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Anastasia Khvorova PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentRNA Therapeutics Institute
AddressUniversity of Massachusetts Medical School
368 Plantation Street, Sherman Center, AS4.1049
Worcester MA 01605
Phone774-455-3638
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionUMMS - School of Medicine
    DepartmentProgram in Molecular Medicine

    InstitutionUMMS - School of Medicine
    DepartmentRNA Therapeutics Institute

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentNeuroscience

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentTranslational Science


    Collapse Biography 
    Collapse education and training
    Moscow State University, Moscow, , Russian FederationBSBiology
    Moscow State University, Moscow, , Russian FederationMSMolecular Biology
    Russian Academy of Sciences, Moscow, , Russian FederationPHDBiochemistry

    Collapse Overview 
    Collapse 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.

    Collapse 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




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Haraszti RA, Roux L, Coles AH, Turanov AA, Alterman JF, Echeverria D, Godinho BMDC, Aronin N, Khvorova A. 5?-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo. Nucleic Acids Res. 2017 Jun 07. PMID: 28591791.
      View in: PubMed
    2. Nikan M, Osborn MF, Coles AH, Biscans A, Godinho BMDC, Haraszti RA, Sapp E, Echeverria D, DiFiglia M, Aronin N, Khvorova A. Synthesis and Evaluation of Parenchymal Retention and Efficacy of a Metabolically Stable O-Phosphocholine-N-docosahexaenoyl-l-serine siRNA Conjugate in Mouse Brain. Bioconjug Chem. 2017 May 10. PMID: 28462988.
      View in: PubMed
    3. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017 Mar; 35(3):238-248. PMID: 28244990.
      View in: PubMed
    4. Khvorova A. Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering Drugs. N Engl J Med. 2017 Jan 05; 376(1):4-7. PMID: 28052224.
      View in: PubMed
    5. Ly S, Navaroli DM, Didiot MC, Cardia J, Pandarinathan L, Alterman JF, Fogarty K, Standley C, Lifshitz LM, Bellve KD, Prot M, Echeverria D, Corvera S, Khvorova A. Visualization of self-delivering hydrophobically modified siRNA cellular internalization. Nucleic Acids Res. 2017 Jan 09; 45(1):15-25. PMID: 27899655.
      View in: PubMed
    6. Haraszti RA, Didiot MC, Sapp E, Leszyk J, Shaffer SA, Rockwell HE, Gao F, Narain NR, DiFiglia M, Kiebish MA, Aronin N, Khvorova A. High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J Extracell Vesicles. 2016; 5:32570. PMID: 27863537.
      View in: PubMed
    7. Nikan M, Osborn MF, Coles AH, Godinho BM, Hall LM, Haraszti RA, Hassler MR, Echeverria D, Aronin N, Khvorova A. Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain. Mol Ther Nucleic Acids. 2016 Aug 09; 5(8):e344. PMID: 27504598.
      View in: PubMed
    8. Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho BM, Chase K, Sapp E, Ly S, Alterman JF, Hassler MR, Echeverria D, Raj L, Morrissey DV, DiFiglia M, Aronin N, Khvorova A. Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing. Mol Ther. 2016 Oct; 24(10):1836-1847. PMID: 27506293.
      View in: PubMed
    9. Amit I, Baker D, Barker R, Berger B, Bertozzi C, Bhatia S, Biffi A, Demichelis F, Doudna J, Dowdy SF, Endy D, Helmstaedter M, Junca H, June C, Kamb S, Khvorova A, Kim DH, Kim JS, Krishnan Y, Lakadamyali M, Lappalainen T, Lewin S, Liao J, Loman N, Lundberg E, Lynd L, Martin C, Mellman I, Miyawaki A, Mummery C, Nelson K, Paz J, Peralta-Yahya P, Picotti P, Polyak K, Prather K, Qin J, Quake S, Regev A, Rogers JA, Shetty R, Sommer M, Stevens M, Stolovitzky G, Takahashi M, Tang F, Teichmann S, Torres-Padilla ME, Tripathi L, Vemula P, Verdine G, Vollmer F, Wang J, Ying JY, Zhang F, Zhang T. Voices of biotech. Nat Biotechnol. 2016 Mar; 34(3):270-5. PMID: 26963549.
      View in: PubMed
    10. Nikan M, Osborn MF, Coles AH, Godinho BM, Hall LM, Haraszti RA, Hassler MR, Echeverria D, Aronin N, Khvorova A. Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain. Mol Ther Nucleic Acids. 2016; 5:e344. PMID: 28131259.
      View in: PubMed
    11. Alterman JF, Hall LM, Coles AH, Hassler MR, Didiot MC, Chase K, Abraham J, Sottosanti E, Johnson E, Sapp E, Osborn MF, Difiglia M, Aronin N, Khvorova A. Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain. Mol Ther Nucleic Acids. 2015 Dec 01; 4:e266. PMID: 26623938.
      View in: PubMed
    12. Coles AH, Osborn MF, Alterman JF, Turanov AA, Godinho BM, Kennington L, Chase K, Aronin N, Khvorova A. A High-Throughput Method for Direct Detection of Therapeutic Oligonucleotide-Induced Gene Silencing In Vivo. Nucleic Acid Ther. 2016 Apr; 26(2):86-92. PMID: 26595721.
      View in: PubMed
    13. Osborn MF, Alterman JF, Nikan M, Cao H, Didiot MC, Hassler MR, Coles AH, Khvorova A. Guanabenz (Wytensin™) selectively enhances uptake and efficacy of hydrophobically modified siRNAs. Nucleic Acids Res. 2015 Oct 15; 43(18):8664-72. PMID: 26400165.
      View in: PubMed
    14. Khvorova A, Osborn MF, Hassler MR. Corrigendum: Taking charge of siRNA delivery. Nat Biotechnol. 2015 May; 33(5):563. PMID: 25965761.
      View in: PubMed
    15. Khvorova A, Osborn MF, Hassler MR. Taking charge of siRNA delivery. Nat Biotechnol. 2014 Dec; 32(12):1197-8. PMID: 25489835.
      View in: PubMed
    16. 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. PMID: 24180627.
      View in: PubMed
    17. Khvorova A, Wolfson A. New competition in RNA regulation. Nat Biotechnol. 2012 Jan; 30(1):58-9. PMID: 22231098.
      View in: PubMed
    18. 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. PMID: 21493786.
      View in: PubMed
    19. Robertson B, Dalby AB, Karpilow J, Khvorova A, Leake D, Vermeulen A. Specificity and functionality of microRNA inhibitors. Silence. 2010; 1(1):10. PMID: 20359337.
      View in: PubMed
    20. 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. PMID: 19160483.
      View in: PubMed
    21. 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. PMID: 18367722.
      View in: PubMed
    22. Anderson E, Boese Q, Khvorova A, Karpilow J. Identifying siRNA-induced off-targets by microarray analysis. Methods Mol Biol. 2008; 442:45-63. PMID: 18369777.
      View in: PubMed
    23. 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. PMID: 17698642.
      View in: PubMed
    24. 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. PMID: 17400817.
      View in: PubMed
    25. 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. PMID: 17853862.
      View in: PubMed
    26. 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. PMID: 16682562.
      View in: PubMed
    27. 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. PMID: 16682561.
      View in: PubMed
    28. 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. PMID: 16611941.
      View in: PubMed
    29. 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. PMID: 16489337.
      View in: PubMed
    30. 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. PMID: 16394140.
      View in: PubMed
    31. 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. PMID: 15811921.
      View in: PubMed
    32. 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. PMID: 15782213.
      View in: PubMed
    33. 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. PMID: 15713901.
      View in: PubMed
    34. 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. PMID: 15611296.
      View in: PubMed
    35. 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. PMID: 15644176.
      View in: PubMed
    36. 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. PMID: 15623615.
      View in: PubMed
    37. 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. PMID: 15547137.
      View in: PubMed
    38. 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. PMID: 15339162.
      View in: PubMed
    39. 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. PMID: 15342789.
      View in: PubMed
    40. 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. PMID: 15131061.
      View in: PubMed
    41. 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. PMID: 15100442.
      View in: PubMed
    42. 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. PMID: 14985334.
      View in: PubMed
    43. 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. PMID: 14769947.
      View in: PubMed
    44. 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. PMID: 14765195.
      View in: PubMed
    45. 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. PMID: 14758366.
      View in: PubMed
    46. Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell. 2003 Oct 17; 115(2):209-16. PMID: 14567918.
      View in: PubMed
    47. 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. PMID: 12881719.
      View in: PubMed
    48. 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. PMID: 12594341.
      View in: PubMed
    49. 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. PMID: 10508395.
      View in: PubMed
    50. 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. PMID: 8389606.
      View in: PubMed
    51. Khvorova AM. Anticodon-dependent aminoacylation of RNA minisubstrate by lysyl-tRNA synthetase. FEBS Lett. 1992 Dec 21; 314(3):256-8. PMID: 1281788.
      View in: PubMed
    52. 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. PMID: 1338185.
      View in: PubMed
    53. 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. PMID: 1383036.
      View in: PubMed
    54. 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. PMID: 1425198.
      View in: PubMed
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