A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates

Molecular Therapy

Volumn 26, Issue 6, 2018, Pages 1509-1519

  Sabnis, Staci ^a   Kumarasinghe, E Sathyajith ^a   Salerno, Timothy ^a   Mihai, Cosmin ^a   Ketova, Tatiana ^a   Senn, Joseph J ^a   Lynn, Andy ^a   Bulychev, Alex ^a   McFadyen, Iain ^a   Chan, Joyce ^a   Almarsson, Örn ^a   Stanton, Matthew G ^a,b   Benenato, Kerry E ^a  

^a MODERNA THERAPEUTICS   (United States)

^b Generation Bio   (United States)

Author keywords

delivery; lipid nanoparticle; mRNA; mRNA therapeutics; safe chronic dosing; tolerability

Indexed keywords

ETHANOLAMINE; LIPID; MESSENGER RNA; NANOPARTICLE;

AMINO ACID SEQUENCE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CD-1 MOUSE; CELL FUNCTION; CLINICAL EFFECTIVENESS; CONTROLLED STUDY; DOSE RESPONSE; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG FORMULATION; ENDOSOMAL ESCAPE; FEMALE; GENE TARGETING; HUMAN; IN VIVO STUDY; MACACA FASCICULARIS; MALE; MOUSE; NONHUMAN; PRIMATE MODEL; REACTION OPTIMIZATION; RODENT; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION; TOXICITY TESTING; ANIMAL; CHEMISTRY; PRIMATE; RAT;

ANIMALS; LIPIDS; NANOPARTICLES; PRIMATES; RATS; RNA, MESSENGER;

EID: 85045109575     PISSN: 15250016     EISSN: 15250024     Source Type: Journal    
DOI: 10.1016/j.ymthe.2018.03.010     Document Type: Article

References (20)

1. Sahin, U., Karikó K., Türeci, Ö., mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug Discov. 13 (2014), 759–780.
2. Hajj, K.A., Whitehead, K.A., Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater., 2, 2017, 17056.
3. Bahl, K., Senn, J.J., Yuzhakov, O., Bulychev, A., Brito, L.A., Hassett, K.J., Laska, M.E., Smith, M., Almarsson, Ö., Thompson, J., et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25 (2017), 1316–1327.
4. Stanton, M.G., Murphy-Benenato, K.E., Messenger RNA as a novel therapeutic approach. Garner, A., (eds.) Topics in Medicinal Chemistry: RNA Therapeutics, Volume 27, 2017, Springer, 237–253.
5. Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P.N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E., et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369 (2013), 819–829.
6. Butler, J.S., Chan, A., Costelha, S., Fishman, S., Willoughby, J.L.S., Borland, T.D., Milstein, S., Foster, D.J., Gonçalves, P., Chen, Q., et al. Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid 23 (2016), 109–118.
7. Nabhan, J.F., Wood, K.M., Rao, V.P., Morin, J., Bhamidipaty, S., LaBranche, T.P., Gooch, R.L., Bozal, F., Bulawa, C.E., Guild, B.C., Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich's ataxia. Sci. Rep., 6, 2016, 20019.
8. Akinc, A., Querbes, W., De, S., Qin, J., Frank-Kamenetsky, M., Jayaprakash, K.N., Jayaraman, M., Rajeev, K.G., Cantley, W.L., Dorkin, J.R., et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18 (2010), 1357–1364.
9. Maier, M.A., Jayaraman, M., Matsuda, S., Liu, J., Barros, S., Querbes, W., Tam, Y.K., Ansell, S.M., Kumar, V., Qin, J., et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21 (2013), 1570–1578.
10. Szebeni, J., Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol. Immunol. 61 (2014), 163–173.
11. Semple, S.C., Akinc, A., Chen, J., Sandhu, A.P., Mui, B.L., Cho, C.K., Sah, D.W., Stebbing, D., Crosley, E.J., Yaworski, E., et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28 (2010), 172–176.
12. Jayaraman, M., Ansell, S.M., Mui, B.L., Tam, Y.K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J.K., et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. Engl. 51 (2012), 8529–8533.
13. Fukami, T., Yokoi, T., The emerging role of human esterases. Drug Metab. Pharmacokinet. 27 (2012), 466–477.
14. Thess, A., Grund, S., Mui, B.L., Hope, M.J., Baumhof, P., Fotin-Mleczek, M., Schlake, T., Sequence-engineered mRNA without chemical nucleoside modifications eables an effective protein therapy in large animals. Mol. Ther. 23 (2015), 1456–1464.
15. DeRosa, F., Guild, B., Karve, S., Smith, L., Love, K., Dorkin, J.R., Kauffman, K.J., Zhang, J., Yahalom, B., Anderson, D.G., Heartlein, M.W., Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system. Gene Ther. 23 (2016), 699–707.
16. Sedic, M., Senn, J.J., Lynn, A., Laska, M., Smith, M., Platz, S.J., Bolen, J., Hoge, S., Bulychev, A., Jacquinet, E., et al. Safety evaluation of lipid nanoparticle-formulated modified mRNA in the Sprague-Dawley rat and cynomolgus monkey. Vet. Pathol. 55 (2018), 341–354.
17. Heyes, J., Palmer, L., Bremner, K., MacLachlan, I., Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J. Control. Release 107 (2005), 276–287.
18. Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31 (2013), 638–646.
19. Patel, S., Ashwanikumar, N., Robinson, E., DuRoss, A., Sun, C., Murphy-Benenato, K.E., Mihai, C., Almarsson, Ö., Sahay, G., Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA. Nano Lett. 17 (2017), 5711–5718.
20. Richner, J.M., Himansu, S., Dowd, K.A., Butler, S.L., Salazar, V., Fox, J.M., Julander, J.G., Tang, W.W., Shresta, S., Pierson, T.C., et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168 (2017), 1114–1125.e10.