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    Anastasia Khvorova PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    55 Lake Ave North
    Worcester MA 01605
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentRNA Therapeutics Institute

        Overview 
        Rotation Projects
        Our laboratory uses a combination of nucleic acid and oligonucleotide chemistry, biochemistry, cell biology, and pharmacology and develops and evaluate novel technologies for development of oligonucleotide therapeutics. A rotation project is available to develop and identify chemically modified self-delivering RNAi compounds for treatment of Huntington and other diseases.

        Post Docs

        POSTDOCTORAL POSITION: RNAI PRECLINICAL DEVELOPMENT
        Excellent training opportunity for a person considering industrial carrier in drug development
         
        Oligonucleotides represent a new class of drugs, which have the promise to become a major class of future therapeutics. There are several classes of oligonucleotides which can efficiently silence genes in various tissues with acceptable level of toxicity. There are also new chemistries being developed to further improve oligonucleotide tissue distribution and cellular uptake.
        The successful candidate will be a key part of an intra-disciplinary team working with biologists and chemists to develop novel types of therapeutics for treatment of neurological disease, liver disease and orphan indications. The work will include compounds identification, screening, characterization, in vivo efficacy and PK/PD studies, novel assays development etc. In addition exposure and training in nucleic acid pre-clinical development, project management etc will be provided.

        QUALIFICATIONS: Applicants must have (or expect to obtain shortly) a Ph.D. in Chemistry, Organic Chemistry Biochemistry, Cell Biology, Molecular Biology or a related field , be bright, ambitious,  independent and collaborative and ideally,  have research experience in nucleic acid molecular cell biology or pharmacology.



        RNAI MEDICINAL CHEMISTRY/ RNA OLIGONUCLEOTIDE CHEMISTRY
        Develop and characterize novel RNA chemistries to promote efficient oligonucleotide internalization and tissue distribution.

        Oligonucleotides represent a new class of drugs, which have the promise to become a major class of future therapeutics. There are several chemistries and formulations developed by us and others that effectively support oligo internalization and favorable PK/PD. In most cases in vivo efficacy is limited by (1) poor PK (2) inefficient tissue distribution (3) compound entrapment in biologically inactive intracellular compartments.
        The objective of future studies will be development of novel chemistries, which promote receptor mediated cellular internalization and/ or endosomal escape. The successful candidate will be responsible for the design and synthesis of novel RNA precursors, optimization of RNA synthesis and conjugation protocols and interface with the biology part of the lab. In addition, exposure to pre-clinical development programs and oligonucleotide manufacturing will be available.

         QUALIFICATIONS: Applicants must have (or expect to obtain shortly) a Ph.D. in Chemistry, Organic Chemistry Biochemistry, Cell Biology, Molecular Biology or a related field , be bright, ambitious, independent and collaborative and have previous experience in nucleic acid / oligonucleotide chemistry.



        SMALL RNA TRAFFICKING
        Discover, characterize and adapt mechanisms of small RNA extracellular and intracellular trafficking for development of novel classes of oligonucleotide drugs.

         A serious limitation in realizing the potential of oligonucleotide based therapies has been the exceedingly inefficient transit of oligonucleotides from outside cells to the intracellular compartments where the biologically relevant activity happens.  On the other hand, there are multiple lines of evidence supporting the notion that nature has implemented evolutionarily conserved mechanisms and pathways for efficiently trafficking small RNAs across cellular boundaries. The objective of future studies will  be the systematic evaluation of mechanisms of cellular uptake of different classes of oligonucleotides and their comparison to mechanisms of  native RNA trafficking using a combination of experimental approaches, including advanced RNA chemistry and high temporal and spatial resolution microscopy in living cells, Mass spectrometry, cell biology and others.  The successful candidate will work closely with Victor Ambros and Silvia Corvera labs and the UMASS imaging group and receive training in RNA chemistry, biochemistry, cell biology and pre-clinical development.

        QUALIFICATIONS:Applicants must have (or expect to obtain shortly) a Ph.D. in Chemistry, Organic Chemistry Biochemistry, Cell Biology, Molecular Biology or a related field , be bright, ambitious,  independent and collaborative and ideally,  have research experience in nucleic acid molecular and cell biology



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Byrne M, Tzekov R, Wang Y, Rodgers A, Cardia J, Ford G, Holton K, Pandarinathan L, Lapierre J, Stanney W, Bulock K, Shaw S, Libertine L, Fettes K, Khvorova A, Kaushal S, Pavco P. Novel Hydrophobically Modified Asymmetric RNAi Compounds (sd-rxRNA) Demonstrate Robust Efficacy in the Eye. J Ocul Pharmacol Ther. 2013 Dec; 29(10):855-64.
          View in: PubMed
        2. Khvorova A, Wolfson A. New competition in RNA regulation. Nat Biotechnol. 2012 Jan; 30(1):58-9.
          View in: PubMed
        3. Lapierre J, Salomon W, Cardia J, Bulock K, Lam JT, Stanney WJ, Ford G, Smith-Anzures B, Woolf T, Kamens J, Khvorova A, Samarsky D. Potent and systematic RNAi mediated silencing with single oligonucleotide compounds. RNA. 2011 Jun; 17(6):1032-7.
          View in: PubMed
        4. Robertson B, Dalby AB, Karpilow J, Khvorova A, Leake D, Vermeulen A. Specificity and functionality of microRNA inhibitors. Silence. 2010; 1(1):10.
          View in: PubMed
        5. Simpson KJ, Selfors LM, Bui J, Reynolds A, Leake D, Khvorova A, Brugge JS. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nat Cell Biol. 2008 Sep; 10(9):1027-38.
          View in: PubMed
        6. Anderson EM, Birmingham A, Baskerville S, Reynolds A, Maksimova E, Leake D, Fedorov Y, Karpilow J, Khvorova A. Experimental validation of the importance of seed complement frequency to siRNA specificity. RNA. 2008 May; 14(5):853-61.
          View in: PubMed
        7. Anderson E, Boese Q, Khvorova A, Karpilow J. Identifying siRNA-induced off-targets by microarray analysis. Methods Mol Biol. 2008; 442:45-63.
          View in: PubMed
        8. Li L, Lin X, Khvorova A, Fesik SW, Shen Y. Defining the optimal parameters for hairpin-based knockdown constructs. RNA. 2007 Oct; 13(10):1765-74.
          View in: PubMed
        9. Vermeulen A, Robertson B, Dalby AB, Marshall WS, Karpilow J, Leake D, Khvorova A, Baskerville S. Double-stranded regions are essential design components of potent inhibitors of RISC function. RNA. 2007 May; 13(5):723-30.
          View in: PubMed
        10. Birmingham A, Anderson E, Sullivan K, Reynolds A, Boese Q, Leake D, Karpilow J, Khvorova A. A protocol for designing siRNAs with high functionality and specificity. Nat Protoc. 2007; 2(9):2068-78.
          View in: PubMed
        11. Jackson AL, Burchard J, Leake D, Reynolds A, Schelter J, Guo J, Johnson JM, Lim L, Karpilow J, Nichols K, Marshall W, Khvorova A, Linsley PS. Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing. RNA. 2006 Jul; 12(7):1197-205.
          View in: PubMed
        12. Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, Leake D, Marshall WS, Khvorova A. Off-target effects by siRNA can induce toxic phenotype. RNA. 2006 Jul; 12(7):1188-96.
          View in: PubMed
        13. Reynolds A, Anderson EM, Vermeulen A, Fedorov Y, Robinson K, Leake D, Karpilow J, Marshall WS, Khvorova A. Induction of the interferon response by siRNA is cell type- and duplex length-dependent. RNA. 2006 Jun; 12(6):988-93.
          View in: PubMed
        14. Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Fedorov Y, Baskerville S, Maksimova E, Robinson K, Karpilow J, Marshall WS, Khvorova A. 3' UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods. 2006 Mar; 3(3):199-204.
          View in: PubMed
        15. Benimetskaya L, Lai JC, Khvorova A, Wu S, Miller P, Stein CA. Induction of apoptosis by G3139 in melanoma cells. Ann N Y Acad Sci. 2005 Nov; 1058:235-45.
          View in: PubMed
        16. Vermeulen A, Behlen L, Reynolds A, Wolfson A, Marshall WS, Karpilow J, Khvorova A. The contributions of dsRNA structure to Dicer specificity and efficiency. RNA. 2005 May; 11(5):674-82.
          View in: PubMed
        17. Fedorov Y, King A, Anderson E, Karpilow J, Ilsley D, Marshall W, Khvorova A. Different delivery methods-different expression profiles. Nat Methods. 2005 Apr; 2(4):241.
          View in: PubMed
        18. Lai JC, Benimetskaya L, Khvorova A, Wu S, Hua E, Miller P, Stein CA. Phosphorothioate oligodeoxynucleotides and G3139 induce apoptosis in 518A2 melanoma cells. Mol Cancer Ther. 2005 Feb; 4(2):305-15.
          View in: PubMed
        19. Kisseleva N, Khvorova A, Westhof E, Schiemann O. Binding of manganese(II) to a tertiary stabilized hammerhead ribozyme as studied by electron paramagnetic resonance spectroscopy. RNA. 2005 Jan; 11(1):1-6.
          View in: PubMed
        20. Boese Q, Leake D, Reynolds A, Read S, Scaringe SA, Marshall WS, Khvorova A. Mechanistic insights aid computational short interfering RNA design. Methods Enzymol. 2005; 392:73-96.
          View in: PubMed
        21. Benimetskaya L, Lai JC, Khvorova A, Wu S, Hua E, Miller P, Zhang LM, Stein CA. Relative Bcl-2 independence of drug-induced cytotoxicity and resistance in 518A2 melanoma cells. Clin Cancer Res. 2004 Dec 15; 10(24):8371-9.
          View in: PubMed
        22. Saksmerprome V, Roychowdhury-Saha M, Jayasena S, Khvorova A, Burke DH. Artificial tertiary motifs stabilize trans-cleaving hammerhead ribozymes under conditions of submillimolar divalent ions and high temperatures. RNA. 2004 Dec; 10(12):1916-24.
          View in: PubMed
        23. Canny MD, Jucker FM, Kellogg E, Khvorova A, Jayasena SD, Pardi A. Fast cleavage kinetics of a natural hammerhead ribozyme. J Am Chem Soc. 2004 Sep 8; 126(35):10848-9.
          View in: PubMed
        24. Miller JT, Khvorova A, Scaringe SA, Le Grice SF. Synthetic tRNALys,3 as the replication primer for the HIV-1HXB2 and HIV-1Mal genomes. Nucleic Acids Res. 2004; 32(15):4687-95.
          View in: PubMed
        25. Raffo A, Lai JC, Stein CA, Miller P, Scaringe S, Khvorova A, Benimetskaya L. Antisense RNA down-regulation of bcl-2 expression in DU145 prostate cancer cells does not diminish the cytostatic effects of G3139 (Oblimersen). Clin Cancer Res. 2004 May 1; 10(9):3195-206.
          View in: PubMed
        26. Penedo JC, Wilson TJ, Jayasena SD, Khvorova A, Lilley DM. Folding of the natural hammerhead ribozyme is enhanced by interaction of auxiliary elements. RNA. 2004 May; 10(5):880-8.
          View in: PubMed
        27. Huang F, Khvorova A, Marshall W, Sorkin A. Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J Biol Chem. 2004 Apr 16; 279(16):16657-61.
          View in: PubMed
        28. Hsieh AC, Bo R, Manola J, Vazquez F, Bare O, Khvorova A, Scaringe S, Sellers WR. A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway: determinants of gene silencing for use in cell-based screens. Nucleic Acids Res. 2004; 32(3):893-901.
          View in: PubMed
        29. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004 Feb 5; 427(6974):541-4.
          View in: PubMed
        30. Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A. Rational siRNA design for RNA interference. Nat Biotechnol. 2004 Mar; 22(3):326-30.
          View in: PubMed
        31. Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell. 2003 Oct 17; 115(2):209-16.
          View in: PubMed
        32. Khvorova A, Lescoute A, Westhof E, Jayasena SD. Sequence elements outside the hammerhead ribozyme catalytic core enable intracellular activity. Nat Struct Biol. 2003 Sep; 10(9):708-12.
          View in: PubMed
        33. Wilson JA, Jayasena S, Khvorova A, Sabatinos S, Rodrigue-Gervais IG, Arya S, Sarangi F, Harris-Brandts M, Beaulieu S, Richardson CD. RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells. Proc Natl Acad Sci U S A. 2003 Mar 4; 100(5):2783-8.
          View in: PubMed
        34. Wolfson AD, Khvorova AM, Sauter C, Florentz C, Giegé R. Mimics of yeast tRNAAsp and their recognition by aspartyl-tRNA synthetase. Biochemistry. 1999 Sep 14; 38(37):11926-32.
          View in: PubMed
        35. Khvorova AM, Motorin IuA, Vol'fson AD. [Mechanism of discrimination of tRNA(Phe) from E. coli by yeast phenylalanine-tRNA-synthetase]. Biokhimiia. 1993 Apr; 58(4):613-9.
          View in: PubMed
        36. Khvorova AM. Anticodon-dependent aminoacylation of RNA minisubstrate by lysyl-tRNA synthetase. FEBS Lett. 1992 Dec 21; 314(3):256-8.
          View in: PubMed
        37. Khvorova AM, Motorin IuA, Vol'fson AD. [Pyrophosphate-dependent inactivation of tyrosyl-tRNA synthetase during aminoacylation of heterologous tRNA]. Biokhimiia. 1992 Dec; 57(12):1913-6.
          View in: PubMed
        38. Khvorova AM. Crucial role of pyrophosphate in the aminoacylation of E. coli tRNA(Phe) by yeast phenylalanyl-tRNA synthetase. FEBS Lett. 1992 Oct 19; 311(2):139-42.
          View in: PubMed
        39. Khvorova AM, Motorin IuA, Vol'fson AD, Gladilin KL. [Specific aminoacylation of oligo U-CCA lysyl-tRNA-synthetase molecules]. Dokl Akad Nauk. 1992; 325(1):179-82.
          View in: PubMed
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