Systemic messenger RNA as an etiological treatment for acute intermittent porphyria
Open accessAbstract
Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.
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The therapeutic potential of mRNA-based protein replacement therapies has been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I, acute intermittent porphyria, Fabry disease, Crigler-Najjar syndrome type 1, α1 antitrypsin deficiency, methylmalonic acidaemia/aciduria, arginase deficiency, citrin deficiency and glycogen storage disease type I.
“The therapeutic potential of mRNA-based protein replacement therapies has also been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I (HTI)142, acute intermittent porphyria222,223, Fabry disease224,225, Crigler–Najjar syndrome type 1 (ref.226), α1 antitrypsin deficiency227, methylmalonic acidaemia/aciduria228, arginase deficiency229, citrin defic”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [222]
i.v. injection of hPBGD mRNA encapsulated in MC3-based LNPs restored hepatic PBGD expression followed by normalization of porphyrin precursor levels.
“A recent preclinical study demonstrated that i.v. injection of human PBGD (hPBGD) mRNA encapsulated in MC3-based LNPs restored hepatic PBGD expression followed by a normalization of porphyrin precursor levels.[130]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [130]
In AIP mice, a single dose of hPBGD mRNA LNPs alleviated mitochondrial dysfunction, hypertension, and pain.
“In AIP mice, a single dose alleviated mitochondrial dysfunction, hypertension, and pain.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [130]
PBGD expression in the liver lasted for at least 10 days, providing full protection throughout the diseased period (5 to 7 days).
“Importantly, the PBGD expression in the liver lasted for at least 10 days, which provided a full protection throughout the diseased period (5 to 7 days).[130]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [130]
Cites
Coding of facial expressions of pain in the laboratory mouse
Langford, D. J., Bailey, A. L., Chanda, M. L., Clarke, S. E. D., Drummond, T. E., Echols, S., Glick, S., Ingrao, J. C., Klassen-Ross, T., LaCroix‐Fralish, M. L., et al. (2010) · Nature Methods · doi:10.1038/nmeth.1455 · Cited by 1,498 · see citing works
Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
Sahay, G., Querbes, W., Alabi, C., Eltoukhy, A., Sarkar, S., Zurenko, C., Karagiannis, E., Love, K., Chen, D., Zoncu, R., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2614 · Cited by 948 · see citing works
Sabnis, S., Kumarasinghe, E. S., Salerno, T., Mihai, C., Ketova, T., Senn, J. J., Lynn, A., Bulychev, A., McFadyen, I., Chan, J., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.03.010 · Cited by 820 · see citing works
Self-citationPuy, H., Gouya, L., & Deybach, J. (2010) · The Lancet · doi:10.1016/s0140-6736(09)61925-5 · Cited by 727 · see citing works
Recommendations for the Diagnosis and Treatment of the Acute Porphyrias
Anderson, K. E., Bloomer, J. R., Bonkovsky, H. L., Kushner, J. P., Pierach, C. A., Pimstone, N. R., & Desnick, R. J. (2005) · Annals of Internal Medicine · doi:10.7326/0003-4819-142-6-200503150-00010 · Cited by 622 · see citing works
Rogers, G. W., Brand, M. D., Petrosyan, S., Ashok, D., Elorza, Á. A., Ferrick, D. A., & Murphy, A. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021746 · Cited by 474 · see citing works
Bissell, D. M., Anderson, K. E., & Bonkovsky, H. L. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1608634 · Cited by 399 · see citing works
Nutritional Regulation of Hepatic Heme Biosynthesis and Porphyria through PGC-1α
Handschin, C., Lin, J. D., Rhee, J., Peyer, A., Chin, S., Wu, P., Meyer, U., & Spiegelman, B. M. (2005) · Cell · doi:10.1016/j.cell.2005.06.040 · Cited by 380 · see citing works
Acute Porphyrias in the USA: Features of 108 Subjects from Porphyrias Consortium
Bonkovsky, H. L., Maddukuri, V. C., Yazıcı, C., Anderson, K. E., Bissell, D. M., Bloomer, J. R., Phillips, J. D., Naik, H., Peter, I., Baillargeon, G. M., et al. (2014) · The American Journal of Medicine · doi:10.1016/j.amjmed.2014.06.036 · Cited by 264 · see citing works
Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia
An, D., Schneller, J. L., Frassetto, A., Liang, S., Zhu, X., Park, J.-S., Theisen, M., Hong, S.-J., Zhou, J., Rajendran, R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.11.081 · Cited by 263 · see citing works
Self-citationAcute Porphyrias: Pathogenesis of Neurological Manifestations
Meyer, U., Schuurmans, M. M., & Lindberg, R. L. P. (1998) · Seminars in Liver Disease · doi:10.1055/s-2007-1007139 · Cited by 233 · see citing works
Matsumiya, L. C., Sorge, R. E., Sotocinal, S. G., Tabaka, J. M., Wieskopf, J. S., Zaloum, A., King, O. D., & Mogil, J. S. (2012) · PubMed Central · Cited by 231 · see citing works
Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging
Atamna, H., Killilea, D. W., Killilea, A. N., & Ames, B. N. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192585799 · Cited by 228 · see citing works
Sedic, M., Senn, J. J., Lynn, A., Laska, M., Smith, M., Platz, S. J., Bolen, J., Hoge, S., Bulychev, A., Jacquinet, E., et al. (2018) · Veterinary Pathology · doi:10.1177/0300985817738095 · Cited by 195 · see citing works
Gouya, L., Ventura, P., Balwani, M., Bissell, D. M., Rees, D. C., Stölzel, U., Phillips, J. D., Kauppinen, R., Langendonk, J. G., Desnick, R. J., et al. (2019) · Hepatology · doi:10.1002/hep.30936 · Cited by 168 · see citing works
Heme Deficiency Selectively Interrupts Assembly of Mitochondrial Complex IV in Human Fibroblasts
Atamna, H., Liu, J., & Ames, B. N. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m108362200 · Cited by 166 · see citing works
Lindberg, R. L. P., Porcher, C., Grandchamp, B., Ledermann, B., Bürki, K., Brandner, S., Aguzzi, A., & Meyer, U. (1996) · Nature Genetics · doi:10.1038/ng0296-195 · Cited by 156 · see citing works
Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria
D’Avola, D., López‐Franco, E., Sangro, B., Pañeda, A., Grosios, N., Gil-Fariña, I., Benito, A., Twisk, J., Paz, M., Ruiz, J. A., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.05.012 · Cited by 142 · see citing works
Self-citationYasuda, M., Gan, L., Chen, B., Kadirvel, S., Yu, C., Phillips, J. D., New, M. I., Liebow, A., Fitzgerald, K. J., Querbes, W., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1406228111 · Cited by 124 · see citing works
Schmitt, C., Lenglet, H., Yu, A., Delaby, C., Benecke, A., Lefèbvre, T., Lettéron, P., Paradis, V., Wåhlin, S., Sandberg, S., et al. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12750 · Cited by 121 · see citing works
Pallet, N., Mami, I., Schmitt, C., Karim, Z., François, A., Rabant, M., Nochy, D., Gouya, L., Deybach, J., Xu-Dubois, Y., et al. (2015) · Kidney International · doi:10.1038/ki.2015.97 · Cited by 116 · see citing works
Dowman, J. K., Gunson, B. K., Mirza, D. F., Bramhall, S. R., Badminton, M. N., & Newsome, P. N. (2011) · Liver Transplantation · doi:10.1002/lt.22345 · Cited by 112 · see citing works
Clinical aspects of acute intermittent porphyria in northern Sweden: A population-based study
Bylesjö, I., Wikberg, A., & Andersson, C. (2009) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510902935979 · Cited by 96 · see citing works
Role of Delta-aminolevulinic Acid in the Symptoms of Acute Porphyria
Bissell, D. M., Lai, J. C., Meister, R., & Blanc, P. D. (2014) · The American Journal of Medicine · doi:10.1016/j.amjmed.2014.10.026 · Cited by 93 · see citing works
CONTROLLED TRIAL OF HAEM ARGINATE IN ACUTE HEPATIC PORPHYRIA
Herrick, A. L., Moore, M. R., McColl, K. E. L., Cook, A., & Goldberg, A. (1989) · The Lancet · doi:10.1016/s0140-6736(89)92688-3 · Cited by 88 · see citing works
Age- and Sex-Based Hematological and Biochemical Parameters for Macaca fascicularis
Xie, L., Xu, F., Liu, S., Ji, Y., Zhou, Q., Wu, Q., Gong, W., Cheng, K., Li, J., Li, L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064892 · Cited by 84 · see citing works
Marsden, J. T., Guppy, S., Stein, P. E., Cox, T. M., Badminton, M. N., Gardiner, T., Barth, J. H., Stewart, M. F., & Rees, D. C. (2015) · JIMD Reports · doi:10.1007/8904_2015_411 · Cited by 82 · see citing works
Experimentally produced porphyria in animals
Goldberg, A., & Rimington, C. (1955) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1955.0009 · Cited by 80 · see citing works
Kim, C.-Y., Lee, H., Han, S., Heo, J., Kwon, M.-S., Ha, C., & Han, S. (2005) · Journal of Medical Primatology · doi:10.1111/j.1600-0684.2005.00097.x · Cited by 72 · see citing works
Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model
Homedan, C., Laafi, J., Schmitt, C., Guéguen, N., Lefèbvre, T., Karim, Z., Desquiret‐Dumas, V., Wetterwald, C., Deybach, J., Gouya, L., et al. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.03.032 · Cited by 70 · see citing works
Innala, E., Bäckström, T. C., Bixo, M., & Andersson, C. (2009) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.3109/00016340903390729 · Cited by 69 · see citing works
A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease
Tchernitchko, D., Tavernier, Q., Lamoril, J., Schmitt, C., Talbi, N., Lyoumi, S., Robréau, A.-M., Karim, Z., Gouya, L., Thervet, É., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2016080918 · Cited by 69 · see citing works
Yasuda, M., Bishop, D. F., Fowkes, M. E., Cheng, S. H., Gan, L., & Desnick, R. J. (2009) · Molecular Therapy · doi:10.1038/mt.2009.250 · Cited by 60 · see citing works
Unzu, C., Sampedro, A., Mauleón, I., Alegre, M., Beattie, S. G., de Salamanca, R. E., Snapper, J., Twisk, J., Petry, H., González‐Aseguinolaza, G., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.210 · Cited by 60 · see citing works
Self-citationBonkowsky, H. L., Tschudy, D. P., Weinbach, E. C., Ebert, P. S., & Doherty, J. M. (1975) · PubMed · Cited by 53 · see citing works
Willandt, B., Langendonk, J. G., Biermann, K., Meersseman, W., D’Heygere, F., George, C., Verslype, C., Monbaliu, D. R. L., & Cassiman, D. M. (2015) · JIMD Reports · doi:10.1007/8904_2015_458 · Cited by 48 · see citing works
Porphobilinogen Deaminase: Methods and Principles of the Enzymatic Assay
Anderson, P. M., & Desnick, R. J. (2017) · Enzyme · doi:10.1159/000459098 · Cited by 43 · see citing works
Vijayasarathy, C., Damle, S., Lenka, N., & Avadhani, N. G. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00843.x · Cited by 38 · see citing works
Management of acute intermittent porphyria
Harper, P., & Sardh, E. (2014) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2014.891456 · Cited by 29 · see citing works
Müller‐Eberhard, U., Eiseman, J. L., Foidart, M., & Alvares, A. P. (1983) · Biochemical Pharmacology · doi:10.1016/0006-2952(83)90147-8 · Cited by 23 · see citing works
Effect of rifampicin on haem and bilirubin metabolism in man.
MCCOLL, K. E. L., Thompson, G., El-Omar, E. M., Moore, M., Park, B. K., & Brodie, M. J. (1987) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1987.tb03091.x · Cited by 21 · see citing works
Unzu, C., Melero, I., Hervás‐Stubbs, S., Sampedro, A., Mancheño, U., Morales‐Kastresana, A., Serrano-Mendioroz, I., de Salamanca, R. E., Benito, A., & Fontanellas, A. (2015) · Gene Therapy · doi:10.1038/gt.2015.64 · Cited by 16 · see citing works
Self-citationTokola, O., Lindén, I., & Tenhunen, R. (1987) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1987.tb01778.x · Cited by 13 · see citing works
The influence of allyl isopropyl acetamide on d-aminolevulinic acid synthetase and cytochrome P-450.
Klinger, W., & Müller, D. (1980) · PubMed · Cited by 7 · see citing works
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Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.012 · Cited by 1,127 · see citing works
mRNA-based therapeutics: powerful and versatile tools to combat diseases
Qin, S., Tang, X., Chen, Y., Chen, K., Fan, N., Xiao, W., Zheng, Q., Li, G., Teng, Y., Wu, M., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01007-w · Cited by 801 · see citing works
Dilliard, S. A., & Siegwart, D. J. (2023) · Nature Reviews Materials · doi:10.1038/s41578-022-00529-7 · Cited by 721 · see citing works
Lipid nanoparticles for nucleic acid delivery: Current perspectives
Samaridou, E., Heyes, J. A., & Lutwyche, P. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.002 · Cited by 593 · see citing works
van Spronsen, F. J., Blau, N., Harding, C. O., Burlina, A., Longo, N., & Bosch, A. M. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00267-0 · Cited by 506 · see citing works
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Huang, X., Kong, N., Zhang, X., Cao, Y., Langer, R., & Tao, W. (2022) · Nature Medicine · doi:10.1038/s41591-022-02061-1 · Cited by 511 · see citing works
The challenge and prospect of mRNA therapeutics landscape
Weng, Y., Li, C., Yang, T., Hu, B., Zhang, M., Guo, S., Xiao, H., Liang, X.-J., & Huang, Y. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107534 · Cited by 417 · see citing works
Microfluidic technologies and devices for lipid nanoparticle-based RNA delivery
Maeki, M., Uno, S., Niwa, A., Okada, Y., & Tokeshi, M. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.02.017 · Cited by 349 · see citing works
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Parhiz, H., Atochina‐Vasserman, E. N., & Weissman, D. (2024) · The Lancet · doi:10.1016/s0140-6736(23)02444-3 · Cited by 296 · see citing works
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Kim, J., Jozić, A., Lin, Y., Eygeris, Y., Bloom, E., Tan, X., Acosta, C., MacDonald, K. D., Welsher, K., & Sahay, G. (2022) · ACS Nano · doi:10.1021/acsnano.2c05647 · Cited by 278 · see citing works
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Gómez-Aguado, I., Rodríguez-Castejón, J., Vicente-Pascual, M., Rodríguez‐Gascón, A., Solinís, M. Á., & del Pozo‐Rodríguez, A. (2020) · Nanomaterials · doi:10.3390/nano10020364 · Cited by 224 · see citing works
Jeong, M., Lee, Y., Park, J., Jung, H., & Lee, H. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114990 · Cited by 227 · see citing works
Self-citationFunctionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing
Zhang, X., Zhao, W., Nguyen, G. N., Zhang, C., Zeng, C., Yan, J., Du, S., Hou, X., Li, W., Jiang, J., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc2315 · Cited by 183 · see citing works
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Chen, S., Huang, X., Xue, Y., Álvarez‐Benedicto, E., Shi, Y., Chen, W., Koo, S., Siegwart, D. J., Dong, Y., & Tao, W. (2023) · Nature Reviews Methods Primers · doi:10.1038/s43586-023-00246-7 · Cited by 172 · see citing works
Zhu, X., Yin, L., Theisen, M., Zhuo, J., Siddiqui, S., Levy, B., Presnyak, V., Frassetto, A., Milton, J., Salerno, T., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.02.003 · Cited by 165 · see citing works
Self-citationClinical guide and update on porphyrias
Stölzel, U., Doss, M. O., & Schuppan, D. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.04.050 · Cited by 175 · see citing works
Novel vectors and approaches for gene therapy in liver diseases
Maestro, S., Weber, N. D., Zabaleta, N., Aldabe, R., & González‐Aseguinolaza, G. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100300 · Cited by 140 · see citing works
Nanomedicine-Based Approaches for mRNA Delivery
Uchida, S., Perche, F., Pichon, C., & Cabral, H. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00618 · Cited by 139 · see citing works
Current Status and Future Perspectives on MRNA Drug Manufacturing
Webb, C., Ip, S. Y., Bathula, N. V., Popova, P. G., Soriano, S. K. V., Ly, B.-H., Eryilmaz, B., Huu, V. A. N., Broadhead, R., Rabel, M., et al. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.2c00010 · Cited by 132 · see citing works
mRNA nanomedicine: Design and recent applications
Kubiatowicz, L. J., Mohapatra, A., Krishnan, N., Fang, R. H., & Zhang, L. (2022) · Exploration · doi:10.1002/exp.20210217 · Cited by 130 · see citing works
Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Jiang, L., Park, J.-S., Yin, L., Laureano, R., Jacquinet, E., Yang, J., Liang, S., Frassetto, A., Zhuo, J., Yan, X., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19156-3 · Cited by 126 · see citing works
Self-citationMessenger RNA therapy for rare genetic metabolic diseases
Berraondo, P., Martini, P. G. V., Avila, M. A., & Fontanellas, A. (2019) · Gut · doi:10.1136/gutjnl-2019-318269 · Cited by 118 · see citing works
Self-citationDelivery of mRNA Therapeutics for the Treatment of Hepatic Diseases
Trepotec, Z., Lichtenegger, E., Plank, C., Aneja, M. K., & Rudolph, C. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2018.12.012 · Cited by 115 · see citing works
DeRosa, F., Smith, L., Shen, Y., Huang, Y., Pan, J., Xie, H., Yahalom, B., & Heartlein, M. W. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.03.001 · Cited by 111 · see citing works
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Lim, S., Khoo, R., Juang, Y.-C., Gopal, P., Zhang, H., Yeo, C., Peh, K. M., Teo, J., Ng, S., Henry, B., et al. (2021) · ACS Central Science · doi:10.1021/acscentsci.0c01337 · Cited by 80 · see citing works
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Wei, G., Cao, J., Huang, P., An, P., Skelton-Badlani, D., Vaid, K. A., Zhao, S., Wang, D. Q. ‐., Zhuo, J., Yin, L., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.12.010 · Cited by 73 · see citing works
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Self-citationCao, J.-S., Choi, M., Guadagnin, E., Soty, M., Silva, M., Verzieux, V., Weisser, E., Markel, A., Zhuo, J., Liang, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23318-2 · Cited by 58 · see citing works
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Shen, G., Liu, J., Yang, H., Xie, N., & Yang, Y. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.03.056 · Cited by 61 · see citing works
Therapeutic mRNA delivery to leukocytes
Granot-Matok, Y., Kon, E., Dammes, N., Mechtinger, G., & Peer, D. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.05.032 · Cited by 61 · see citing works
Balakrishnan, B., An, D., Nguyen, V., DeAntonis, C. M., Martini, P. G. V., & Lai, K. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.09.018 · Cited by 57 · see citing works
Self-citationSystemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency
Karadagi, A., Cavedon, A. G., Zemack, H., Nowak, G., Eybye, M. E., Zhu, X., Guadagnin, E., White, R. A., Rice, L. M., Frassetto, A. L., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-64017-0 · Cited by 54 · see citing works
Self-citationFirdessa-Fite, R., & Creusot, R. J. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.10.015 · Cited by 53 · see citing works
Li, X., Li, J., Wei, J., Du, W., Su, C., Shen, X., Zhao, A., & Xu, M. (2025) · MedComm · doi:10.1002/mco2.70414 · Cited by 56 · see citing works
Robust, Durable Gene Activation In Vivo via mRNA-Encoded Activators
Beyersdorf, J. P., Bawage, S. S., Iglesias, N., Peck, H. E., Hobbs, R. A., Wroe, J. A., Zurla, C., Gersbach, C. A., & Santangelo, P. J. (2022) · ACS Nano · doi:10.1021/acsnano.1c10631 · Cited by 51 · see citing works
Modern therapeutic approaches to liver-related disorders
Gardin, A., Remih, K., Gonzales, E. M., Andersson, E. R., & Strnad, P. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2021.12.015 · Cited by 50 · see citing works
Bustad, H. J., Kallio, J. P., Vorland, M., Fiorentino, V., Sandberg, S., Schmitt, C., Aarsand, A. K., & Martı́nez, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020675 · Cited by 47 · see citing works
Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases
Moosavi, S. G., Rahiman, N., Jaafari, M. R., & Arabi, L. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113641 · Cited by 52 · see citing works
Sultana, N., Hadas, Y., Sharkar, M. T. K., Kaur, K., Magadum, A., Kurian, A. A., Hossain, N., Alburquerque, B., Ahmed, S. M. M., Chepurko, E., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.03.019 · Cited by 45 · see citing works
Attarwala, H. Z., Lumley, M., Liang, M., Ivaturi, V. D., & Senn, J. J. (2022) · Nucleic Acid Therapeutics · doi:10.1089/nat.2022.0036 · Cited by 44 · see citing works
Dickey, A. K., Leaf, R. K., & Balwani, M. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-123602 · Cited by 43 · see citing works
Development of Lipid Nanoparticle Formulation for the Repeated Administration of mRNA Therapeutics
Lee, Y., Jeong, M., Lee, G., Park, J., Jung, H., Im, S., & Lee, H. (2024) · Biomaterials Research · doi:10.34133/bmr.0017 · Cited by 46 · see citing works
Self-citationEftekhari, Z., Zohrabi, H., Oghalaie, A., Ebrahimi, T., Shariati, F. S., Behdani, M., & Kazemi‐Lomedasht, F. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102313 · Cited by 43 · see citing works
Nanoscale delivery platforms for RNA therapeutics: Challenges and the current state of the art
Rhym, L. H., & Anderson, D. G. (2022) · Med · doi:10.1016/j.medj.2022.02.001 · Cited by 45 · see citing works
Current and Future Treatments for Classic Galactosemia
Delnoy, B., Coelho, A. I., & Rubio‐Gozalbo, M. E. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11020075 · Cited by 42 · see citing works
Delivery of synthetic mRNAs for tissue regeneration
Steinle, H., Weber, M., Stoppelkamp, S., Große‐Berkenbusch, K., Golombek, S., Weber, M., Çanak-Ipek, T., Trenz, S.-M., Schlensak, C., & Avci‐Adali, M. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114007 · Cited by 41 · see citing works
Bartesaghi, S., Wallenius, K., Hovdal, D., Liljeblad, M., Wallin, S., Dekker, N., Barlind, L., Davies, N. M., Seeliger, F., Winzell, M. S., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.04.010 · Cited by 40 · see citing works
Gurung, S., Timmermand, O. V., Perocheau, D. P. B., Gil-Martínez, A. L., Minnion, M., Touramanidou, L., Fang, S., Messina, M., Khalil, Y., Śpiewak, J., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adh1334 · Cited by 39 · see citing works
Self-citationmRNA and gene editing: Late breaking therapies in liver diseases
Zabaleta, N., Torella, L., Weber, N. D., & González‐Aseguinolaza, G. (2022) · Hepatology · doi:10.1002/hep.32441 · Cited by 36 · see citing works
Chambers, C., Soo, G. L., Engel, A. L., Glass, I. A., Frassetto, A., Martini, P. G. V., & Cherry, T. J. (2024) · Translational Vision Science & Technology · doi:10.1167/tvst.13.7.7 · Cited by 36 · see citing works
Self-citationCurrent and innovative emerging therapies for porphyrias with hepatic involvement
Fontanellas, A., Avila, M. A., Anderson, K. E., & Deybach, J. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.05.003 · Cited by 36 · see citing works
Self-citationGenetic-Based Approaches to Inherited Metabolic Liver Diseases
Zabaleta, N., Hommel, M., Salas, D., & González‐Aseguinolaza, G. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.140 · Cited by 35 · see citing works
Petrides, P. E., Klein, M., Schuhmann, E., Torkler, H., Molitor, B., Loehr, C., Obermeier, Z., & Beykirch, M. K. (2021) · Annals of Hematology · doi:10.1007/s00277-021-04547-3 · Cited by 35 · see citing works
Costabile, G., Conte, G., Brusco, S., Savadi, P., Miro, A., Quaglia, F., d’Angelo, I., & Ungaro, F. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16030347 · Cited by 35 · see citing works
Therapeutic strategies for acute intermittent porphyria
Zhao, L., Wang, X., Zhang, X., Liu, X., Ma, N., Zhang, Y., & Zhang, S. (2020) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2020.03089 · Cited by 33 · see citing works
mRNA vaccines in tumor targeted therapy: mechanism, clinical application, and development trends
Gao, Y., Yang, L., Li, Z., Peng, X., & Li, H. (2024) · Biomarker Research · doi:10.1186/s40364-024-00644-3 · Cited by 33 · see citing works
mRNA-based modalities for infectious disease management
Zhang, M., Hussain, A., Yang, H., Zhang, J., Liang, X., & Huang, Y. (2022) · Nano Research · doi:10.1007/s12274-022-4627-5 · Cited by 33 · see citing works
Gene therapy for inherited metabolic diseases
Yılmaz, B. Ş., Gurung, S., Perocheau, D. P. B., Counsell, J. R., & Baruteau, J. (2020) · PubMed Central · doi:10.34763/jmotherandchild.20202402si.2004.000009 · Cited by 31 · see citing works
Challenges of Gene Therapy for the Treatment of Glycogen Storage Diseases Type I and Type III
Jauze, L., Monteillet, L., Mithieux, G., Rajas, F., & Ronzitti, G. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.102 · Cited by 29 · see citing works
Lipid-nanoparticle-enabled nucleic acid therapeutics for liver disorders
Arjunan, P., Kathirvelu, D., Mahalingam, G., Goel, A., Zacharaiah, U. G., Srivastava, A., & Marepally, S. K. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.04.015 · Cited by 31 · see citing works
Considerations for mRNA Product Development, Regulation and Deployment Across the Lifecycle
Skerritt, J. H. (2025) · Vaccines · doi:10.3390/vaccines13050473 · Cited by 30 · see citing works
RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria
Sardh, E., & Harper, P. (2022) · Journal of Internal Medicine · doi:10.1111/joim.13443 · Cited by 28 · see citing works
Ige, M. A., Ren, X., Yang, Y., Zhang, H., Shen, C., Jiang, Y., Li, J., & Wan, X. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102721 · Cited by 29 · see citing works
Khoja, S., Liu, X.-B., Truong, B., Nitzahn, M., Lambert, J., Eliav, A., Nasser, E., Randolph, E., Burke, K. E., White, R. A., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.04.012 · Cited by 26 · see citing works
Self-citationThe Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review
Halma, M. T. J., Rose, J., Jenks, A., & Lawrie, T. A. (2023) · J — Multidisciplinary Scientific Journal · doi:10.3390/j6020017 · Cited by 25 · see citing works
The design, manufacture and LNP formulation of mRNA for research use
Leighton, L. J., Chaudhary, N., Tompkins, H. E., Kulkarni, A., Carrodus, N. L., Budzinska, M. A., Das, S. L., Cheetham, S. W., & Mercer, T. R. (2025) · Nature Protocols · doi:10.1038/s41596-025-01174-4 · Cited by 24 · see citing works
Gardin, A., & Ronzitti, G. (2023) · Archives de Pédiatrie · doi:10.1016/s0929-693x(23)00227-0 · Cited by 22 · see citing works
RNA-based therapies in liver metabolic diseases
Fontanellas, A., Berraondo, P., Urigo, F., Jericó, D., Martini, P. G. V., Pastor, F., & Avila, M. A. (2025) · Gut · doi:10.1136/gutjnl-2023-331742 · Cited by 23 · see citing works
Self-citationGivosiran for the treatment of acute hepatic porphyria
Ricci, A., & Ventura, P. (2022) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2022.2075848 · Cited by 23 · see citing works
mRNA delivery technologies: Toward clinical translation
Gómez-Aguado, I., Rodríguez-Castejón, J., Beraza-Millor, M., Rodríguez‐Gascón, A., del Pozo‐Rodríguez, A., & Solinís, M. Á. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.04.010 · Cited by 23 · see citing works
mRNA-Based Approaches to Treating Liver Diseases
Cacicedo, M. L., Limeres, M. J., & Gehring, S. (2022) · Cells · doi:10.3390/cells11203328 · Cited by 22 · see citing works
Kukreja, A., Lasaro, M. A., Cobaugh, C., Forbes, C. D., Tang, J., Gao, X., Martín-Higueras, C., Pey, A. L., SALIDO, E. C., Sobolov, S. B., et al. (2019) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0740 · Cited by 21 · see citing works
Marcacci, M., Ricci, A., Cuoghi, C., Marchini, S., Pietrangelo, A., & Ventura, P. (2022) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-022-02314-9 · Cited by 21 · see citing works
Solares, I., Izquierdo‐Sánchez, L., Morales‐Conejo, M., Jericó, D., Castelbón, F. J., Córdoba, K. M., Sampedro, A., Lumbreras, C., Moreno-Aliaga, M. J., de Salamanca, R. E., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9030255 · Cited by 21 · see citing works
Self-citationThe Potential of Nanomedicine to Unlock the Limitless Applications of mRNA
Taina-González, L., & de la Fuente, M. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14020460 · Cited by 21 · see citing works
Longo, M., Paolini, E., Meroni, M., & Dongiovanni, P. (2022) · Biomedicines · doi:10.3390/biomedicines10030648 · Cited by 20 · see citing works
Overcoming the limitations of cytokines to improve cancer therapy
Trani, C. A. D., Cirella, A., Arrizabalaga, L., Fernández-Sendin, M., Bella, Á., Aranda, F., Melero, I., & Berraondo, P. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.05.002 · Cited by 20 · see citing works
Self-citationAcute Intermittent Porphyria’s Symptoms and Management: A Narrative Review
Kizilaslan, E. Z., Ghadge, N. M., Martínez, A., Bass, M., Winayak, R., Mathew, M., Amin, R., Khan, M. K., & Kizilbash, N. (2023) · Cureus · doi:10.7759/cureus.36058 · Cited by 20 · see citing works
RNA nanomedicine in liver diseases
Bakrania, A. K., Mo, Y., Zheng, G., & Bhat, M. (2023) · Hepatology · doi:10.1097/hep.0000000000000606 · Cited by 21 · see citing works
Current knowledge on the tissue distribution of mRNA nanocarriers for therapeutic protein expression
Zadory, M., Lopez, E., Babity, S., Gravel, S., & Brambilla, D. (2022) · Biomaterials Science · doi:10.1039/d2bm00859a · Cited by 18 · see citing works
Novel treatment options for acute hepatic porphyrias
Wang, B. (2021) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000734 · Cited by 19 · see citing works
Jericó, D., Córdoba, K. M., Jiang, L., Schmitt, C., Morán, M., Sampedro, A., Alegre, M., Collantes, M., Santamaría, E., Alegre, E., et al. (2021) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2021.05.010 · Cited by 19 · see citing works
Self-citationHeme (dys)homeostasis and liver disease
Duarte, T. L., Viveiros, N., Godinho, C., & Duarte, D. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1436897 · Cited by 18 · see citing works
Emerging mRNA Technology for Liver Disease Therapy
Wang, J., Fang, Y., Luo, Z., Wang, J., & Zhao, Y. (2024) · ACS Nano · doi:10.1021/acsnano.4c02987 · Cited by 20 · see citing works
Lipid nanoparticle formulation for gene editing and RNA-based therapies for glioblastoma
Zhang, Y., Rabinovsky, R., Deforzh, E., Kobayashi, A., Kuzkina, A., Varghese, J. F., Rai, D., Korecka, J. A., Khurana, V., Murugaiyan, G., et al. (2025) · Neuro-Oncology · doi:10.1093/neuonc/noaf162 · Cited by 18 · see citing works
RNA interference therapy in acute hepatic porphyrias
Yasuda, M., Keel, S., & Balwani, M. (2023) · Blood · doi:10.1182/blood.2022018662 · Cited by 17 · see citing works
Yasuda, M., & Desnick, R. J. (2019) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2019.01.007 · Cited by 17 · see citing works
- Authors
- Jiang, L., Berraondo, P., Jericó, D., Guey, L. T., Sampedro, A., Frassetto, A., Benenato, K. E., Burke, K., Santamaría, E., Alegre, M., Pejenaute, Á., Kalariya, M., Butcher, W., Park, J.-S., Zhu, X., Sabnis, S., Kumarasinghe, E. S., Salerno, T., Kenney, M., Lukacs, C. M., Ávila, M. A., Martini, P. G. V., & Fontanellas, A.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Instituto de Salud Carlos III (ES)
- Navarre Institute of Health Research (ES)
- Centro de Investigación Médica Aplicada (ES)
- Universidad de Navarra (ES)
- Corresponding author
- Martini, Paolo G. V.
- Fontanellas, Antonio
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-10-08
- Volume
- 24
- Issue
- 12
- Pages
- 1899-1909
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2895539268
- Cited by
- 181
- References
- 44
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 26 · 2023: 18 · 2022: 40 · 2021: 14 · 2020: 24 · 2019: 24 · 2018: 3 · 2013: 1
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- acute intermittent porphyria, porphobilinogen deaminase, hydroxymethylbilane synthase, mRNA therapeutics, lipid nanoparticles, gene therapy, heme biosynthesis, porphyrin precursors, mitochondrial dysfunction, hypertension, pain, motor impairment, non-human primates, hepatotoxicity
- MeSH terms
- Animals, Disease Models, Animal, Female, Heme, Humans, Liver, Male, Hydroxymethylbilane Synthase, RNA, Messenger, Genetic Therapy, Porphyria, Acute Intermittent, Hepatocytes, Haploinsufficiency
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