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Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria

By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxalu...

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Autores principales: McGregor, Tracy L, Hunt, Karen A, Yee, Elaine, Mason, Dan, Nioi, Paul, Ticau, Simina, Pelosi, Marissa, Loken, Perry R, Finer, Sarah, Lawlor, Deborah A, Fauman, Eric B, Huang, Qin Qin, Griffiths, Christopher J, MacArthur, Daniel G, Trembath, Richard C, Oglesbee, Devin, Lieske, John C, Erbe, David V, Wright, John, van Heel, David A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108859/
https://www.ncbi.nlm.nih.gov/pubmed/32207686
http://dx.doi.org/10.7554/eLife.54363
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author McGregor, Tracy L
Hunt, Karen A
Yee, Elaine
Mason, Dan
Nioi, Paul
Ticau, Simina
Pelosi, Marissa
Loken, Perry R
Finer, Sarah
Lawlor, Deborah A
Fauman, Eric B
Huang, Qin Qin
Griffiths, Christopher J
MacArthur, Daniel G
Trembath, Richard C
Oglesbee, Devin
Lieske, John C
Erbe, David V
Wright, John
van Heel, David A
author_facet McGregor, Tracy L
Hunt, Karen A
Yee, Elaine
Mason, Dan
Nioi, Paul
Ticau, Simina
Pelosi, Marissa
Loken, Perry R
Finer, Sarah
Lawlor, Deborah A
Fauman, Eric B
Huang, Qin Qin
Griffiths, Christopher J
MacArthur, Daniel G
Trembath, Richard C
Oglesbee, Devin
Lieske, John C
Erbe, David V
Wright, John
van Heel, David A
author_sort McGregor, Tracy L
collection PubMed
description By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.
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spelling pubmed-71088592020-04-01 Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria McGregor, Tracy L Hunt, Karen A Yee, Elaine Mason, Dan Nioi, Paul Ticau, Simina Pelosi, Marissa Loken, Perry R Finer, Sarah Lawlor, Deborah A Fauman, Eric B Huang, Qin Qin Griffiths, Christopher J MacArthur, Daniel G Trembath, Richard C Oglesbee, Devin Lieske, John C Erbe, David V Wright, John van Heel, David A eLife Genetics and Genomics By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development. eLife Sciences Publications, Ltd 2020-03-24 /pmc/articles/PMC7108859/ /pubmed/32207686 http://dx.doi.org/10.7554/eLife.54363 Text en © 2020, McGregor et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
McGregor, Tracy L
Hunt, Karen A
Yee, Elaine
Mason, Dan
Nioi, Paul
Ticau, Simina
Pelosi, Marissa
Loken, Perry R
Finer, Sarah
Lawlor, Deborah A
Fauman, Eric B
Huang, Qin Qin
Griffiths, Christopher J
MacArthur, Daniel G
Trembath, Richard C
Oglesbee, Devin
Lieske, John C
Erbe, David V
Wright, John
van Heel, David A
Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
title Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
title_full Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
title_fullStr Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
title_full_unstemmed Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
title_short Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria
title_sort characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108859/
https://www.ncbi.nlm.nih.gov/pubmed/32207686
http://dx.doi.org/10.7554/eLife.54363
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