Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria

Tracy L. McGregor; Karen A. Hunt; Elaine Yee; Dan Mason; Paul Nioi; Simina Ticau; Marissa Pelosi; Perry R. Loken; Sarah Finer; Deborah A. Lawlor; Eric B. Fauman; Qin Qin Huang; Christopher J. Griffiths; Daniel G. Macarthur; Richard C. Trembath; Devin Oglesbee; John C. Lieske; David V. Erbe; John Wright; David A. van Heel

doi:10.7554/eLife.54363

Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria

Tracy L. McGregor, Karen A. Hunt, Elaine Yee, Dan Mason, Paul Nioi, Simina Ticau, Marissa Pelosi, Perry R. Loken, Sarah Finer, Deborah A. Lawlor, Eric B. Fauman, Qin Qin Huang, Christopher J. Griffiths, Daniel G. Macarthur, Richard C. Trembath, Devin Oglesbee, John C. Lieske, David V. Erbe, John Wright, David A. van Heel

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

11 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e54363
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.54363
State	Published - Mar 2020

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

Access to Document

10.7554/eLife.54363

Cite this

McGregor, T. L., Hunt, K. A., Yee, E., Mason, D., Nioi, P., Ticau, S., Pelosi, M., Loken, P. R., Finer, S., Lawlor, D. A., Fauman, E. B., Huang, Q. Q., Griffiths, C. J., Macarthur, D. G., Trembath, R. C., Oglesbee, D., Lieske, J. C., Erbe, D. V., Wright, J., & van Heel, D. A. (2020). Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria. eLife, 9, Article e54363. https://doi.org/10.7554/eLife.54363

McGregor, TL, Hunt, KA, Yee, E, Mason, D, Nioi, P, Ticau, S, Pelosi, M, Loken, PR, Finer, S, Lawlor, DA, Fauman, EB, Huang, QQ, Griffiths, CJ, Macarthur, DG, Trembath, RC, Oglesbee, D , Lieske, JC, Erbe, DV, Wright, J & van Heel, DA 2020, 'Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria', eLife, vol. 9, e54363. https://doi.org/10.7554/eLife.54363

@article{6021ce9e982148428010200ebc7c17fb,

title = "Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria",

abstract = "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.",

author = "McGregor, {Tracy L.} and Hunt, {Karen A.} and Elaine Yee and Dan Mason and Paul Nioi and Simina Ticau and Marissa Pelosi and Loken, {Perry R.} and Sarah Finer and Lawlor, {Deborah A.} and Fauman, {Eric B.} and Huang, {Qin Qin} and Griffiths, {Christopher J.} and Macarthur, {Daniel G.} and Trembath, {Richard C.} and Devin Oglesbee and Lieske, {John C.} and Erbe, {David V.} and John Wright and {van Heel}, {David A.}",

note = "Publisher Copyright: {\textcopyright} McGregor et al.",

year = "2020",

month = mar,

doi = "10.7554/eLife.54363",

language = "English (US)",

volume = "9",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria

AU - McGregor, Tracy L.

AU - Hunt, Karen A.

AU - Yee, Elaine

AU - Mason, Dan

AU - Nioi, Paul

AU - Ticau, Simina

AU - Pelosi, Marissa

AU - Loken, Perry R.

AU - Finer, Sarah

AU - Lawlor, Deborah A.

AU - Fauman, Eric B.

AU - Huang, Qin Qin

AU - Griffiths, Christopher J.

AU - Macarthur, Daniel G.

AU - Trembath, Richard C.

AU - Oglesbee, Devin

AU - Lieske, John C.

AU - Erbe, David V.

AU - Wright, John

AU - van Heel, David A.

PY - 2020/3

Y1 - 2020/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85082881539&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082881539&partnerID=8YFLogxK

U2 - 10.7554/eLife.54363

DO - 10.7554/eLife.54363

M3 - Article

C2 - 32207686

AN - SCOPUS:85082881539

SN - 2050-084X

VL - 9

JO - eLife

JF - eLife

M1 - e54363

ER -

Characterising a healthy adult with a rare hao1 knockout to support a therapeutic strategy for primary hyperoxaluria

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this