。许多幸存者长期遭受肺部疤痕的折磨，这会降低呼吸功能。仍然需要有效的治疗方法来预防或减少病毒引起的肺损伤和/或促进组织愈合。重组人NELL1蛋白在修复组织损伤方面具有极好的安全性，并且具有病毒不可知的作用模式。在临床开发中，NELL1与新冠肺炎疗法有很大的不同，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方面具有广泛的效用，而不依赖于引起病毒、毒株或变种。拟议的研究将使用新冠肺炎快速路径(S)迅速将NELL1推进到临床前和临床研究。这个小型企业创新研究(SBIR)第一阶段项目将展示将NELL1作为一种蛋白质疗法用于治疗基于病毒的呼吸损伤，包括SARS-CoV-2造成的损伤的科学和技术可行性。第一个技术目标是证明NELL1在低氧条件下促进细胞存活和减少上皮细胞培养中的炎症的潜力。在NELL1处理和暴露在低氧生长条件下后，相对于没有处理的对照组，将监测支气管上皮细胞的存活和活性氧的积累。同样，NELL1处理的原代上皮细胞将被诱导炎症，炎症标志物的丰度和细胞存活率将与未处理的对照细胞进行比较。成功的证据是，≥在每种条件下的细胞存活率为30%，并且NELL1处理的细胞中的活性氧物种和炎症标记物的相应减少。第二个技术目标是证明NELL1在体内调节SARS-Co-V-2诱导的细胞因子风暴的有效性。这些研究将在经过验证的hACE2转基因小鼠模型中进行，预计在处理的动物中，至少三种细胞因子的丰度将减少≥30%。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.