Viral RNA Targets

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Steven F. Dowdy, PhD
Professor
Dept. Cellular & Molecular Medicine
UCSD School of Medicine

Dr. Dowdy is an RNA therapeutics expert, focused on siRNA and ASO delivery and new chemistry.  Hereceived his Ph.D. in Molecular Genetics from UC Irvine and performed his postdoctoral fellowship with Prof. Bob Weinberg at the Whitehead Institute at MIT. Dr. Dowdy sits on five Science Advisory Boards for biotech companies and was a thrice elected member to the Board of Directors of the Oligonucleotide Therapeutics Society (OTS) (2014-2021). Previously, Dr. Dowdy was a Howard Hughes Medical Institute Investigator (1994-2012) and an Assistant Professor at Washington University School of Medicine (1994-2001).
 

Over the last 27 years, Dr. Dowdy’s lab has pioneered delivery of macromolecular therapeutics and for the last 17 years on the molecular details of delivery of RNA therapeutics across the endosomal lipid bilayer. His lab was the first to synthesize bioreversible, charge neutralizing phosphotriester backbone RNAi prodrug triggers that increase metabolic stability, pharmacokinetics and enhance endosomal escape. Currently, his lab is synthesizing novel biomimetic endosomal escape domains to overcome the rate-limiting delivery step of endosomal entrapment. Dr. Dowdy will lead development of anti-viral siRNAs and enhancement of endosomal escape.

Feng Guo, PhD
Professor
Dept. of Biological Chemistry
UCLA David Geffen School of Medicine

Dr. Guo is a structural and molecular biologist. He received his Ph.D. in Biochemistry and Biophysics from University of Pennsylvania and did his postdoctoral training with Prof. Thomas Cech at University of Colorado at Boulder. He determined the structures of Cre/loxP DNA recombination complexes and the Tetrahymena ribozyme, discovered an essential role of heme in microRNA biogenesis in humans, and invented a structure-based design method for antisense oligonucleotides.

Dr. Guo’s lab has been applying his structural biology expertise to develop RNA-targeting therapeutics. His lab has developed a technology called structure-based antisense oligonucleotides (3D-ASOs) that includes eight design templates and novel structure determination methods. Dr. Guo will contribute this technology and relevant expertise in development of anti-viral ASOs and small molecules.

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Thomas Hermann, PhD
Professor
Dept. of Chemistry & Biochemistry
UC San Diego

Thomas Hermann is a pioneer in RNA targeting by small molecules. Dr. Hermann received a MS in Chemistry from the University of Ulm, Germany, and performed graduate research at the Max-Planck Institute of Biochemistry for which he received his Ph.D. in Biochemistry from the Ludwig-Maximilians-University in Munich. He worked as a postdoctoral fellow at the CNRS in Strasbourg, France, and the Memorial Sloan Kettering Cancer Center in New York. Before joining UC San Diego, Dr. Hermann worked in biotech where he led structure-guided drug discovery of therapies treating bacterial and viral infections.

Dr. Hermann has studied molecular recognition of RNA by small molecules, ions, and proteins. His research on RNA has been guided by the mantra that what is structure is prologue to function and targeting. The Hermann lab’s investigations on targeting a noncoding RNA domain in the hepatitis C virus genome, and mechanistic studies of small molecule translation inhibitors directed at the viral mRNA are recognized as landmark studies that provide the gold standard for structure-based targeting approaches to RNA. Dr. Hermann will lead development of small molecule antivirals directed at structured domains in the genome of RNA viruses.

Simpson Joseph, PhD
Professor
Dept. of Chemistry & Biochemistry
UCSD

Simpson Joseph is an expert on RNA structure, RNA catalysis, mechanism of protein synthesis, and translational regulation.  Dr. Joseph received his Ph.D. in Microbiology & Molecular Genetics from the University of Vermont.  For his Ph.D. thesis with Prof. John Burke, he studied RNA catalysis by the hairpin ribozyme and developed an anti-HIV hairpin ribozyme.  Dr. Joseph performed his postdoctoral research on ribosome structure and function with Prof. Harry Noller at UC Santa Cruz. 

Dr. Joseph has worked on the mechanism of protein synthesis, translational regulation, and viral mRNA translation for over 20 years.  He has developed fluorescence and FRET-based assays to understand the process of protein synthesis.  Recently, Dr. Joseph’s group showed that translation initiation on influenza A virus mRNAs are resistant to inhibition of cap-dependent translation and may be translated by a specialized mechanism.  His group is currently studying the role of the 5’UTR of SARS-CoV2 in viral mRNA translation with the goal to develop antiviral molecules that target this highly conserved viral RNA structure.

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Anders M. Näär, Ph.D

Professor and Vice Chair

Dept. of Nutritional Sciences & Toxicology

Innovative Genomics Institute

University of California, Berkeley

Dr. Anders M. Näär received his Ph.D. in Molecular Pathology from UC San Diego/HHMI with Prof. Michael Geoff Rosenfeld and performed his postdoctoral fellowship with Prof. Robert Tjian at UC Berkeley/HHMI. Dr. Näär is an expert on gene regulation mechanisms, having discovered and extensively characterized the human Mediator transcriptional co-activator complex. He is also an RNA Medicine expert, focused on locked nucleic acid (LNA) antisense oligonucleotide (ASO) therapeutics targeting non-coding RNAs (e.g., microRNAs) in a range of rare and prevalent diseases (HoFH/CVD, dry AMD, DMD, NASH, T2D, morbid obesity), as well as in viral infectious diseases (e.g., COVID-19 and Ebola). Dr. Näär has recently launched three biotech companies.

A substantial portion of the research in Dr. Näär’s lab has been focused on using LNA ASOs to target pathological RNAs contributing to disease, and his lab pivoted when the COVID-19 pandemic began to therapeutically target the SARS-CoV-2 viral RNA. They identified potent LNA ASOs targeting highly conserved non-coding viral RNA structures, showing pM-nM efficacy in preventing infection in human cells, and with 80-100-fold decrease in viral load in the lungs of infected mice after intranasal delivery. Dr. Näär will lead the development of LNA ASOs as inhaled anti-viral agents that can act both prophylactically and therapeutically post-infection as a novel treatment for COVID-19.

Davey Smith, MD, MAS, FIDSA, FACP
Head, Division of Infectious Diseases and Global Public Health
Professor and Vice-Chair of Research, Department of Medicine
Co-Director, San Diego Center for AIDS Research (CFAR)
Director, PREPARE Institute
Florence Seeley Riford Chair in AIDS Research
UCSD, School of Medicine

Davey Smith, MD, MAS, is an infectious disease specialist and translational research virologist, and has published over 300 scientific publications in these areas. In 2010, Dr. Smith was named HIV Researcher of the Year by the HIV Medical Association, and in 2016, he became the co-director and principal investigator of the San Diego Center for AIDS Research (CFAR). Since the outbreak of SARS-CoV-2 in 2019, Dr. Smith has been engaged in the international effort to find safe and effective treatments. In particular, he is the international protocol chair for the ACTIV-2 treatment study, which is a part of the US government’s response to COVID-19 to find effective therapies for persons with early COVID-19.

 

Davey has also extensive experience in high containment viral research, including HIV, Zika, Ebola and SARS-CoV-2 in in vitro and animal models. He is the current director of the UCSD BSL-3 laboratory and has authored a number of recent high-profile studies in SARS-CoV-2 drug discovery, including human immune response, viral entry, among others. With respect to this UCNL ATTACK Center application, Dr. Smith will add to the RNA targetig therapeutic approaches and also provide translational science and clinical trial expertise, especially as it relates to lead candidate development to ultimately enter a clinical trial.

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Navtej Toor, PhD
Associate Professor
Dept of Chemistry and Biochemistry
UC San Diego

Navtej Toor is an expert in RNA structure, with a focus on pre-mRNA splicing and viral RNA genome structure. Dr. Toor received his Ph.D. in Biochemistry from the University of Calgary and performed his postdoctoral fellowship in RNA structural biology with Prof. Anna Marie Pyle at Yale University. 
Dr. Toor’s lab has been focused on the high-resolution structure determination of non-coding RNAs using x-ray crystallography and cryo-electron microscopy. Recently, his lab has determined the first high-resolution structure of a retroelement invading double-stranded DNA.  This mechanism of retrotransposition is similar to that seen during viral DNA integration.  His lab is now applying their knowledge of RNA structure to the study of viruses with RNA genomes.  Dr. Toor will lead the identification of conserved RNA structures in viral genomes that will be targeted for disruption to prevent replication.