Deep phenotyping of a healthy human HAO1 knockout informs therapeutic development for primary hyperoxaluria type 1., bioRxiv, 2019-01-19
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder of oxalate metabolism leading to kidney failure as well as multi-organ damage. Overproduction of oxalate occurs in the liver due to an inherited genetic defect in the enzyme alanine-glyoxylate aminotransferase (AGXT), causing pathology due to the insolubility of calcium oxalate crystals in body fluids. The main current therapy is dual liver-kidney transplant, which incurs high morbidity and has poor availability in some health systems where PH1 is more prevalent. One approach currently in active clinical investigation targets HAO1 (hydroxyacid oxidase 1), encoding glycolate oxidase, to reduce substrate levels for oxalate production. To inform drug development, we sought individuals with reduced HAO1 function due to naturally occurring genetic variation. Analysis of loss of function variants in 141,456 sequenced individuals suggested individuals with complete HAO1 knockout would only be observed in 1 in 30 million outbred people. However in a large sequencing and health records program (Genes & Health), in populations with substantial autozygosity, we identified a healthy adult individual predicted to have complete knockout of HAO1 due to an ultra rare homozygous frameshift variant (rs1186715161, ENSP00000368066.3p.Leu333SerfsTer4). Primary care and hospital health records confirmed no apparently related clinical phenotype. At recall, urine and plasma oxalate levels were normal, however plasma glycolate levels (171 nmolmL) were 12 times the upper limit of normal in healthy, reference individuals (mean+2sd=14 nmolmL, n=67) while her urinary glycolate levels were 6 times the upper limit of normal. Comparison with preclinical and phase 1 clinical trial data of an RNAi therapeutic targeting HAO1 (lumasiran) suggests the individual likely retains <2% residual glycolate oxidase activity. These results provide important data to support the safety of HAO1 inhibition as a potential chronic therapy for a devastating metabolic disease (PH1). We also suggest that the effect of glycolate oxidase suppression in any potential other roles in humans beyond glycolate oxidation do not lead to clinical phenotypes, at least in this specific individual. This demonstrates the value of studying the lifelong complete knockdown of a target protein in a living human to aid development of a potential therapeutic, both in de-risking the approach and providing potential hypotheses to optimize its development. Furthermore, therapy for PH1 is likely to be required lifelong, in contrast to data from chronicity studies in non-human species or relatively short-term therapeutic studies in people. Our approach demonstrates the potential for improved drug discovery through unlocking relevant evidence hiding in the diversity of human genetic variation.
biorxiv genetics 0-100-users 2019Hunter-gatherer genomes reveal diverse demographic trajectories following the rise of farming in East Africa, bioRxiv, 2019-01-12
A major outstanding question in human prehistory is the fate of hunting and gathering populations following the rise of agriculture and pastoralism. Genomic analysis of ancient and contemporary Europeans suggests that autochthonous groups were either absorbed into or replaced by expanding farmer populations. Many of the hunter-gatherer populations persisting today live in Africa, perhaps because agropastoral transitions occurred later on the continent. Here, we present the first genomic data from the Chabu, a relatively isolated and marginalized hunting-and-gathering group from the Southwestern Ethiopian highlands. The Chabu are a distinct genetic population that carry the highest levels of Southwestern Ethiopian ancestry of any extant population studied thus far. This ancestry has been in situ for at least 4,500 years. We show that the Chabu are undergoing a severe population bottleneck which began around 40 generations ago. We also study other Eastern African populations and demonstrate divergent patterns of historical population size change over the past 60 generations between even closely related groups. We argue that these patterns demonstrate that, unlike in Europe, Africans hunter-gatherers responded to agropastoralism with diverse strategies.
biorxiv genetics 0-100-users 2019Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. Supplementary Methods And Results, bioRxiv, 2019-01-08
Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.
biorxiv genetics 100-200-users 2019