Laura CROFT, PhD
Senior Research Fellow, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology, Australia
Team Leader Drug Development, Cancer and Ageing Research Program, Queensland University of Technology, Australia
Dr Croft received her Bachelor of Science degree from Griffith University, Brisbane, Australia in 2001, and continued her doctoral studies from 2002 to 2006 at Griffith University and at the Queensland Institute of Medical Research, Brisbane, Australia. Dr Croft’s doctoral studies focused on selenoprotein translation mechanisms, and selenium biology and metabolism. Dr Croft also spent one year of her PhD at the Karolinska Institute, Stockholm, Sweden to study redox regulation of protein function in Prof Arne Holmgren’s lab. During her post-doctoral position at QIMR, 2006-2011, Dr Croft started utilising antisense oligonucleotides as a means to alter splicing and study protein function. In 2012, Dr Croft joined the Cancer and Ageing Research Program (CARP) at Queensland University of Technology (QUT) where her research focus became targeting DNA repair proteins in cancer using oligonucleotides and translating basic research into novel cancer therapeutics. Dr Croft is currently developing novel, nucleic acid-based cancer therapies by targeting DNA repair pathways. Dr Croft is team leader of drug development within CARP at QUT.
Targeting DNA repair pathways in cancer using oligonucleotides
Genome stability pathways offer a promising area of therapeutic intervention in cancer. Specific inhibitors of key DNA repair proteins have shown promising results as combination therapies and more recently also as single agents. We use nucleic acid-based technology to target DNA repair proteins in cancer and explore this technology as a potential cancer therapeutic. We show that specific oligonucleotides inhibit DNA repair, induce DNA damage, genomic fragmentation and apoptosis in multiple cancer cell lines, and suppress tumour growth in mouse xenograft models of prostate and lung cancer without any apparent toxicity to the animals.
Housheng Hansen HE, PhD
Associate Professor, Department of Medical
Biophysics, University of Toronto, Canada
Senior Scientist, Princess Margaret Cancer Centre,
University Health Network, Canada
Dr. He received his B.S. degree in physics from Beijing Normal University in the year of 2003, and then transitioned to the genomics and noncoding RNA fields for his Ph.D training in the Institute of Biophysics, Chinese Academy of Sciences. He received his postdoctoral training in cancer genomics and epigenomics at Dana-Farber Cancer Institute. After completing his postdoctoral training in 2011, Dr. He worked as an instructor at Harvard Medical School and was recruited as a scientist at the Princess Margaret Cancer Centre in 2013.
The He laboratory applies a variety of genomic, epigenomic experimental and computational approaches to elucidate the functional role of epigenetic regulation in cancer development, progression and drug response/resistance, with a special focus on the interplay between epigenetic regulator and noncoding RNA under stress conditions such as hypoxia. Dr. He’s work in the fields of noncoding RNA and epigenetics has resulted in ~50 peer-reviewed publications in high-impact journals including Nature, Cell, Nature Genetics, Nature Methods, Cancer Cell and Genome Research.
Professor, Institute for Genetic Medicine
Hokkaido University, Japan
Chandrasekhar KANDURI, PhD
Professor in RNA Biology
Department of Medical Biochemistry and Cell Biology
University of Gothenburg, Sweden
He became full professor of RNA biology at Uppsala university in 2010. In 2012, he moved his research activities to University of Gothenburg. His current research primarily focused on developing novel long noncoding RNAs (lncRNA) based strategies for the treatment of drug resistant and difficult to treat cancers through exploiting cell cycle based functional screens.
Ailong KE , PhD
Professor, Department of Molecular Biology and Genetics,
Cornell University, USA
Ekkehard LEBERER, PhD
Professor, Senior Director, Sanofi, Germany
Founding Director, COMPACT Consortium
Since joining Hoechst Marion Roussel in 1998, Dr. Leberer carried out various managing roles in this company, Sanofi’s predecessor companies and Sanofi itself, including responsibilities in functional genomics, biological sciences and external innovation for oligonucleotide-based therapeutics. He has also served as Head of Biotechnology Germany and a member of the Scientific Review Committee of Aventis Pharma Germany.
Prior to joining pharmaceutical industry, Dr. Leberer served as Senior Research Officer in genetics and genomics at the Biotechnology Research Institute, National Research Council of Canada, Montreal. His research has focused on the molecular mechanisms of signal transduction and the role of signalling molecules in human diseases. He is the principal discoverer of the p21 activated protein kinase (PAK) family of cell signalling proteins and of novel virulence-inducing genes in pathogenic fungi. He is co-author of more than 60 publications in prestigious peer-reviewed journals including Nature and Science.
• The presentation will address these delivery limitations and summarize the work of a European consortium (www.compact-research.org) of pharma companies and academic partners to improve nanocarrier-based delivery technologies that can overcome these limitations.
Dong-ki LEE, PhD
Professor of Chemistry, Sungkyunkwan University, Korea
Founder and CEO, OliX Pharmaceuticals, Korea
Wei LI, PhD
Professor of Bioinformatics, Dan L. Duncan Cancer Center
Department of Molecular and Cellular Biology
Baylor College of Medicine, USA
.0 million per year, including 4 PI grants from NIH and Texas CPRIT. (3) Mentored the first 6 postdoc trainees to start their tenure-track faculty positions in the US. Dr. Li received many prestigious awards, including the New Investigator Award from Department of Defense (2010), and the Michael E. DeBakey Excellence in Research Award (2016).
Zhen LI, PhD
Senior Vice President, Chemistry and Non-Clinical Development
Arrowhead Pharmaceuticals, USA
The presentation will focus on Arrowhead’s clinical candidate ARO-HBV for the treatment of Hepatitis B Virus infection. HBV infection presents a huge unmet medical need, as it affects over 250 million people worldwide and currently there is no cure for this devastating disease. In the presentation, some of our earliest clinical data on ARO-HBV will be presented, and the journey in discovering this powerful drug candidate will be discussed. The presentation will also discuss Arrowhead’s preclinical candidates ARO-ANG3 and ARO-APOC3 for the treatment of cardiometabolic disease such as hypertriglyceridemia. Gene knockdown, reduction of protein levels, and reduction of triglycerides in disease models for Arrowhead’s preclinical candidates ARO-ANG3 and ARO-APOC3 will be presented.
Muthiah MANOHARAN, PhD
Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, USA
Board Director, Oligonucleotide Therapeutics Society
Dr. Muthiah (Mano) Manoharan serves as a Senior Vice President and a Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. Dr. Manoharan joined Alnylam in 2003. He built the chemistry group at Alnylam and pioneered the discovery and development of RNA interference-based human therapeutics. Dr. Manoharan has had a distinguished career as a world-leading chemist in the areas of oligonucleotide chemical modifications, conjugation chemistry, and delivery platforms (lipid nanoparticles, polymer conjugates, and complex-forming strategies). He is an author of more than 200 publications (nearly 37,000 citations with an h-index of 85 and an i10-index of 329) and over 400 abstracts, as well as the inventor of over 225 issued U.S. patents.
Advances in RNAi Therapeutics Using Chemistry
RNA interference (RNAi) based therapeutics has evolved for the past two decades, and this year finally there is one approved siRNA-based drug representing the success of RNAi mechanisms of action: ONPATTRO or patisiran. On celebrating this occasion, we will review the key milestones of the past 16 years of drug discovery at Alnylam. This includes
• Chemical modifications, their functions, and pharmacological properties
• Delivery platforms (lipid nanoparticles and conjugates)
• Mechanisms of Delivery of RNAi therapeutics targeted to liver
• Emerging new approaches of overcoming RNAi-mediated, hybridization based off-target effects
• Use of Reversirs to modulate the RNAi effects
Craig MELLO, PhD
Professor, University of Massachusetts
Howard Hughes Medical Institute, USA
Nobel Prize in Physiology or Medicine (2006)
Dr. Mello received his BS degree in Biochemistry from Brown University in 1982, and PhD from Harvard University in 1990. From 1990 to 1994, he conducted postdoctoral research at the Fred Hutchinson Cancer Research Center in Seattle, WA. Now Dr. Mello is an Investigator of the Howard Hughes Medical Institute, the Blais University Chair in Molecular Medicine and Co-director of the RNA Therapeutics Institute at the University of Massachusetts Medical School.
Besides the Nobel Prize, Dr. Mello’s work was recognized with numerous awards and honors, including the National Academy of Sciences Molecular Biology Award (2003), the Wiley Prize in Biomedical Sciences from Rockefeller University (2003), Brandeis University’s Lewis S. Rosnstiel Award for Distinguished Work in Medical Research (2005), the Gairdner Foundation International Award (2005), the Massry Prize (2005), the Paul Ehrlich and Ludwig Darmstaedter Award (2006), the Dr. Paul Janssen Award for Biomedical Research (2006), the Hope Funds Award of Excellence in Basic Research (2008). He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society.
Phase-separated Domains of mRNA Regulation and Epigenetic Memory
In the C. elegans germline, three distinct Argonaute (AGO) systems act in concert with nearly 1 million distinct guide RNAs to scan the entire transcriptome inclusive of the coding regions. These AGO systems include a scanning AGO (Piwi) and its genomically encoded piRNA cofactors, and two ‘memory’ AGO systems whose guides are synthesized and maintained by RNA-dependent RNA polymerase, (RdRP). The CSR-1 memory Argonaute targets but does not silence expressed germline mRNAs, while the WAGO memory Argonautes target mRNAs that are silenced in the germline. These RNA-surveillance pathways reside in, and help drive the association of perinuclear nuage, (P-granules), which form liquid-like condensates around nuclei in transcriptionally active germ cells.
In mature gametes, CSR-1 and WAGO small RNA complexes are transmitted in cytoplasmic P-granules (in oocytes), and in a perinuclear halo of Ago/RNPs in sperm. Interestingly piRNA targeting induces a muted recruitment of RdRP on CSR-1 targets, suggesting that CSR-1 protects its targets from silencing. In contrast, piRNAs induce the robust localized recruitment of RdRP on WAGO targets (or foreign mRNAs) to amplify WAGO guide RNAs that maintain (or induce) the silencing of the target mRNA. In addition to completely silencing its targets, experimental studies reveal that germline-expressed mRNAs can respond to artificially-increased piRNA targeting with partial reductions in mRNA and protein expression.
piRNAs are abundantly expressed in the germlines of diverse animals, and because they tolerate mismatched pairing, have a vast potential target space. Thus, the repertoire of piRNAs in metazoan germlines provides a wealth of potential post-transcriptional regulatory capacity. Our findings suggest that piRNAs can access and regulate mRNAs throughout the mature transcript, including the ORF, and that even the coding regions of mRNAs are free to sample regulatory inputs from piRNAs. Importantly, because piRNAs are expressed as independent genes, they are also free to evolve independently, unconstrained by the coding requirements of their target regions. Thus piRNAs may unlock a vast regulatory space, the coding regions of genes, for the control of gene expression. Thus all germline mRNAs appear to undergo Argonaute surveillance and regulation within peri-nuclear nuage as they export to the cytoplasm. The assembly of the nuage around the nuclear periphery may facilitate access of this scanning machinery to RNAs as they emerge, prior to Ribosome loading, thus permitting regulation through the entire transcript. The ubiquity of AGO scanning within nuage begs the question of whether the condensate forms to drive the function, or whether the function drives the form.
In other words, perhaps the massive scale of protein-RNA and RNA-RNA targeting within nuage drives the exclusion of water (which always happens on a molecular scale) but simply becomes evident in the light microscope—function drives the form?
Joseph (Jody) PUGLISI, PhD
Professor, Department of Structural Biology
Stanford University School of Medicine, USA
Member of the US National Academy of Sciences
Born and raised in New Jersey, Joseph (Jody) Puglisi received a B.A. degree in Chemistry in 1984 from The Johns Hopkins University and a Ph.D. in Biophysical Chemistry from UC Berkeley in 1989. After postdoctoral research in Strasbourg and MIT, he joined the faculty at UC Santa Cruz in Chemistry and Biochemistry in 1993. He moved to Stanford University in 1997 in the Department of Structural Biology.
Dr. Puglisi’s group investigates the role of RNA in cellular processes and disease. Their goal is to understand RNA function in terms of molecular structure and dynamics using a variety of biophysical and biological tools. They use nuclear magnetic resonance (NMR) spectroscopy to determine structures of biological molecules, and integrate structural understanding into further mechanistic and functional studies. They investigate dynamics using single-molecule approaches. Their goal is a unified picture of structure, dynamics and function. They are currently focused on the mechanism and regulation of translation, and the role of RNA in viral infections. A long-term goal is to target processes involving RNA with novel therapeutic strategies.
Translation by the ribosome is a central and final step in gene expression in all organisms. The goal of our research is to understand the underlying conformational and compositional dynamics of translation. We have applied single-molecule fluorescence and structural approaches to both prokaryotic and eukaryotic translation systems. We have explored the dynamics of translation initiation, elongation and termination. Here we will describe recent investigations of eukaryotic translation initiation in both yeast and humans that reveal the underlying dynamics of translational control.
Elisabetta Viani PUGLISI, PhD
Senior Research Scientist Department of Structural Biology,
Stanford University School of Medicine, USA
Elisabetta Viani Puglisi was born in Parma and received her Laurea in Chemistry from the University of Parma in 1985, her Doctorate in Chemistry from the University of Parma in 1987 and Ph.D in Microbiology from the University of Brescia in 1994 for research performed at MIT. After postdoctoral research at UC Santa Cruz, she joined the Department of Structural Biology at Stanford in 1997. Her research focuses on the role of RNA structure in HIV replication.
Reverse transcription of the HIV-1 RNA genome into double-stranded DNA is a central step in infection and a common target of antiretroviral therapy. The reaction is catalyzed by viral reverse transcriptase (RT) that is packaged in an infectious virion along with 2 copies of dimeric viral genomic RNA and host tRNALys3, which acts as a primer for initiation of reverse transcription. Upon viral entry, initiation is slow and non-processive compared to elongation. We applied cryo-electron microscopy (cryo-EM) to determine the three-dimensional structure of the HIV RT initiation complex. RT is in an inactive polymerase conformation with open fingers and thumb and the nucleic acid primer-template complex is shifted away from the active site. The primer binding site (PBS) helix formed between tRNALys3 and HIV RNA lies in the cleft of RT, extended by additional pairing interactions. The 5’ end of the tRNA refolds and stacks on the PBS to create a long helical structure, while the remaining viral RNA forms two helical stems positioned above the RT active site, with a linker that connects these helices to the RNase H region of the PBS. Our results illustrate how RNA structure in the initiation complex alters RT conformation to decrease activity, highlighting a potential target for drug action.
Laura SEPP-LORENZINO, PhD
Vice President, Head of Nucleic Acid Therapies,
Vertex Pharmaceuticals, USA
Innovation at Vertex: Nucleic Acid Therapies as Transformative Medicines
Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious and life-threatening diseases, through internal research and external partnerships. We discovered and developed the first medicines to treat the underlying cause of cystic fibrosis (CF), a rare, life-threatening genetic disease. In addition to cystic fibrosis, the following are diseases of further research interest: adrenoleukodystrophy, alpha-1 antitrypsin deficiency, polycystic kidney disease, and sickle cell disease.
Nucleic Acid Therapies expand our ability to target genes that are considered undruggable or difficult to drug with small molecules and biologics. Vertex established strategic research collaborations with Moderna and CRISPR to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. Highlights from these efforts will be presented, in particular, our gene editing clinical program. As part of the CRISPR collaboration, we are co-developing CTX001, an investigational ex vivo CRISPR gene-edited therapy for patients suffering from β-thalassemia or sickle cell disease in which a patient’s hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen carrying hemoglobin that is naturally present at birth and is then replaced by the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate transfusion-requirements for β-thalassemia patients and painful and debilitating sickle crises for sickle cell patients. CTX001 in on track to initiate a Phase 1/2 clinical study in SCD by the end of 2018 and are currently enrolling patients with transfusion dependent β-thalassemia in a Phase 1/2 trial in β-thalassemia in Europe.
Mikiko C. SIOMI, PhD
Professor, Department of Biological Sciences,
Graduate School of Science, The University of Tokyo, Japan
Andreas STRASSER, PhD
Division Head, Molecular Genetics of Cancer,
The Walter and Eliza Hall Institute of Medical Research, Australia
Contributors to this work and affiliations:
G Kelly*, S Glaser*, S Grabow*, JM Adams*, M Herold*, M Brennan*, O Geneste#, AL Maragno#, A Kotschy# and A Strasser*
*The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia; #Servier, Paris, France
Bruce SULLENGER, PhD
Professor, Duke University Medical Center, USA
Dr. Sullenger’s research program focuses upon the discovery and development of therapeutic RNAs. His group has been a leader in the development of nucleic acid aptamers for inhibiting the activities of therapeutically important proteins including coagulation factors and platelet proteins. He is on the Board of Directors of the American Society of Gene and Cell Therapy and the Oligonucleotide Therapeutics Society and is Editor-in-Chief for the Society’s journal Nucleic Acid Therapeutics. Dr. Sullenger founded Regado Biosciences Inc, a company focused upon the development and commercialization of the aptamer-antidote technology his laboratory invented. The lead compound, an aptamer targeting factor IXa and its matched antidote, is in phase 3 clinical studies.
Dr. Sullenger earned his Bachelor of Science Degree from Indiana University (Bloomington, IN) and his Ph.D. from Cornell University Graduate School of Medical Sciences (New York, NY) working at the Memorial Sloan-Kettering Cancer Center. He performed postdoctoral studies at the University of Colorado (Boulder, CO) in the Department of Biochemistry in Dr. Thomas Cech’s laboratory.
Andrew YOO, PhD
Associate Professor, Department of Developmental Biology,
Washington University School of Medicine, USA
Brain-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), are potent cell fate regulators that can induce direct conversion (reprogramming) of non-neural human somatic cells to neurons. As such, ectopic expression of miR-9/9*-124 in human adult fibroblasts has been shown to directly target multiple components of chromatin modifiers leading to an extensive reconfiguration of the chromatin landscape while erasing the pre-existing fibroblast fate and adopting the neuronal identity. Our recent efforts in identifying direct targets of miR-9/9*-124 during neuronal conversion of human fibroblasts indicate multifactorial components in maintaining the non-neuronal fibroblast fate and repressors of neuronal fate. Some of the targeted pathways that converge to promote the fate switch include the downregulation of the USP14-EZH2-REST protein stability cascade, switching of subunit components of BAF chromatin remodeling complexes, alternative-splicing factors, and DNA methyltransferases. The resulting miRNA-induced chromatin then becomes permissive to the inputs of additional subtype-defining transcription factors that could guide the conversion to specific types of neurons including cortical neurons, striatal medium spiny neurons, and spinal cord motor neurons. Generation of specific types of human neurons through miRNA-mediated reprogramming then serves as an effective platform to model neurological disorders. Importantly for modeling late-onset diseases, directly converted human neurons have been shown to maintain the age signatures of fibroblast donors. As such, medium spiny neurons, a primary target of Huntington’s disease (HD), generated from direct conversion of HD fibroblasts reliably recapitulated hallmarks of adult-onset HD including the aggregation of Huntingtin protein, increased DNA damage, mitochondrial dysfunction and spontaneous neuronal death. Collectively, our studies demonstrate the potent activity of microRNAs as cell fate regulators and its utility to generate a patient-derived cellular platform to model diseases.
Nucleic acids science plays a key role in precision medicine, genetic therapy and new solutions for human health. Continuous discovery of new RNA functions and constant emergence of innovative nucleic acids technologies are driving forces for the field and hold enormous promise for the future scientific and technological progress. The China Nucleic Acids Forum (CNAF) led by Nobel Prize winners is an international forum at the forefront of these developments, aims to push forward communications and collaborations in and abroad, and has been successfully held five times since 2013. The CNAF has attracted high-profile speakers, including Nobel Prize winners, to highlight recent advances in nucleic-acid based medicine, scientific discoveries, diagnostics and industrial trends. It has been widely recognized as the premier forum in Asia for advancing nucleic acids research and drug development. The 2018 CNAF will feature 20+ globally prominent experts discussing the latest advances in nucleic acids research and development.
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