GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy
Abstract Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with h...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37465-1 |
| _version_ | 1797822790091407360 |
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| author | Lisa N. Kasiewicz Souvik Biswas Aaron Beach Huilan Ren Chaitali Dutta Anne Marie Mazzola Ellen Rohde Alexandra Chadwick Christopher Cheng Sara P. Garcia Sowmya Iyer Yuri Matsumoto Amit V. Khera Kiran Musunuru Sekar Kathiresan Padma Malyala Kallanthottathil G. Rajeev Andrew M. Bellinger |
| author_facet | Lisa N. Kasiewicz Souvik Biswas Aaron Beach Huilan Ren Chaitali Dutta Anne Marie Mazzola Ellen Rohde Alexandra Chadwick Christopher Cheng Sara P. Garcia Sowmya Iyer Yuri Matsumoto Amit V. Khera Kiran Musunuru Sekar Kathiresan Padma Malyala Kallanthottathil G. Rajeev Andrew M. Bellinger |
| author_sort | Lisa N. Kasiewicz |
| collection | DOAJ |
| description | Abstract Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia. |
| first_indexed | 2024-03-13T10:13:20Z |
| format | Article |
| id | doaj.art-3005b2e0a2d6495d964d5dc6d482dff2 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:13:20Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-3005b2e0a2d6495d964d5dc6d482dff22023-05-21T11:20:03ZengNature PortfolioNature Communications2041-17232023-05-0114111010.1038/s41467-023-37465-1GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapyLisa N. Kasiewicz0Souvik Biswas1Aaron Beach2Huilan Ren3Chaitali Dutta4Anne Marie Mazzola5Ellen Rohde6Alexandra Chadwick7Christopher Cheng8Sara P. Garcia9Sowmya Iyer10Yuri Matsumoto11Amit V. Khera12Kiran Musunuru13Sekar Kathiresan14Padma Malyala15Kallanthottathil G. Rajeev16Andrew M. Bellinger17Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of PennsylvaniaVerve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Verve Therapeutics, 201 Brookline Avenue, Suite 601Abstract Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.https://doi.org/10.1038/s41467-023-37465-1 |
| spellingShingle | Lisa N. Kasiewicz Souvik Biswas Aaron Beach Huilan Ren Chaitali Dutta Anne Marie Mazzola Ellen Rohde Alexandra Chadwick Christopher Cheng Sara P. Garcia Sowmya Iyer Yuri Matsumoto Amit V. Khera Kiran Musunuru Sekar Kathiresan Padma Malyala Kallanthottathil G. Rajeev Andrew M. Bellinger GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy Nature Communications |
| title | GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy |
| title_full | GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy |
| title_fullStr | GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy |
| title_full_unstemmed | GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy |
| title_short | GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy |
| title_sort | galnac lipid nanoparticles enable non ldlr dependent hepatic delivery of a crispr base editing therapy |
| url | https://doi.org/10.1038/s41467-023-37465-1 |
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