Small molecules, gene therapy systems, RNAi-based systems, and the use of certain inhibitors to control NCOA7 expression to prevent or improve infection.
The seriousness of the COVID-19 pandemic is largely in part due to its novelty; our understanding of its pathology is still developing, and our lack of knowledge contributes to our inability to effectively treat it. An understanding of the viral mechanism of action is critical to developing treatments for it. It is thought that SARS-CoV-2 gains entry to cells using a pathway that relies upon lysosomal acidification for entry, but the crucial molecules that regulate such lysosomal activity have not been defined; further, it may be that functional genetic variants in molecules could confer either cellular protection or susceptibility, as indicated by the wide and unexplained variation of disease severity in the global population. Identification of these molecules could serve as a crucial foundation for development of novel therapeutic drugs and genotypic risk assessment, expediting global recovery from this devastating pandemic.
Technology Description
Prior research in a University of Pittsburgh laboratory had focused on investigating the pathobiology of endothelial cell nuclear receptor coactivator 7 (NCOA7). NCOA7 has been shown to regulate immunoactivation of the endothelium and subsequent leukocyte adhesion, leading to presumable viral infiltration. NCOA7 accomplishes this by altering lysosomal acidification, a process that has been independently found to affect entry of other enveloped viruses such as the similarly-structured influenza virus. Researchers have also identified an allele-specific mechanism that may influence NCOA7 expression and cellular susceptibility to infection. This invention includes the development of small molecules, gene therapy systems, RNAi-based systems, or the use of certain inhibitors to control NCOA7 expression to prevent or improve infection in addition to the use of NCOA7 SNP genotyping as a means of individual risk of infection and disease severity in order to prevent infection or complications. NCOA7 may prove to be immediately relevant for development of new drugs and repurposing of old drugs for therapies for this new pandemic.Advantages
No prior initiatives have explored the therapeutic or diagnostic benefit of modulating NCOA7 or its functional SNP
Enables genotype-based assessment of risk in order to protect vulnerable populations from infection or disease complications, in addition to predicting disease severity and progression to proactively treat and triage patients
Prevents cellular entry by SARS-CoV-2Applications
Platform for developing drugs to prevent or improve infection and downstream disease from SARS-CoV-2/COVID-19
Repurposing of old drugs
Public health initiatives to identify persons at high and low risk of infection and severity of disease
Development of gene editing platforms to prevent infection or disease complications in vulnerable populationsStage of Development
In vitro testing of predicted compounds in cultured human cellsIP Status
Provisional patent application filedExternal links
Chan Lab
Innovators
Stephen Yu-Wah Chan, MD, PhD, FAHA
Professor of Medicine, Division of Cardiology
Director, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute
Director, Center for Pulmonary Vascular Biology and Medicine
Associate Program Director, Fellowship Research, Cardiology
Dr. Chan’s research interests include the molecular mechanisms of pulmonary vascular disease and pulmonary hypertension, and his work includes being among the first to identify the systems-level functions of miRNAs as a root cause of pulmonary hypertension and developing in silico approaches to analyze gene network architecture coupled with in vivo experimentation. Dr. Chan has been awarded research grants from the National Institutes of Health, the American Heart Association, the Pulmonary Hypertension Association, and Gilead Sciences, and has been the recipient of philanthropic awards from Brigham and Women’s Hospital including the Lerner Scholarship, the Watkins Discovery Award, the Harris Family Research Prize, and the McArthur-Radovsky Research Scholarship. He has also received international research awards from the American College of Cardiology, the American Heart Association, and the American Society of Microbiology, and has presented his research at both national and international venues.Education
MD, University of California San Francisco
PhD, Biomedical Sciences, University of California San Francisco
BS, Biology, Massachusetts Institute of TechnologyRecent Publications
Goncharova EA, Chan SY, Ventetuolo CE, Weissmann N, Schermuly RT, Mullin CJ, Gladwin MT. Update in Pulmonary Vascular Diseases and Right Ventricular Dysfunction in 2019. J Respir Crit Care Med. 2020 Apr 20. doi: 10.1164/rccm.202003-0576UP. [Epub ahead of print]
Saygin D, Tabib T, Bittar HET, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R. Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension. Pulm Circ. 2020 Feb 28;10(1). pii: ???. doi: 10.1177/2045894020908782. eCollection 2020 Jan-Mar.
Zou RH, Wallace WD, Nouraie SM, Chan SY, Risbano MG. Lower DLco% identifies exercise pulmonary hypertension in patients with parenchymal lung disease referred for dyspnea. Pulm Circ. 2020 Feb 19;10(1):2045894019891912. doi: 10.1177/2045894019891912. eCollection 2020 Jan-Mar.
Pi H, Kosanovich CM, Handen A, Tao M, Visina J, Vanspeybroeck G, Simon MA, Risbano MG, Desai A, Mathier MA, Rivera-Lebron BN, Nguyen Q, Kliner J, Nouraie M, Chan SY. Outcomes of Pulmonary Arterial Hypertension Are Improved in a Specialty Care Center. Chest. 2020 Feb 25. pii: S0012-3692(20)30334-2. doi: 10.1016/j.chest.2020.01.046. [Epub ahead of print]
Jin S, Zeng X, Fang J, Lin J, Chan SY, Erzurum SC, Cheng F. A network-based approach to uncover microRNA-mediated disease comorbidities and potential pathobiological implications. NPJ Syst Biol Appl. 2019 Nov 13;5:41. doi: 10.1038/s41540-019-0115-2. eCollection 2019.
Kotecha S, Lebot MN, Sukkarn B, Ball G, Moseley PM, Chan SY, Green AR, Rakha E, Ellis IO, Martin SG, Storr SJ. Dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and survival in breast cancer: a retrospective analysis of protein and mRNA expression. Sci Rep. 2019 Nov 18;9(1):16987. doi: 10.1038/s41598-019-53529-z.
Hansmann G, Calvier L, Risbano MG, Chan SY. Activation of the Metabolic Master Regulator PPARγ: A Potential PIOneering Therapy for Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol. 2020 Feb;62(2):143-156. doi: 10.1165/rcmb.2019-0226PS.