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1,183 results on '"Akinc A"'

6. Multivalent N‑Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing

Author

Nair, Jayaprakash K, Willoughby, Jennifer LS, Chan, Amy, Charisse, Klaus, Alam, Rowshon, Wang, Qianfan, Hoekstra, Menno, Kandasamy, Pachamuthu, Kel’in, Alexander V, Milstein, Stuart, Taneja, Nate, O’Shea, Jonathan, Shaikh, Sarfraz, Zhang, Ligang, van der Sluis, Ronald J, Jung, Michael E, Akinc, Akin, Hutabarat, Renta, Kuchimanchi, Satya, Fitzgerald, Kevin, Zimmermann, Tracy, van Berkel, Theo JC, Maier, Martin A, Rajeev, Kallanthottathil G, and Manoharan, Muthiah

Subjects
Engineering, Chemical Sciences, Gene Therapy, Genetics, Liver Disease, Biotechnology, Digestive Diseases, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Generic health relevance, Acetylgalactosamine, Animals, Gene Silencing, Hepatocytes, Mice, Mice, Inbred C57BL, Molecular Structure, RNA, Small Interfering, General Chemistry, Chemical sciences
Abstract

Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA-GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.

Published
2014

25. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates

Author

Dong, Yizhou, Love, Kevin T., Dorkin, J. Robert, Sirirungruang, Sasilada, Zhang, Yunlong, Chen, Delai, Bogorad, Roman L., Yin, Hao, Chen, Yi, Vegas, Arturo J., Alabi, Christopher A., Sahay, Gaurav, Olejnik, Karsten T., Wang, Weiheng, Schroeder, Avi, Lytton-Jean, Abigail K. R., Siegwart, Daniel J., Akinc, Akin, Barnes, Carmen, Barros, Scott A., Carioto, Mary, Fitzgerald, Kevin, Hettinger, Julia, Kumar, Varun, Novobrantseva, Tatiana I., Qin, June, Querbes, William, Koteliansky, Victor, Langer, Robert, and Anderson, Daniel G.

Published
2014

31. Tailoring the toughness and CTE of high temperature bisphenol E cyanate ester (BECy) resin

Author

M. Thunga, M. R. Kessler, and M. Akinc

Subjects
Thermosetting resins, bisphenol E cyanate ester, polymer matrix composites, injection repair, polymer blends and alloys, Materials of engineering and construction. Mechanics of materials, TA401-492, Chemical technology, TP1-1185
Abstract

The objective of the present work is to enhancing the toughness and minimizing the CTE of a special class of bisphenol E cyanate ester (BECy) resin by blending it with a thermoplastic toughening agent. Poly(ether sulfone) was chosen as a high temperature resistant thermoplastic resin to enhance the thermo-mechanical properties of BECy. The influence of poly(ether sulfone)/BECy blend composition on the morphology and phase behavior was studied using scanning electron microscopy and dynamic mechanical analysis. The mechanical properties of the blends were evaluated by flexural tests, which demonstrated significant enhancement in the material’s toughness with an increase in PES concentration from 0 to 15 wt%. The coefficient of thermal expansion of pure BECy was reduced from 61 to 48 ppm/°C in the blends with PES, emphasizing the multi-functional benefits of PES as a toughening agent in BECy.

Published
2014
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41. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia

Author

Sehgal, Alfica, Barros, Scott, Ivanciu, Lacramioara, Cooley, Brian, Qin, June, Racie, Tim, Hettinger, Julia, Carioto, Mary, Jiang, Yongfeng, Brodsky, Josh, Prabhala, Harsha, Zhang, Xuemei, Attarwala, Husain, Hutabarat, Renta, Foster, Don, Milstein, Stuart, Charisse, Klaus, Kuchimanchi, Satya, Maier, Martin A., Nechev, Lubo, Kandasamy, Pachamuthu, Kel'in, Alexander V., Nair, Jayaprakash K., Rajeev, Kallanthottathil G., Manoharan, Muthiah, Meyers, Rachel, Sorensen, Benny, Simon, Amy R., Dargaud, Yesim, Negrier, Claude, Camire, Rodney M., and Akinc, Akin

Subjects
Care and treatment, Genetic aspects, Dosage and administration, Methods, Health aspects, Drug targeting -- Methods -- Genetic aspects, Hemostasis -- Health aspects -- Genetic aspects, Antithrombins -- Dosage and administration, Hemophilia -- Genetic aspects -- Care and treatment, Coagulation -- Health aspects, RNA -- Health aspects
Abstract

The coagulation system balances the need to control blood loss with the need to prevent thrombosis. This balance is achieved through a well-defined system of procoagulant and anticoagulant factors that [...], Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia (1-9), we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia. When administered subcutaneously, ALN-AT3 showed potent, dose-dependent, and durable reduction of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs). In NHPs, a 50% reduction in AT levels was achieved with weekly dosing at approximately 0.125 mg/kg, and a near-complete reduction in AT levels was achieved with weekly dosing at 1.5 mg/kg. Treatment with ALN-AT3 promoted hemostasis in mouse models of hemophilia and led to improved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors. This investigational compound is currently in phase 1 clinical testing in subjects with hemophilia A or B.

Published
2015

46. Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells

Author

Novobrantseva, Tatiana I, Borodovsky, Anna, Wong, Jamie, Klebanov, Boris, Zafari, Mohammad, Yucius, Kristina, Querbes, William, Ge, Pei, Ruda, Vera M, Milstein, Stuart, Speciner, Lauren, Duncan, Rick, Barros, Scott, Basha, Genc, Cullis, Pieter, Akinc, Akin, Donahoe, Jessica S, Narayanannair Jayaprakash, K, Jayaraman, Muthusamy, Bogorad, Roman L, Love, Kevin, Whitehead, Katie, Levins, Chris, Manoharan, Muthiah, Swirski, Filip K, Weissleder, Ralph, Langer, Robert, Anderson, Daniel G, de Fougerolles, Antonin, Nahrendorf, Matthias, and Koteliansky, Victor

Published
2012
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48. Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2

Author

Yesseinia I. Anglero-Rodriguez, Florian A. Lempp, James McIninch, Mark K. Schlegel, Christopher R. Brown, Donald J. Foster, Adam B. Castoreno, Tuyen Nguyen, Megha Subramanian, Martin Montiel-Ruiz, Hannah Kaiser, Anna Sahakyan, Roberto Spreafico, Svetlana Shulga Morskaya, Joseph D. Barry, Daniel Berman, Stephanie Lefebvre, Anne Kasper, Timothy Racie, Diann Weddle, Melissa Mobley, Arlin Rogers, Joseph Dybowski, Saeho Chong, Jayaprakash Nair, Amy Simon, Kevin Sloan, Seungmin Hwang, Herbert W. Virgin, Kevin Fitzgerald, Martin A. Maier, Gregory Hinkle, Christy M. Hebner, Akin Akinc, and Vasant Jadhav

Abstract

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.

Published
2022
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50. Lipid-Like Materials for Low-Dose, in vivo Gene Silencing

Author

Love, Kevin T., Mahon, Kerry P., Levins, Christopher G., Whitehead, Kathryn A., Querbes, William, Dorkin, J. Robert, Qin, June, Cantley, William, Qin, Liu Liang, Racie, Timothy, Frank-Kamenetsky, Maria, Yip, Ka Ning, Alvarez, Rene, Sah, Dinah W. Y., de Fougerolles, Antonin, Fitzgerald, Kevin, Koteliansky, Victor, Akinc, Akin, Langer, Robert, Anderson, Daniel G., and Klibanov, Alexander

Published
2010
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