In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels

Tanja Rothgangl; Gerald Schwank; Melissa K Dennis; Paulo JC Lin; Rurika Oka; Dominik Witzigmann; Lukas Villiger; Weihong Qi; Martina Hruzova; Lucas Kissling; Daniela Lenggenhager; Costanza Borrelli; Sabrina Egli; Nina Frey; Noelle Bakker; John Walker; Anastasia P Kadina; Denis Victorov; Martin Pacesa; Susanne Kreutzer; Zacharias Kontarakis; Andreas Moor; Martin Jinek; Drew Weissman; Markus Stoffel; Ruben van Boxtel; Kevin Holden; Norbert Pardi; Beat Thöny; Johannes Häberle; Ying K Tam; Sean Semple

doi:https://doi.org/10.1038/s41587-021-00933-4

In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels

Tanja Rothgangl, Gerald Schwank, Melissa K Dennis, Paulo JC Lin, Rurika Oka, Dominik Witzigmann, Lukas Villiger, Weihong Qi, Martina Hruzova, Lucas Kissling, Daniela Lenggenhager, Costanza Borrelli, Sabrina Egli, Nina Frey, Noelle Bakker, John Walker, Anastasia P Kadina, Denis Victorov, Martin Pacesa, Susanne KreutzerZacharias Kontarakis, Andreas Moor, Martin Jinek, Drew Weissman, Markus Stoffel, Ruben van Boxtel, Kevin Holden, Norbert Pardi, Beat Thöny, Johannes Häberle, Ying K Tam, Sean Semple

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.

Original language	English
Pages (from-to)	949–957
Number of pages	9
Journal	Nature biotechnology
Volume	39
Issue number	August 2021
DOIs	https://doi.org/10.1038/s41587-021-00933-4
Publication status	Published - 19 May 2021

Keywords

Base editing
LDL cholesterol
PCSK9

Access to Document

https://doi.org/10.1038/s41587-021-00933-4

Cite this

Rothgangl, T., Schwank, G., K Dennis, M., Lin, P. JC., Oka, R., Witzigmann, D., Villiger, L., Qi, W., Hruzova, M., Kissling, L., Lenggenhager, D., Borrelli, C., Egli, S., Frey, N., Bakker, N., Walker, J., Kadina, A. P., Victorov, D., Pacesa, M., ... Semple, S. (2021). In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nature biotechnology, 39(August 2021), 949–957. https://doi.org/10.1038/s41587-021-00933-4

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title = "In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels",

abstract = "Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.",

keywords = "Base editing, LDL cholesterol, PCSK9",

author = "Tanja Rothgangl and Gerald Schwank and {K Dennis}, Melissa and Lin, {Paulo JC} and Rurika Oka and Dominik Witzigmann and Lukas Villiger and Weihong Qi and Martina Hruzova and Lucas Kissling and Daniela Lenggenhager and Costanza Borrelli and Sabrina Egli and Nina Frey and Noelle Bakker and John Walker and Kadina, {Anastasia P} and Denis Victorov and Martin Pacesa and Susanne Kreutzer and Zacharias Kontarakis and Andreas Moor and Martin Jinek and Drew Weissman and Markus Stoffel and {van Boxtel}, Ruben and Kevin Holden and Norbert Pardi and Beat Th{\"o}ny and Johannes H{\"a}berle and Tam, {Ying K} and Sean Semple",

year = "2021",

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Rothgangl, T, Schwank, G, K Dennis, M, Lin, PJC, Oka, R, Witzigmann, D, Villiger, L, Qi, W, Hruzova, M, Kissling, L, Lenggenhager, D, Borrelli, C, Egli, S, Frey, N, Bakker, N, Walker, J, Kadina, AP, Victorov, D, Pacesa, M, Kreutzer, S, Kontarakis, Z, Moor, A, Jinek, M, Weissman, D, Stoffel, M, van Boxtel, R, Holden, K, Pardi, N, Thöny, B, Häberle, J, Tam, YK & Semple, S 2021, 'In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels', Nature biotechnology, vol. 39, no. August 2021, pp. 949–957. https://doi.org/10.1038/s41587-021-00933-4

TY - JOUR

T1 - In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels

AU - Rothgangl, Tanja

AU - Schwank, Gerald

AU - K Dennis, Melissa

AU - Lin, Paulo JC

AU - Oka, Rurika

AU - Witzigmann, Dominik

AU - Villiger, Lukas

AU - Qi, Weihong

AU - Hruzova, Martina

AU - Kissling, Lucas

AU - Lenggenhager, Daniela

AU - Borrelli, Costanza

AU - Egli, Sabrina

AU - Frey, Nina

AU - Bakker, Noelle

AU - Walker, John

AU - Kadina, Anastasia P

AU - Victorov, Denis

AU - Pacesa, Martin

AU - Kreutzer, Susanne

AU - Kontarakis, Zacharias

AU - Moor, Andreas

AU - Jinek, Martin

AU - Weissman, Drew

AU - Stoffel, Markus

AU - van Boxtel, Ruben

AU - Holden, Kevin

AU - Pardi, Norbert

AU - Thöny, Beat

AU - Häberle, Johannes

AU - Tam, Ying K

AU - Semple, Sean

PY - 2021/5/19

Y1 - 2021/5/19

N2 - Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.

AB - Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.

KW - Base editing

KW - LDL cholesterol

KW - PCSK9

U2 - https://doi.org/10.1038/s41587-021-00933-4

DO - https://doi.org/10.1038/s41587-021-00933-4

M3 - Article

SN - 1087-0156

VL - 39

SP - 949

EP - 957

JO - Nature biotechnology

JF - Nature biotechnology

IS - August 2021

ER -