Anastasia Khvorova

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Anastasia Khvorova
Anastasia Khvorova headshot.png
Born
Moscow, Russia
Alma materA. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, PhD (1994) Moscow State University, BS/MS (1991)
Known forChemical engineering of siRNAs to allow efficient extrahepatic delivery
Scientific career
FieldsNucleic acid chemistry, biochemistry, molecular biology
InstitutionsUMass Chan Medical School

RXi Pharmaceuticals

Thermo Fisher Scientific (formerly Dharmacon)

Amgen
Website https://www.umassmed.edu/khvorovalab/

Anastasia Khvorova (born August 3, 1969) is a Russian-born American biochemist. She is a professor at the University of Massachusetts Chan Medical School, [1] where she is a member of the RNA Therapeutics Institute and the Program in Molecular Medicine and holds the Remondi Family Chair in Biomedical Sciences. [2] [3] Khvorova's research focuses on the development of oligonucleotide- and RNA interference (RNAi)-based therapeutics.

Contents

Early life and education

Khvorova was born in Moscow, USSR on August 3, 1969. Her father, Mike Ivanovich Khvorov, was a Russian physicist; her mother, Diana, a mathematician, and brother Alexei Mikhailovich Lidov, a Russian art historian and Byzantinist. Khvorova earned her PhD in biochemistry from the A. N. Bakh Institute of Biochemistry of the Russian Academy of Sciences in 1994. Her doctoral research examined mechanisms of transfer RNA recognition.

After relocating to the United States in 1995, she completed postdoctoral training at Temple University with Patrick Piggot and at the University of Colorado Boulder with Michael Yarus.

Scientific career

Khvorova has held research and leadership positions in both academia and industry. In industry, she worked at Amgen and later, Dharmacon, a division of Thermo Fisher Scientific, where she advanced RNA biology and chemistry programs and served as Chief Scientific Officer. She later served as Chief Scientific Officer of RXi Pharmaceuticals.

In 2012, Khvorova joined UMass Chan Medical School as a professor in the RNA Therapeutics Institute and the Program in Molecular Medicine. She founded the Nucleic Acid Chemistry Center [4] within the RNA Therapeutics Institute at UMass Chan Medical School, which provides RNA synthesis and chemistry expertise to academic research groups.

Research

Chemical modification and siRNA design

A central theme of Khvorova's work is the systematic study of chemical modifications to small interfering RNAs (siRNAs). Her laboratory has examined how alterations to ribose sugars, internucleotide linkages, and terminal groups affect RNA-induced silencing complex (RISC) loading and gene-silencing activity. This work contributed to the development of fully chemically modified siRNA scaffolds that retain RNAi potency while exhibiting improved metabolic stability and reduced off-target effects. [5]

Her studies, in tandem with Phillip D. Zamore, helped define principles of thermodynamic asymmetry and strand selection during RISC assembly, [6] clarifying how siRNA duplex design influences guide strand incorporation and silencing efficiency. [7] [8]

Extrahepatic delivery of RNA therapeutics

Khvorova has made key contributions to strategies for delivering RNAi therapeutics beyond the liver. Her laboratory demonstrated that extensive chemical stabilization is required for effective conjugate-mediated delivery and identified lipid and other hydrophobic conjugates that enable functional RNAi activity in extrahepatic tissues.

This work established that conjugate hydrophobicity and chemical composition govern systemic distribution through endogenous lipid transport pathways, enabling silencing activity in tissues such as the heart, [9] muscle, [9] central nervous system, [10] [11] eye, [12] kidney, [13] lung, [14] [15] [16] and placenta. [17]

Backbone chemistry and allele-selective silencing

Khvorova's research has also explored novel backbone chemistries designed to enhance tissue retention and specificity. Her group characterized extended nucleic acid (exNA) [18] [19] and internally constrained vinyl phosphonate linkages, [20] demonstrating that these chemistries improve extrahepatic accumulation and support allele-selective gene silencing in vivo. These approaches have been applied to therapeutic strategies for dominantly inherited neurological and genetic disorders. [10] [21]

Multivalent and divalent siRNA architectures

More recently, Khvorova introduced multivalent and divalent siRNA architectures in which increased molecular valency, combined with optimized chemical modification, produces prolonged tissue retention and sustained gene silencing following a single administration. These designs have been applied to multiple extrahepatic targets and represent an approach to extending the durability of RNAi therapeutics. [10] [12] [14] [15] [22]

Off-target effects and RNA specificity

In parallel with applied therapeutic research, Khvorova has contributed to the understanding of off-target effects in RNAi. Her work demonstrated that seed-mediated interactions are a primary driver of miRNA-like off-target silencing, informing both computational prediction methods [23] and chemical strategies to improve siRNA specificity.

Collectively, these lines of research have contributed to defining design principles that underlie contemporary RNAi-based therapeutics.

Contributions to RNA therapeutics

Therapeutic RNA delivery beyond the liver remains a major challenge in the field. [24] To address these challenges, Khvorova's research centers on chemical modification of therapeutic RNAs to improve stability, specificity, and delivery, enabling delivery to tissues that have traditionally been difficult to target, including the brain, heart, muscle, lung, placenta, and eye. Khvorova is known for research that helped define principles of siRNA design, strand selection, and chemical modification. Her work has contributed to the development of RNA-based approaches for the treatment of genetic, neurodegenerative, and infectious diseases, including Huntington's disease. [21]

She has authored more than 130 peer-reviewed publications across academic and industry settings and has more than 49,000 citations on Google Scholar. [25] Her research includes highly cited articles in journals such as Cell, Nature, Nature Biotechnology, Nature Communications, and Proceedings of the National Academy of Sciences.

Involvement with biotechnology

Khvorova has co-founded several biotechnology companies, including Atalanta Therapeutics, [26] which develops RNA-based approaches for neurodegenerative diseases using branched siRNA technology licensed from UMass Chan Medical School, as well as Comanche Biopharma, [27] which develops RNA-based therapeutics for preeclampsia based on work done by Drs. Anastasia Khvorova and Melissa J. Moore. [28] Khvorova also serves on the scientific advisory boards of Advirna, Aldena, Alltrna, Prime Medicine, and Evox Therapeutics. Khvorova is listed as an inventor on more than 180 issued patents and several hundred patent applications related to RNA chemistry and therapeutic delivery. [29] She is a Fellow of the National Academy of Inventors. [30] [31]

Honors and awards

Selected publications

  1. Yamada K, Vignesh N. Hariharan VN, Jillian Caiazzi J, Miller R, Ferguson CM, Sapp E, Fakih HH, Tang Q, Nozomi Yamada N, Furgal RC, Paquette JD, Biscans A, Bramato BM, McHugh N, Summers A, Lochmann C, Hildebrand S, Jackson SO, Hassler MR, Alterman JF, and Khvorova A. Enhancing siRNA efficacy in vivo with extended nucleic acid backbones. Nat Biotech. Aug 1; (2024). PubMedPMID: 39090305
  2. Hariharan VN, Shin M, Chang CW, O'Reilly D, Biscans A, Yamada K, Guo Z, Somasundaran M, Tang Q, Monopoli K, Krishnamurthy PM, Devi G, McHugh N, Cooper DA, Echeverria D, Cruz J, Chan IL, Liu P, Lim SY, McConnell J, Singh SP, Hildebrand S, Sousa J, Davis SM, Kennedy Z, Ferguson C, Godinho BMDC, Thillier Y, Caiazzi J, Ly S, Muhuri M, Kelly K, Humphries F, Cousineau A, Parsi KM, Li Q, Wang Y, Maehr R, Gao G, Korkin D, McDougall WM, Finberg RW, Fitzgerald KA, Wang JP, Watts JK, Khvorova A. Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 120(11): e2219523120 (2023). PubMed Central PMCID: PMC10089225.
  3. Conroy F, Miller R, Alterman JF, Hassler MR, Echeverria D, Godinho BMDC, Knox EG, Sapp E, Sousa J, Yamada K, Mahmood F, Boudi A, Kegel-Gleason K, DiFiglia M, Aronin N, Khvorova A, Pfister EL. Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models. Nat Commun. 13(1): 5802 (2022).
  4. Alterman JF, Godinho BMDC, Hassler MR, Ferguson CM, Echeverria D, Sapp E, Haraszti RA, Coles AH, Conroy F, Miller R, Roux L, Yan P, Knox EG, Turanov AA, King RM, Gernoux G, Mueller C, Gray-Edwards HL, Moser RP, Bishop NC, Jaber SM, Gounis MJ, Sena-Esteves M, Pai AA, DiFiglia M, Aronin N, Khvorova A. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat Biotechnol. 37(8): 884–894 (2019).
  5. Turanov AA, Lo A, Hassler MR, Makris A, Ashar-Patel A, Alterman JF, Coles AH, Haraszti RA, Roux L, Godinho BMDC, Echeverria D, Pears S, Iliopoulos J, Shanmugalingam R, Ogle R, Zsengeller ZK, Hennessy A, Karumanchi SA, Moore MJ, Khvorova A. RNAi modulation of placental sFLT1 for the treatment of preeclampsia. Nat Biotechnol. Nov 19; (2018).
  6. Osborn MF, Coles AH, Golebiowski D, Echeverria D, Moazami MP, Watts JK, Sena-Esteves M, Khvorova A. Efficient Gene Silencing in Brain Tumors with Hydrophobically Modified siRNAs. Mol Cancer Ther. 17(6): 1251–1258 (2018).
  7. 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. 45(1): 15–25 (2017).
  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. (10):1836–1847 (2016).
  9. 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. Nature Protocols. 2(9): 2068–78 (2007).
  10. Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell. 115(2): 209–16 (2003).

References

  1. ↑ "Anastasia Khvorova | Profiles RNS". profiles.umassmed.edu. Retrieved 2026-01-07.
  2. 1 2 "Research Chairs". UMass Chan Medical School. 2018-11-09. Retrieved 2026-01-06.
  3. 1 2 "UMass Medical School appoints five faculty members to endowed chairs | UMass System". www.massachusetts.edu. 2020-07-20. Retrieved 2026-01-06.
  4. ↑ "Nucleic Acid Chemistry Center at UMass Chan Medical School". UMass Chan Medical School. 2013-09-05. Retrieved 2026-01-06.
  5. ↑ Hassler, Matthew R.; Turanov, Anton A.; Alterman, Julia F.; Haraszti, Reka A.; Coles, Andrew H.; Osborn, Maire F.; Echeverria, Dimas; Nikan, Mehran; Salomon, William E.; Roux, Loïc; Godinho, Bruno M. D. C.; Davis, Sarah M.; Morrissey, David V.; Zamore, Phillip D.; Karumanchi, S. Ananth (2018-03-16). "Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo". Nucleic Acids Research. 46 (5): 2185–2196. doi:10.1093/nar/gky037. ISSN   1362-4962. PMC   5861422 . PMID   29432571.
  6. ↑ Khvorova, Anastasia; Reynolds, Angela; Jayasena, Sumedha D. (2003-10-17). "Functional siRNAs and miRNAs exhibit strand bias". Cell. 115 (2): 209–216. Bibcode:2003Cell..115..209K. doi:10.1016/s0092-8674(03)00801-8. ISSN   0092-8674. PMID   14567918.
  7. ↑ Birmingham, Amanda; Anderson, Emily; Sullivan, Kevin; Reynolds, Angela; Boese, Queta; Leake, Devin; Karpilow, Jon; Khvorova, Anastasia (2007-08-23). "A protocol for designing siRNAs with high functionality and specificity". Nature Protocols. 2 (9): 2068–2078. doi:10.1038/nprot.2007.278. ISSN   1750-2799. PMID   17853862.
  8. ↑ Reynolds, Angela; Leake, Devin; Boese, Queta; Scaringe, Stephen; Marshall, William S.; Khvorova, Anastasia (2004-02-01). "Rational siRNA design for RNA interference". Nature Biotechnology. 22 (3): 326–330. Bibcode:2004NatBi..22..326R. doi:10.1038/nbt936. ISSN   1546-1696. PMID   14758366.
  9. 1 2 Fakih, Hassan H.; Lochmann, Clemens; Gagnon, Rosemary; Summers, Ashley; Caiazzi, Jillian; Buchwald, Julianna E.; Tang, Qi; Maru, Bruktawit; Hildebrand, Samuel R.; Abideen, Mohammad Zain U. I.; Furgal, Raymond C.; Gross, Katherine Y.; Yang, Yeon-Suk; Cooper, David; Monopoli, Kathryn R. (2025-11-26). "Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs". Nucleic Acids Research. 53 (22) gkaf1374. doi:10.1093/nar/gkaf1374. ISSN   1362-4962. PMC   12723224 . PMID   41432033.
  10. 1 2 3 Alterman, Julia F.; Godinho, Bruno M. D. C.; Hassler, Matthew R.; Ferguson, Chantal M.; Echeverria, Dimas; Sapp, Ellen; Haraszti, Reka A.; Coles, Andrew H.; Conroy, Faith; Miller, Rachael; Roux, Loic; Yan, Paul; Knox, Emily G.; Turanov, Anton A.; King, Robert M. (2019-08-02). "A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system". Nature Biotechnology. 37 (8): 884–894. doi:10.1038/s41587-019-0205-0. ISSN   1546-1696. PMC   6879195 . PMID   31375812.
  11. ↑ Davidson, Beverly L. (2019-08-02). "Doubling down on siRNAs in the brain". Nature Biotechnology. 37 (8): 865–866. doi:10.1038/s41587-019-0204-1. ISSN   1546-1696. PMID   31375811.
  12. 1 2 Cheng, Shun-Yun; Caiazzi, Jillian; Biscans, Annabelle; Alterman, Julia F.; Echeverria, Dimas; McHugh, Nicholas; Hassler, Matthew; Jolly, Samson; Giguere, Delaney; Cipi, Joris; Khvorova, Anastasia; Punzo, Claudio (2024-03-12). "Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors". Molecular Therapy Nucleic Acids. 35 (1) 102088. doi:10.1016/j.omtn.2023.102088. ISSN   2162-2531.
  13. ↑ Fakih, Hassan H.; Tang, Qi; Summers, Ashley; Shin, Minwook; Buchwald, Julianna E.; Gagnon, Rosemary; Hariharan, Vignesh N.; Echeverria, Dimas; Cooper, David A.; Watts, Jonathan K.; Khvorova, Anastasia; Sleiman, Hanadi F. (2023-12-12). "Dendritic amphiphilic siRNA: Selective albumin binding, in vivo efficacy, and low toxicity". Molecular Therapy Nucleic Acids. 34 102080. doi:10.1016/j.omtn.2023.102080. ISSN   2162-2531. PMC   10711485 . PMID   38089931.
  14. 1 2 "UMass Chan Scientists Deliver siRNA Therapy to Lung | April 12, 2023 | Harrington Discovery Institute at University Hospitals". www.harringtondiscovery.org. Retrieved 2026-01-07.
  15. 1 2 Hariharan, Vignesh N.; Shin, Minwook; Chang, Ching-Wen; O'Reilly, Daniel; Biscans, Annabelle; Yamada, Ken; Guo, Zhiru; Somasundaran, Mohan; Tang, Qi; Monopoli, Kathryn; Krishnamurthy, Pranathi Meda; Devi, Gitali; McHugh, Nicholas; Cooper, David A.; Echeverria, Dimas (2023-03-14). "Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection". Proceedings of the National Academy of Sciences of the United States of America. 120 (11) e2219523120. Bibcode:2023PNAS..12019523H. doi: 10.1073/pnas.2219523120 . ISSN   1091-6490. PMC   10089225 . PMID   36893269.
  16. ↑ "UMass Chan Scientists Deliver siRNA Therapy to Lung | April 12, 2023 | Harrington Discovery Institute at University Hospitals". www.harringtondiscovery.org. Retrieved 2026-01-07.
  17. ↑ Turanov, Anton A.; Lo, Agnes; Hassler, Matthew R.; Makris, Angela; Ashar-Patel, Ami; Alterman, Julia F.; Coles, Andrew H.; Haraszti, Reka A.; Roux, Loic; Godinho, Bruno M. D. C.; Echeverria, Dimas; Pears, Suzanne; Iliopoulos, Jim; Shanmugalingam, Renuka; Ogle, Robert (2018-11-19). "RNAi modulation of placental sFLT1 for the treatment of preeclampsia". Nature Biotechnology. 36 (12): 1164–1173. doi:10.1038/nbt.4297. ISSN   1546-1696. PMC   6526074 . PMID   30451990.
  18. ↑ Fessenden, Jim (2024-08-05). "Novel siRNA backbone developed at UMass Chan enhances stability, durability of potentially therapeutic platform". UMass Chan Medical School. Retrieved 2026-01-07.
  19. ↑ Yamada, Ken; Hariharan, Vignesh N.; Caiazzi, Jillian; Miller, Rachael; Ferguson, Chantal M.; Sapp, Ellen; Fakih, Hassan H.; Tang, Qi; Yamada, Nozomi; Furgal, Raymond C.; Paquette, Joseph D.; Biscans, Annabelle; Bramato, Brianna M.; McHugh, Nicholas; Summers, Ashley (2024-08-01). "Enhancing siRNA efficacy in vivo with extended nucleic acid backbones". Nature Biotechnology. 43 (6): 904–913. doi:10.1038/s41587-024-02336-7. ISSN   1546-1696. PMID   39090305.
  20. ↑ Haraszti, Reka A.; Roux, Loic; Coles, Andrew H.; Turanov, Anton A.; Alterman, Julia F.; Echeverria, Dimas; Godinho, Bruno M. D. C.; Aronin, Neil; Khvorova, Anastasia (2017-07-27). "5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo". Nucleic Acids Research. 45 (13): 7581–7592. doi:10.1093/nar/gkx507. ISSN   1362-4962. PMC   5570069 . PMID   28591791.
  21. 1 2 Conroy, Faith; Miller, Rachael; Alterman, Julia F.; Hassler, Matthew R.; Echeverria, Dimas; Godinho, Bruno M. D. C.; Knox, Emily G.; Sapp, Ellen; Sousa, Jaquelyn; Yamada, Ken; Mahmood, Farah; Boudi, Adel; Kegel-Gleason, Kimberly; DiFiglia, Marian; Aronin, Neil (2022-10-03). "Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models". Nature Communications. 13 (1): 5802. Bibcode:2022NatCo..13.5802C. doi:10.1038/s41467-022-33061-x. ISSN   2041-1723.
  22. ↑ O'Reilly, Daniel; Belgrad, Jillian; Ferguson, Chantal; Summers, Ashley; Sapp, Ellen; McHugh, Cassandra; Mathews, Ella; Boudi, Adel; Buchwald, Julianna; Ly, Socheata; Moreno, Dimas; Furgal, Raymond; Luu, Eric; Kennedy, Zachary; Hariharan, Vignesh (2023-05-11). "Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease". Molecular Therapy. 31 (11): 3355–3356. doi:10.1016/j.ymthe.2023.09.016. ISSN   1525-0016. PMC   10638064 . PMID   37751745.
  23. ↑ Monopoli, Kathryn R.; Korkin, Dmitry; Khvorova, Anastasia (2023-09-12). "Asymmetric trichotomous partitioning overcomes dataset limitations in building machine learning models for predicting siRNA efficacy". Molecular Therapy. Nucleic Acids. 33: 93–109. doi:10.1016/j.omtn.2023.06.010. ISSN   2162-2531. PMC   10338369 . PMID   37456778.
  24. ↑ Corey, David R.; Damha, Masad J.; Manoharan, Muthiah (2022-01-31). "Challenges and Opportunities for Nucleic Acid Therapeutics". Nucleic Acid Therapeutics. 32 (1): 8–13. doi:10.1089/nat.2021.0085. ISSN   2159-3345. PMC   8817707 . PMID   34931905.
  25. ↑ "Anastasia Khvorova". scholar.google.com. Retrieved 2026-01-06.
  26. ↑ Shelton, Mark L. (2021-01-12). "Atalanta Therapeutics founded by UMass Medical School and three faculty members". UMass Chan Medical School. Retrieved 2026-01-06.
  27. ↑ Spencer, Susan E. W. (2023-10-02). "Science for Living: Understanding preeclampsia, its toll on Black women and a promising therapeutic on the way". UMass Chan Medical School. Retrieved 2026-01-06.
  28. ↑ "RNAi therapy mitigates preeclampsia symptoms in UMass Medical School study". UMass Chan Medical School. 2018-11-19. Retrieved 2026-01-06.
  29. ↑ "Google Patents". patents.google.com. Retrieved 2026-01-06.
  30. 1 2 Sargent, Pat (2022-12-12). "UMass Chan researcher Anastasia Khvorova named 2022 National Academy of Inventors Fellow". UMass Chan Medical School. Retrieved 2026-01-06.
  31. 1 2 "Fellows". NAI. Retrieved 2026-01-06.
  32. ↑ "Else Kröner Fresenius Prize for Medical Research 2025 | Else Kröner-Fresenius-Stiftung". www.ekfs.de. Retrieved 2026-01-06.
  33. ↑ "Pioneering work in the field of RNA-based therapies for Huntington's disease". healthcare-in-europe.com. Retrieved 2026-01-07.
  34. ↑ OTS (2025-09-10). "2025 Paper of the Year – Basic Research Category". Oligonucleotide Therapeutics Society. Retrieved 2026-01-15.
  35. ↑ Khvorova, Anastasia (2024-10-16). "Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Nucleic Acid Therapeutics". Nucleic Acid Therapeutics. 34 (5): 213. doi:10.1089/nat.2024.84674.rfs2023. ISSN   2159-3337.
  36. ↑ Spencer, Susan E. W. (2021-09-10). "Convocation 2021: Chancellor Collins outlines vision for new era at UMass Chan". UMass Chan Medical School. Retrieved 2026-01-06.
  37. ↑ "2020 Women's Faculty Awards honor six for excellence across the career spectrum". UMass Chan Medical School. 2020-05-19. Retrieved 2026-01-06.

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