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)

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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.