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Unicorn startup trawls databases for protective genetic modifers Startup aims to identify disease modifying genes in people with milder than expected phenotypes as starting points for drug discovery programs.

fter two-and-a-half years in stealth mode, Maze Therapeutics unveiled a A$191 million series A funding round and a stellar line-up of scientists who aim to discover new biology and new drug targets by systematically mining human genetic databases for genetic modifiers that reduce the impact of disease-causing mutations. The company is, at the same time, establishing a functional genomics platform to study the phenotypic consequences of disrupting the genome. Combining these two types of data will, it hopes, lead to new insights into disease biology that can be translated into starting points for drug discovery programs. The general concept is not new, but Maze’s founding team and its backers hold that this is an opportune time to pursue such a strategy at scale because of the simultaneous availability of large volumes of human genomic and associated clinical data and the tools and technologies for conducting detailed phenotypic analyses. The hunt for such genetic exceptions At DeCode in Reykjavik, blood samples from Icelanders are stored for genetic testing. Credit: dpa picture came to prominence in 2016 when a group alliance / Alamy Stock Photo of researchers—headed by Stephen Friend, founder of Sage Bionetworks, and Eric Schadt of Mount Sinai under the collective the other 3.199 billion base pairs in your forms the basis of gene editing programs umbrella of the Resilience Project— genome are irrelevant to your disease,” underway at CRISPR Therapeutics and announced they had identified 13 people says Nicholas Katsanis, professor of cell Sangamo Biosciences. Each firm has who should have had serious childhood biology at Duke University. However, some disrupted the gene encoding BCL11A, a diseases, but didn’t (Nat. Biotechnol. 34, protective variants may only operate within transcriptional repressor of fetal hemoglobin 531–538, 2016). The study confirmed why, very specific genetic contexts. “One question production, which normally switches on in human monogenic disorders, individuals is whether the effects seen are sufficiently as soon as the adult form of hemoglobin with the same disease-causing variant often generalizable to be captured in a drug starts to be produced in early childhood. have a different course of disease, in terms of therapy,” says Stephen Friend, now professor Understanding the underlying biology has time of onset or degree of severity, because of connected medicine at Oxford University. opened up an additional—and potentially modifiers can alter the disease phenotype. Several firms are already developing more easily druggable—route to achieving The very term ‘monogenic disorder’ is therapies based on well-known genetic the same effect. A group at the University actually a gross simplification of what is modifiers. For instance, fetal hemoglobin of Pennsylvania recently identified a invariably a far more complex picture. “The expressed in adulthood is known to have a translational repressor of fetal hemoglobin moment that we say that one mutation is protective effect in sickle cell disease and using a CRISPR–Cas9 screen to knock the cause of your disease, we’re saying that in some forms of β-thalassemia; as such, it out 482 kinase domains in turn from a

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Table 1 | Selected population genetics initiatives Project (year Goal Funders Partners, participants established) DeCode Genetics, DeCode has whole-genome sequence Amgen SomaLogic a subsidiary of data on about 15% of Iceland’s population Amgen (1996) and genotype data from about 50%, which it combines with clinical and genealogical data from Iceland and open-source data from around the globe for biological discovery China Kadoorie Blood samples collected from over Kadoorie Charitable Foundation, Chinese Academy of Medical Sciences, Biobank (2004) 510,000 individuals from 2004–2008; Wellcome Trust, Chinese Natural Science Oxford University analyses combined with clinical and Foundation, Chinese Ministry of Science mortality data, as well as biological data and Technology, British Heart Foundation, from periodic follow-up studies Cancer Research UK UK Biobank (2006) Prospective cohort study involving Medical Research Council, Wellcome Trust Regeneron is leading exome sequencing, collection and analysis of genetic, with support from AbbVie, Alnylam physical and health data on 500,000 Pharmaceuticals, AstraZeneca, , people aged 40–69 at time of GlaxoSmithKline and ; data are recruitment available to 10,000 approved industry and academic researchers Million Veteran Collecting blood samples, health, military US Department of Veterans Affairs Office Veterans Affairs-affiliated researchers Program (2009) experience and lifestyle information from of Research & Development one million US military veterans to study the genetic factors that influence health Regeneron Genetics Has sequenced 400,000 exomes of Regeneron Pharmaceutica Geisinger Health System, US National Center (2014) 500,000-exome target; combining Institutes of Health, academic medical genetic data with electronic health centers record data Genomics Medicine Combining medical and health data with Arch Venture Partners, Ireland Strategic AbbVie, University College Dublin, Ireland (Dublin), sequence data from 400,000 genomes Investment Initiative, Polaris Partners, University of Cambridge, hospitals in a subsidiary of (>10,000 completed so far); studies in Temasek Holdings, Yunfeng Capital, Ireland and Northern Ireland, UK WuXi NextCode rare and chronic diseases ongoing Sequoia Capital (Shanghai) (2015) All of Us (formerly Building a research database containing US National Institutes of Health; US Accredited academic and industry Precision Medicine biological, physiological, environmental National Cancer Institute researchers, as well as interested Initiative Cohort and health data from over one million citizen scientists, will have access to a Program) (2016) people who reflect the diversity of research portal the US population Kaiser Permanente Aims to collect biological samples from Kaiser Permanante Kaiser Permanante and accredited Research Bank 500,000 members, which it will combine researchers (2016) with electronic health records, lifestyle and environmental data FinnGen (2017) The University of Helsinki is responsible Business Finland, industry partners AbbVie, AstraZeneca (Cambridge, for the study, which involves the collection UK), Biogen, Celgene, , of genome and longitudinal clinical GlaxoSmithKline (London), Merck, Sanofi data from 500,000 individuals through (Paris), Pfizer a nationwide network of biobanks, universities and hospitals

Sources: organization websites, PubMed human cell line that expresses high levels and MIT, and Harvard Medical School, a number of addressable targets that can of adult hemoglobin and low levels of fetal points to the work of his Harvard and delay or accelerate disease onset. “The genes hemoglobin (Science 361, 285–290, 2018). Massachusetts General colleague James are basically involved in repair of DNA,” Their screen uncovered an erythroid- Gusella in identifying genetic factors says Kathiresan. specific kinase, called heme-regulated that alter the age of onset of Huntington’s Maze is agnostic both in terms of inhibitor, that is required to produce the disease as “an example of how all this therapeutic modality and in terms of BCL11A repressor. might work.” The CAG trinucleotide repeats therapeutic focus. It already has discovery Maze cofounder Sekar Kathiresan, in the gene encoding huntingtin protein programs underway in rare metabolic, who holds posts at Massachusetts General cause the condition but are not easily neurodegenerative and kidney diseases, Hospital, the Broad Institute of Harvard druggable. Instead, Gusella has identified based on known genetic effects. Whether

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Maze’s approach is distinctive is debatable. motor function in a TDP-43-based mouse Regeneron,” says Aris Baras, senior vice “The basic notion that it is something model of ALS. Although Maze is not president at the biotech firm and head of the different to go after modifiers is a bit funny,” commenting publicly on the question, it Regeneron Genetics Center. Not only has says Kári Stefánsson, the CEO and founder represents an obvious drug target for the it led to a flood of new discoveries—about of Reykjavik, Iceland-based DeCode company to pursue. 50 novel findings have already advanced Genetics, who pioneered the use of large- into formal target biology programs—it scale human genetic studies to unlock new Some genetic fndings are has deepened the company’s biological biology. Everyone is looking for genetic so obvious and compelling understanding of ongoing clinical programs, variants that affect disease phenotypes, he such as those targeting interleukin-33 in says. “You use exactly the same approach, that they are immediately autoimmune disease and angiopoietin- no matter whether you’re looking for translated into a drug like 3 in familial hypercholesterolemia. major genes or genes that have a more In addition, some genetic findings are subtle influence.” Kathiresan counters that discovery program. so obvious and compelling that they Maze’s focus on seeking protective factors are immediately translated into a drug in populations carrying risk mutations is In parallel with its early development discovery program. “We do have a handful distinctive. “Most of the work to date has programs, Maze is also embarking on of those,” Baras says. They include programs been just searching for protection in the a large-scale genetics discovery effort. in diabetes–obesity–metabolism and in general population.” In contrast to DeCode (now owned by glaucoma, as well as a publicly disclosed In studying individuals carrying disease- Amgen; Nat. Biotechnol. 31, 87–88, 2013) finding in chronic liver disease. Regeneron causing variants who have milder than and Regeneron Pharmaceuticals, which has scientists and academic colleagues reported expected phenotypes, the challenge for also made a big bet on genetics-powered last year on a loss-of-function mutation Maze will be to develop analyses that have discovery research (Nat. Biotechnol. 32, in the gene encoding hydroxysteroid 17-β sufficient statistical power to detect rare but 208–209, 2014), Maze will not build its dehydrogenase 13 (HSD17B13), which, high-impact genetic variants in relatively own genomics database but will tap into Baras says, “substantially” modifies the small populations. “Variants with large multiple open data sources. The Maze risk associated with a variant of PNPLA3, effects usually turn out to be rare,” says team of scientific founders includes the best known genetic risk factor for Stefánsson. “You need a disease cohort and another influential geneticist, Mark Daly fatty liver disease. It has entered a drug a replication cohort,” says Katsanis, who has of the Broad Institute and the Helsinki- development collaboration with Alnylam also established a start-up that is looking based Institute for Molecular Medicine Pharmaceuticals in a bid to replicate for novel drug targets based on genetic Finland, who is one of the architects of the the effect in an RNA interference drug. modifiers. His firm remains in stealth mode, FinnGen project. The FinnGen initiative Stefánsson says that DeCode is “generating but it is progressing two small-molecule launched in 2017 and has already attracted an avalanche of discovery” by layering RNA drug assets in undisclosed indications. widespread industry involvement because sequence and proteomics data on top of “We’re hoping to go into early clinical trials of its rich dataset, based on longitudinal the genomic information it already has. But in a year or two,” he says. Katsanis’s venture data stretching back 50 years, and because there is plenty of room for other players to differs from Maze in focusing primarily on of the relative homogeneity of Finland’s participate in the task of understanding the phenotypic analysis of model systems, such population. “Being a founder population, genetic contribution to complex disease. as zebrafish, mice and cell lines, rather than it is enriched for higher frequencies of “We have miles to go,” he says. ❐ genotypic analysis of large genetic datasets. many functional genetic variants that can “Had we gone through a purely statistical offer insights for many genes that could Cormac Sheridan approach we would have arrived at precisely not be detected in other populations,” Dublin, Ireland nothing,” he says. Amsterdam-based Scenic states Matthew Nelson, head of genetics at Biotech is also taking a functional genomics London-based GlaxoSmithKline. Published online: 5 April 2019 approach, screening libraries of human The UK Biobank is the most advanced https://doi.org/10.1038/d41587-019-00010-x haploid cell lines that have undergone initiative, having, as Kathiresan and random mutagenesis. co-author Kiran Musunuru of the “If you can’t fnd a better use of R&D dollars Kathiresan notes that Maze can pursue University of Pennsylvania note in a recent than running another phase 3 beta-amyloid either phenotype- or genomics-driven review, already made “genetic and clinical antibody study, then you should not be doing R&D at all.” Baird analyst Brian Skorney wrote approaches. Indeed, another scientific phenotype data from ~500,000 participants a memo to investors after the colossal failure of yet cofounder, Aaron Gitler, of Stanford available to any interested researchers.” another amyloid targeting antibody, this time Biogen’s University, and colleagues, identified Other sources coming on stream, they note, ‘‘aducanumab. (STAT, 1 April 2019) ataxin-2 as a modifier of TDP-43-mediated include the Million Veteran Program, run amyotrophic lateral sclerosis by conducting by the US Department of Veterans Affairs, “2019 is the year when the training wheels come an unbiased screen in yeast followed by the China Kadoorie Biobank, and the All of of and the world gets to see what CRISPR can really do for the world in the most positive sense.” mouse genetics studies. TDP-43 (transactive Us Research Program from the US National Fyodor Urnov, a gene-editing scientist at the Altius response DNA-binding protein 43 Institute of Health’s Precision Medicine Institute for Biomedical Sciences and the University of kilodaltons), a DNA- and RNA-binding Initiative. Numerous other national California, Berkeley. (NPR Shots, 16 April 2019) protein normally found in the nucleus, and private healthcare genetics research forms cytoplasmic aggregates in the brains initiatives are underway, with varying “We have to fnd a way to take CO2 out of the of most patients with ALS, but it is not easily degrees of industry involvement (Table 1). atmosphere, and I think plants are the only way to do that afordably. I feel like I have the weight of the druggable because of its key roles in RNA For some firms, genetics-powered world on my shoulders.” The Salk Institute’s Joanne processing. Ataxin-2 reduction—achieved discovery is no longer a toe-in-the-water Chory is breeding plants with higher levels of suberin, either through gene knockouts or antisense experiment. “It has become an absolutely a naturally occurring CO2 binder, in their roots. oligonucleotides—improves survival and core approach to how we do R&D at (The Guardian, 16 April 2019) Nature Biotechnology | VOL 37 | MAY 2019 | 487–496 | www.nature.com/naturebiotechnology ’’489