Speaker at Pharmaceutics and Drug Delivery Systems 2022 - Yong Xiao Wang
Albany Medical College, United States
Title : Novel Biotherapy for Asthma

Abstract:

Biotherapy in cancer and several other diseases has been rapidly growing. On the other hand,  litter is known about biotherapy in respiratory diseases. One of common and devastating respiratory diseases is asthma. The current medications in asthma are not always effective, often produce serious side effects, sometimes worsen symptoms and even cause death. Evidently, the development of novel and effective medications has reached a new level of urgency. Lentivirus- and shRNA-mediated loss and gain of gene function have been shown to embody a promising human gene therapy. Thus, we have started to develop lentivirus-based shRNA targeting at new specific molecules as a biotherapy to treat asthma.

Taking our unique expertise in using technically-challenging gold-standard single channel recording technique with other state-of-the art approaches, we have demonstrated that among a family of transient receptor potential canonical (TRPC1-7) channels, only TRPC3 channel is highly expressed and functional in single animal and human airway smooth muscle cells (ASMCs). The expression and function of this channel are upregulated in ASMCs from asthmatic animals and humans. Similar results have been observed by other scientists as well. More importantly, we have successfully developed lentivirus-based SMC-specific shRNAs for TRPC3 channel. Our in-vivo experiments have revealed that intravenous injection of lentiviral SMC-specific TRPC3 channel shRNAs using a hydrodynamic intravenous injection method blocks the channel activity and associated calcium signaling in single ASMCs. Moreover, treatment with lentiviral SMC-specific TRPC3 channel shRNAs also abolishes airway SMC proliferation, hyperresponsiveness and remodeling, the most important asthmatic cellular responses, in mice with allergen-induced asthma. In contrast, TRPC3 channel overexpression produces opposite effects. The roles of TRPC3 channel in asthma are mediated by both calcium-associated protein kinase C-alpha/nuclear factor kappa B (NFkB) inhibitor-alpha (PKCα/IkBα)-mediated and calcineurin/IkBb-dependent, NFkB-linked cyclin D1 signaling pathways. These TRPC3 channel-initiated, calcium-associated PKCα/IkBα-mediated and calcineurin/IkBb-dependent, NFkB-linked cyclin D1 signaling pathways are also observed in asthmatic human ASMCs.

Based on the current novel and important findings with previous vigorous reports, we conclude that TRPC3 channel plays an essential role in the development of asthma, the roles of TRPC3 channel are mediated by both PKCα/IkBα-mediated and calcineurin/IkBb-dependent, NFkB-linked cyclin D1 signaling pathways, and lentiviral SMC-specific TRPC3 channel shRNAs may become a novel and effective bio-based therapeutics for asthma.

Biography:

Dr. Yong-Xiao Wang has been a Full Professor in Department of Molecular and Cellular Physiology at Albany Medical College since 2006. Dr. Wang obtained his MD at Wannan Medical University and PhD at Fourth Military Medical University. He received his postdoctoral training at Technology University of Munich and at University of Pennsylvania. His research interests are mainly focusing on basic, translational and drug discovery research in respiratory and cardiovascular biology and diseases, specifically on ion channel, calcium, redox and other signaling. He has had numerous publications in highly peer-reviewed journals including Nat Commun, 2020; Proc Natl Acad Sci USA, 2009; Nature, 2002; and Circ Res, 1995.

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