Oligonucleotide Therapeutics: Technology Evolution for Clinically Relevant Tissue Delivery
Presenter: Anastasia Khvorova, PhD, RNA Therapeutics Institute, University of Massachusetts Medical School
Date: 10 September 2018
Description: A decade of progress in oligonucleotide chemistry and formulation development has resulted in several compounds, both siRNAs and antisense, demonstrating robust clinical activity. Based on sequence, these types of drugs can be designed to modulate the expression of any disease-causing gene.
Clinical utility is defined by the ability to deliver to the tissue of interest. The most promising approach is modulation of oligonucleotide delivery through direct chemical modification. Full chemical stabilization, identification of optimal conjugates (GalNAc and others), and understanding the relationship between structure and pharmacokinetic/pharmacodynamic behavior are essential to enabling sustained (many months) efficacy following a single administration.
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- Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Planté-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB.
N Engl J Med. 2018 Jul 5;379(1):11-21.
- Oligonucleotide Therapeutics – A New Class of Cholesterol-Lowering Drugs.
N Engl J Med. 2017 Jan 5;376(1):4-7.
- Novel Cluster and Monomer-Based GalNAc Structures Induce Effective Uptake of siRNAs in Vitro and in Vivo.
Sharma VK, Osborn MF, Hassler MR, Echeverria D, Ly S, Ulashchik EA, Martynenko-Makaev YV, Shmanai VV, Zatsepin TS, Khvorova A, Watts JK.
Bioconjug Chem. 2018 Jul 18;29(7):2478-2488.
- The chemical evolution of oligonucleotide therapies of clinical utility.
Khvorova A, Watts JK.
Nat Biotechnol. 2017 Mar;35(3):238-248.
- Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo.
Hassler MR, Turanov AA, Alterman JF, Haraszti RA, Coles AH, Osborn MF, Echeverria D, Nikan M, Salomon WE, Roux L, Godinho BMDC, Davis SM, Morrissey DV, Zamore PD, Karumanchi SA, Moore MJ, Aronin N, Khvorova A.
Nucleic Acids Res. 2018 Mar 16;46(5):2185-2196.
- 5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo.
Haraszti RA, Roux L, Coles AH, Turanov AA, Alterman JF, Echeverria D, Godinho BMDC, Aronin N, Khvorova A.
Nucleic Acids Res. 2017 Jul 27;45(13):7581-7592.
- Single-stranded siRNAs activate RNAi in animals.
Lima WF, Prakash TP, Murray HM, Kinberger GA, Li W, Chappell AE, Li CS, Murray SF, Gaus H, Seth PP, Swayze EE, Crooke ST.
Cell. 2012 Aug 31;150(5):883-94.
- Identification of metabolically stable 5′-phosphate analogs that support single-stranded siRNA activity.
Prakash TP, Lima WF, Murray HM, Li W, Kinberger GA, Chappell AE, Gaus H, Seth PP, Bhat B, Crooke ST, Swayze EE.
Nucleic Acids Res. 2015 Mar 31;43(6):2993-3011.
- 5′-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA-GalNAc Conjugates.
Parmar R, Willoughby JL, Liu J, Foster DJ, Brigham B, Theile CS, Charisse K, Akinc A, Guidry E, Pei Y, Strapps W, Cancilla M, Stanton MG, Rajeev KG, Sepp-Lorenzino L, Manoharan M, Meyers R, Maier MA, Jadhav V.
Chembiochem. 2016 Jun 2;17(11):985-9.
- 5′-C-Malonyl RNA: Small Interfering RNAs Modified with 5′-Monophosphate Bioisostere Demonstrate Gene Silencing Activity.
Zlatev I, Foster DJ, Liu J, Charisse K, Brigham B, Parmar RG, Jadhav V, Maier MA, Rajeev KG, Egli M, Manoharan M.
ACS Chem Biol. 2016 Apr 15;11(4):953-60.
- Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates.
Foster DJ, Brown CR, Shaikh S, Trapp C, Schlegel MK, Qian K, Sehgal A, Rajeev KG, Jadhav V, Manoharan M, Kuchimanchi S, Maier MA, Milstein S.
Mol Ther. 2018 Mar 7;26(3):708-717.
- Functional features defining the efficacy of cholesterol-conjugated, self-deliverable, chemically modified siRNAs.
Shmushkovich T, Monopoli KR, Homsy D, Leyfer D, Betancur-Boissel M, Khvorova A, Wolfson AD.
Nucleic Acids Res. 2018 Aug 29.
- Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.
Janas MM, Schlegel MK, Harbison CE, Yilmaz VO, Jiang Y, Parmar R, Zlatev I, Castoreno A, Xu H, Shulga-Morskaya S, Rajeev KG, Manoharan M, Keirstead ND, Maier MA, Jadhav V.
Nat Commun. 2018 Feb 19;9(1):723.
- 2′-Fluoro-modified phosphorothioate oligonucleotide can cause rapid degradation of P54nrb and PSF.
Shen W, Liang XH, Sun H, Crooke ST.
Nucleic Acids Res. 2015 May 19;43(9):4569-78.
- Acute hepatotoxicity of 2′ fluoro-modified 5-10-5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins.
Shen W, De Hoyos CL, Sun H, Vickers TA, Liang XH, Crooke ST.
Nucleic Acids Res. 2018 Mar 16;46(5):2204-2217.
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 VP of Research & Development and CSO of Dharmacon (now a Thermo Fisher Scientific company), Founder and Scientific Advisor of Advirna, and CSO and SVP of RXi Pharmaceuticals. Dr Khvorova is credited with several major advances in the field of RNA interference. Her team at Dharmacon developed and facilitated the commercialization of the first functional siRNA collection targeting the human genome (siGENOME), and at RXi, her group made significant progress in chemically modifying RNAi compounds to create self-delivering rxRNA compounds.
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 OTS Board of Directors and 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.