In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice
Abstract Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in i...
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| Published in | Nature communications Vol. 13; no. 1; pp. 5215 - 10 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group
05.09.2022
Nature Publishing Group UK Nature Portfolio |
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| Abstract | Abstract
Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the
HFE
gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfe
tm.1.1Nca
mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans. |
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| AbstractList | Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfetm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans.Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfetm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans. Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfe tm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans. Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an Adenine Base Editor facilitates efficient in vivo gene correction in hepatocytes and leads to improvement of iron-specific parameters in the liver and the blood in mouse models of the disease. Abstract Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfe tm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans. Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an Adenine Base Editor facilitates efficient in vivo gene correction in hepatocytes and leads to improvement of iron-specific parameters in the liver and the blood in mouse models of the disease. Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfetm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans.Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an Adenine Base Editor facilitates efficient in vivo gene correction in hepatocytes and leads to improvement of iron-specific parameters in the liver and the blood in mouse models of the disease. |
| ArticleNumber | 5215 |
| Author | Hu, Qingluan Kempf, Tibor Grimm, Dirk Talbot, Steven R Götting, Jasper Steinbrück, Lars Schmidt, Florian Hook, Sebastian Bohne, Jens Rovai, Alice Yuan, Qinggong Krooss, Simon A Ott, Michael Chung, BoMee |
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| CitedBy_id | crossref_primary_10_1097_HEP_0000000000000578 crossref_primary_10_1016_S0140_6736_23_00287_8 crossref_primary_10_5483_BMBRep_2023_0221 crossref_primary_10_1007_s11010_023_04726_y |
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| Snippet | Abstract
Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y... Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in... Hemochromatosis is a metabolic disorder caused by mutations in the HFE gene. Here, the authors show that a single administration of AAV8 vectors expressing an... |
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| StartPage | 5215 |
| SubjectTerms | Adenine Animal models Cell culture Cell membranes gRNA Hemochromatosis Hepatocytes Hereditary diseases HFE protein Iron Liver Metabolic disorders Metabolism Mutation Protein folding Transferrin Transferrin receptors |
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| Title | In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice |
| URI | https://www.proquest.com/docview/2709801939/abstract/ https://www.proquest.com/docview/2710973137/abstract/ https://pubmed.ncbi.nlm.nih.gov/PMC9445023 https://doaj.org/article/41baa3360d14427b871c13b614264a6d |
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