Anastasia Khvorova,
Professor, RNA Therapeutics Institute,
University of Massachusetts Medical School
Anastasia Khvorova, PhD, is Professor in the RNA Therapeutics Institute and the Program in Molecular Medicine at the University of Massachusetts Medical School (UMMS) in Worcester, Massachusetts. Before joining the UMMS faculty, she held leadership positions in industry, including Vice President of Research & Development and Chief Science Officer of Dharmacon, Founder and Scientific Advisor of Advirna, and Chief Science Officer and Senior Vice President of RXi Pharmaceuticals. Dr Khvorova’s industry experience in drug discovery and development collaborations with pharmaceutical companies along with her expertise in chemistry and cell biology allowed her to establish a lab at UMMS that brings together organic chemists and RNA biologists to develop novel approaches and solutions to understanding natural and therapeutic RNA trafficking and delivery. Dr Khvorova is a member of the Board of Directors of the Oligonucleotide Therapeutics Society and sits on the editorial board of Nucleic Acid Research. She is the author of more than 150 abstracts, more than 50 peer-reviewed articles, several book chapters, and more than 250 patents and patent applications; her publications are widely cited.
Expanding the Chemical Diversity of Therapeutic Oligonucleotides
Monday, 13 November 2017 at 11:00
Add to Calendar ▼2017-11-13 11:00:002017-11-13 12:00:00Europe/LondonExpanding the Chemical Diversity of Therapeutic OligonucleotidesThe RNA Summit: Research, Diagnostics and Therapeutics in Boston, USABoston, USASELECTBIOenquiries@selectbiosciences.com
RNA interference has revolutionized human functional genomics and therapeutics, but its impact on neuroscience research has been limited by the lack of simple and efficient methods to deliver oligonucleotides to primary neurons and the brain. We show that primary neurons rapidly internalize fully stabilized, hydrophobically modified siRNAs (hsiRNAs) added directly to the culture medium and that hsiRNAs induce potent and long-lasting silencing in vitro. A single injection of unformulated hsiRNA (cholesterol-conjugated) into mouse brain silences locally with great potency and longevity. Limited distribution from the site of administration precludes direct use of this type of chemistry for modulation of gene expression in larger brains and potential therapeutic development. Using fully chemically modified siRNA scaffolds, we systematically screened a wide range of bioactive conjugates and demonstrated that the chemical nature of the conjugation modality has a major impact on brain tissue retention, distribution and cellular internalization. We have identified several novel chemical classes of conjugates that demonstrate markedly improved brain distribution and robust in vivo efficacy. Direct conjugation of a fully chemically modified siRNA to docosahexaenoic acid (DHA), the most abundant poly-unsaturated fatty acid in the brain, results in improved tissue retention with wide distribution and robust efficacy in the striatum and cortex after single injection. Most importantly, DHA-hsiRNA conjugates do not induce neural cell death or measurable innate immune activation following administration of concentrations 20-fold over the efficacious dose, establishing a new approach toward development of RNAi-based therapeutics for a wide range of neurodegenerative disorders.
Add to Calendar ▼2017-11-13 00:00:002017-11-14 00:00:00Europe/LondonThe RNA Summit: Research, Diagnostics and TherapeuticsThe RNA Summit: Research, Diagnostics and Therapeutics in Boston, USABoston, USASELECTBIOenquiries@selectbiosciences.com
Add to Calendar ▼2017-11-13 11:00:002017-11-13 12:00:00Europe/LondonExpanding the Chemical Diversity of Therapeutic OligonucleotidesThe RNA Summit: Research, Diagnostics and Therapeutics in Boston, USABoston, USASELECTBIOenquiries@selectbiosciences.com
