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.
Highlights
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder of oxalate metabolism with prevalence of 1-3/1,000,000 in Europe, accounting for 1-2% of paediatric end stage kidney disease, but with higher prevalence in some Middle East and North African countries[1]
The cumulative frequency of known pLOF variants in HAO1 is low: in gnomAD v2.1 (141,456 whole exome/genome sequenced individuals) around 1 in 2700 individuals is heterozygous for a predicted loss of function (pLoF) variant
The results presented here provide important data to support the safety of HAO1-encoded glycolate oxidase inhibition as a potential chronic therapeutic approach for a devastating metabolic disease
Summary
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder of oxalate metabolism with prevalence of 1-3/1,000,000 in Europe, accounting for 1-2% of paediatric end stage kidney disease, but with higher prevalence in some Middle East and North African countries[1]. The earliest symptoms among those affected are kidney, urinary tract and bladder stones, leading to progressive kidney involvement and chronic kidney disease for most individuals. The disease course can lead to multi-organ damage from systemic oxalosis, affecting bones, eyes, blood vessels, heart, thyroid, skin, and other tissues. The main definitive therapy is a dual liver-kidney transplant with long-term immunosuppression, which is dependent on a suitable donor being found, carries substantial morbidity and mortality, and can be unavailable in developing country health systems for some of the populations that are most affected. Substantial need exists for therapies to treat PH1 without requiring liver transplantation
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