APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA
Open accessAbstract
The novel class of compounds represented by lipid nanoparticle (LNP)-encapsulated siRNA formulations has an enormous potential to target disease, notably of the liver. Endocytosis of LNPs is believed to be mediated by APOE, an important serum protein of lipoprotein homeostasis. APOE polymorphisms affect binding to hepatic receptors and have been associated with development of specific disease. Here, the role of APOE was investigated with regard to the efficacy of Patisiran, the first LNP-siRNA recently approved for clinical use in patients having transthyretin amyloidosis (ATTR amyloidosis). Patisiran was evaluated in the human hepatoma cell line HepG2 after knockdown of APOE. The APOE genotype was determined in ATTR amyloidosis patients treated with Patisiran. TTR knockdown was monitored in consecutive plasma up to week 12. Downregulation of APOE suppressed efficacy of Patisiran in HepG2 cells. TTR levels were found to be robustly reduced (84.7% ± 1%) following Patisiran treatment in patients plasma. Analysis of APOE polymorphisms in ATTR amyloidosis patients revealed three most frequent genotypes E3/3, E3/4 and E3/2. APOE stratification of patients did not show significant differences of TTR plasma concentrations following treatment. Our results suggest that APOE is an important mediator of TTR silencing by Patisiran, however efficacy is independent of the APOE genotype.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LNP-based in vivo gene editing has already led to investigational new drugs in clinical trials (NCT04601051).
“which has already lead to investigational new drugs in clinical trials (NCT04601051)”
From Off-target effects in CRISPR/Cas9 gene editing (2023) · cites this paper as Niemietz et al., 2020
The Discussion (page unavailable) says LNPs are used to carry sequences involved in gene editing. It does not say that LNP-based gene-editing drugs had entered clinical trials or mention NCT04601051; its discussion of clinical use concerns the siRNA therapeutic Patisiran instead. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans
Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998) · Nature · doi:10.1038/35888 · Cited by 15,429 · see citing works
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716153 · Cited by 3,047 · see citing works
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681 · see citing works
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis
Benson, M. D., Waddington‐Cruz, M., Berk, J. L., Polydefkis, M. J., Dyck, P. J. B., Wang, A. K., Planté‐Bordeneuve, V., Barroso, F. A., Merlini, G., Obici, L. P., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716793 · Cited by 1,452 · see citing works
Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms
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. (2010) · Molecular Therapy · doi:10.1038/mt.2010.85 · Cited by 1,261 · see citing works
ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y. D., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., et al. (2012) · Science · doi:10.1126/science.1217697 · Cited by 1,050 · see citing works
Safety and efficacy of RNAi therapy for transthyretin amyloidosis
Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P. N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1208760 · Cited by 971 · see citing works
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade
Bulawa, C., Connelly, S., DeVit, M. J., Wang, L., Weigel, C., Fleming, J., Packman, J., Powers, E. T., Wiseman, R. L., Foss, T. R., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121005109 · Cited by 750 · see citing works
Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34954-8 · Cited by 673 · see citing works
Lipid nanoparticles enabling gene therapies: from concepts to clinical utility
Kulkarni, J. A., Cullis, P. R., & van der Meel, R. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0721 · Cited by 592 · see citing works
Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
Dong, Y., Love, K. T., Dorkin, J. R., Sirirungruang, S., Zhang, Y., Chen, D., Bogorad, R. L., Yin, H., Chen, Y., Vegas, A. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322937111 · Cited by 488 · see citing works
Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA
Chen, S., Tam, Y. Y. C., Lin, P. J. C., Sung, M. M. H., Tam, Y. K., & Cullis, P. R. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.05.059 · Cited by 366 · see citing works
Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy
Coelho, T., Maia, L. F., SILVA, A. C. F. D., Waddington‐Cruz, M., Planté‐Bordeneuve, V., Suhr, O. B., Conceição, I. M., Schmidt, H., Trigo, P., Kelly, J. W., et al. (2013) · Journal of Neurology · doi:10.1007/s00415-013-7051-7 · Cited by 347 · see citing works
Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall
Getz, G. S., & Reardon, C. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800058-jlr200 · Cited by 319 · see citing works
Liver Transplantation for Hereditary Transthyretin Amyloidosis
Ericzon, B., Wilczek, H., Larsson, M., Wijayatunga, P. D. C., Stangou, A. J., Peña, J., Furtado, E., Barroso, E., Daniel, J., Samuel, D., et al. (2015) · Transplantation · doi:10.1097/tp.0000000000000574 · Cited by 311 · see citing works
Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277 · see citing works
Estimating the global prevalence of transthyretin familial amyloid polyneuropathy
Schmidt, H., Waddington‐Cruz, M., Botteman, M. F., Carter, J. A., Chopra, A. S., Hopps, M., Stewart, M., Fallet, S., & Amass, L. (2017) · Muscle & Nerve · doi:10.1002/mus.26034 · Cited by 209 · see citing works
Chen, D., Ganesh, S., Wang, W., & Amiji, M. M. (2019) · Nanoscale · doi:10.1039/c8nr09855g · Cited by 153 · see citing works
Schiele, F., Bacquer, D. D., Vincent‐Viry, M., Beisiegel†, U., Ehnholm, C., Evans, A., Kafatos, A., Martins, M. C., Sans, S., Sass, C., et al. (2000) · Atherosclerosis · doi:10.1016/s0021-9150(99)00501-8 · Cited by 143 · see citing works
Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells
Novobrantseva, T. I., Borodovsky, A., Wong, J., Klebanov, B., Zafari, M. R., Yucius, K., Querbes, W., Ge, P., Ruda, V. M., Milstein, S., et al. (2012) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2011.3 · Cited by 135 · see citing works
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Mooijaart, S. P., Berbée, J. F. P., van Heemst, D., Havekes, L. M., de Craen, A. J. M., Slagboom, P. E., Rensen, P. C. N., & Westendorp, R. G. J. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030176 · Cited by 129 · see citing works
Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis.
de Andrade, M., Thandi, I., Brown, S., Gotto, A. M., Patsch, W., & Boerwinkle, E. (1995) · PubMed Central · Cited by 103 · see citing works
Waddington‐Cruz, M., Schmidt, H., Botteman, M. F., Carter, J. A., Stewart, M., Hopps, M., Fallet, S., & Amass, L. (2019) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-019-1000-1 · Cited by 70 · see citing works
The expression of type III hyperlipoproteinemia: involvement of lipolysis genes
Henneman, P., Beer, F. V. D. S.-D., Moghaddam, P. H., Huijts, P. E. A., Stalenhoef, A. F. H., Kastelein, J. J. P., van Duijn, C. M., Havekes, L. M., Frants, R. R., van Dijk, K. W., et al. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.202 · Cited by 66 · see citing works
Suzuki, Y., & Ishihara, H. (2016) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2016.06.124 · Cited by 57 · see citing works
Li, L., Wang, R., Wilcox, D. M., Sarthy, A. V., Lin, X., Huang, X., Tian, L., Dande, P., Hubbard, R. D., Hansen, T. M., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0983-t · Cited by 36 · see citing works
Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis
Niemietz, C., Chandhok, G., & Schmidt, H. (2015) · Molecules · doi:10.3390/molecules201017944 · Cited by 33 · see citing works
Designer Lipids Advance Systemic siRNA Delivery
Liu, Y., & Huang, L. (2010) · Molecular Therapy · doi:10.1038/mt.2010.39 · Cited by 31 · see citing works
APOE ε4 and the cognitive genetics of multiple sclerosis
Ghaffar, O., Reis, M. D., Pennell, N., O'Connor, P. W., & Feinstein, A. (2010) · Neurology · doi:10.1212/wnl.0b013e3181e074a7 · Cited by 27 · see citing works
Niemietz, C., Sauer, V., Stella, J., Fleischhauer, L., Chandhok, G., Guttmann, S., Avsar, Y., Guo, S., Ackermann, E. J., Gollob, J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161455 · Cited by 22 · see citing works
Schaffer, S., Lam, V. Y. M., Ernst, I. M. A., Huebbe, P., Rimbach, G. H., & Halliwell, B. B. (2013) · Genes & Nutrition · doi:10.1007/s12263-013-0364-4 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Off-target effects in CRISPR/Cas9 gene editing
Guo, C., Ma, X., Gao, F., & Guo, Y. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1143157 · Cited by 625 · see citing works
“Nevertheless, accumulative studies have proved that sgRNAindependent off-target effects also exist, urging unbiased experimental detection and validation (Richter et al., 2020; O’Geen et al., 2015).”
BackgroundLipid nanoparticle technology for therapeutic gene regulation in the liver
Witzigmann, D., Kulkarni, J. A., Leung, J., Chen, S., Cullis, P. R., & van der Meel, R. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.026 · Cited by 376 · see citing works
Lipid-based nanoparticle technologies for liver targeting
Böttger, R., Pauli, G., Chao, P., Fayez, N. A., Hohenwarter, L., & Li, S. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.017 · Cited by 268 · see citing works
Engineering nanoparticle toolkits for mRNA delivery
Sun, B., Wu, W., Narasipura, E. A., Ma, Y., Yu, C., Fenton, O. S., & Song, H. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115042 · Cited by 93 · see citing works
Kawaguchi, M., Noda, M., Ono, A., Kamiya, M., Matsumoto, M., Tsurumaru, M., Mizukami, S., Mukai, H., & Kawakami, S. (2022) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2022.12.026 · Cited by 81 · see citing works
Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders
Chu, R., Wang, Y., Kong, J., Pan, T. S., Yang, Y., & He, J. F. (2024) · Journal of Materials Chemistry B · doi:10.1039/d3tb02766j · Cited by 48 · see citing works
Alradwan, I. A., Fayez, N. A., Alomary, M. N., Alshehri, A. A., Aodah, A. H., Almughem, F. A., Alsulami, K. A., Aldossary, A. M., Alawad, A. O., Tawfik, Y. M. K., et al. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16081037 · Cited by 37 · see citing works
Shuvaev, V. V., Tam, Y. K., Lee, B. W., Myerson, J. W., Herbst, D. A., Kiseleva, R. Y., Glassman, P. M., Parhiz, H., Alameh, M., Pardi, N., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2409266122 · Cited by 23 · see citing works
Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs
Fumoto, S., Yamamoto, T., Okami, K., Maemura, Y., Terada, C., Yamayoshi, A., & Nishida, K. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020159 · Cited by 23 · see citing works
Ahmed, T. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16336 · Cited by 16 · see citing works
Liver cancer cells as the model for developing liver-targeted RNAi therapeutics
Hou, B., Qin, L., & Huang, L. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.01.007 · Cited by 12 · see citing works
Gene based nanocarrier delivery for the treatment of hepatocellular carcinoma
Deepak, P., Siddalingam, R., Kumar, P., Anand, S., Thakur, S., Balasubramaniam, J., & Jaiswal, S. (2020) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2020.101837 · Cited by 10 · see citing works
Gan, C., Leng, M., Liu, Y., Zheng, Z., He, S., Qiao, W., Lin, X., Xiao, Y., Ye, J., Zhou, L., et al. (2024) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2024.101399 · Cited by 7 · see citing works
Guarding the genome: strategies for off-target detection and minimization in CRISPR/Cas9 system
Lotfi, M., Yazdi, Z. F., Hashemi, M. R., Abbaszadegan, M. R., & Sharif, S. (2025) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2025.2581677 · Cited by 6 · see citing works
Zeng, Z., Zeng, X., Li, X., Feng, Y., Kan, Y., Liu, X., & Zeng, Y. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16010075 · Cited by 6 · see citing works
Bathula, N. V., Casmil, I. C., Friesen, J. J., Yuan, E., Liao, S., Maiti, B., Liou, J., Lai, M.-J., Li, S., Chen, S., et al. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.114736 · Cited by 3 · see citing works
A concise review on nanoscale carriers to target intracellular infections
Maithania, H. V., & Gundeti, M. (2026) · Discover Pharmaceutical Sciences · doi:10.1007/s44395-026-00038-4 · Cited by 2 · see citing works
Unlocking the potential of mRNA nanomedicines for comprehensive fibrosis therapy
Yang, Y., Li, C., Xiong, W., Li, C., & Xiao, J. (2026) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2026.102917 · Cited by 2 · see citing works
Vectorisation d'ARN par voie orale et parentérale
Stalder, T. (2024) · theses.fr (ABES) · doi:10.70675/d509592fzbb96z4f17zb286z5040de22fd65
CRISPR/Cas based genome editing for liver diseases: Promise and challenge
Guan, J., Yang, M., Yang, X., He, Q., Wang, B., & Zhan, C. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.09.027
Emerging Lipid Nanoparticle Targeting Strategies for Extrahepatic Delivery of RNA Therapeutics
Li, J., Liu, J., Wang, N., Zhang, K., Zhang, W., Gao, M., Lu, Z., Chen, X. S., & Li, Y. (2026) · Advanced Materials · doi:10.1002/adma.75408
Amin, A., Nawaz, T., fadili, M. E., & Rasdi, F. L. M. (2026) · Journal of drug targeting · doi:10.1080/1061186x.2026.2751938
- Authors
- Niemietz, C., Nadzemova, O., Zibert, A., & Schmidt, H. H.-J.
- Affiliations
- University Hospital Münster (DE)
- Corresponding author
- Schmidt, Hartmut H.-J.
- Venue
- Amyloid
- Publisher
- Informa UK Limited
- Published
- 2019-10-25
- Volume
- 27
- Issue
- 1
- Pages
- 45-51
- ISSN
- 1350-6129 (ISSN-L)
- 1744-2818
- OpenAlex
- W2981504990
- Cited by
- 22
- References
- 33
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 3
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Amyloid (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- APOE polymorphism, transthyretin amyloidosis, patisiran, APOE genotype, siRNA delivery, HepG2 cells, patient stratification
- MeSH terms
- Apolipoproteins E, Female, Genotype, Humans, Male, Polymorphism, Genetic, Prealbumin, Gene Silencing, Amyloid Neuropathies, Familial, RNA, Small Interfering, Nanoparticles, Gene Knockdown Techniques, Hep G2 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
