Decades of research on genetic mutations have had one overriding goal: to understand how specific mutations interfere with physiological processes and promote disease. Adrestia Therapeutics, a spin-out of the University of Cambridge in the UK, is taking a new tack. Rather than looking at how mutations cause illness, they are scouring the genome for mutations that keep people healthy despite a genetic predisposition to disease. The idea is that mutations that put an individual at high risk of developing a disease can be overridden by mutations elsewhere in the genome. This phenomenon, called ‘synthetic rescue’, holds out the tantalizing possibility of providing an entirely new strategy for discovering therapeutic targets and drugs.

Genes do not act in isolation, but form nodes in a vast network. Some can regulate the activity of other genes that act downstream in a particular pathway whereas others might serve redundant functions and thus act as a buffer against the damaging effects of mutations in other genes.

Adrestia co-founder Steve Jackson, a cancer biologist at the University of Cambridge, is interested in finding ways to exploit these network effects for therapeutic benefit. Previously he focused on discovering ‘synthetic lethal’ interactions. These are secondary gene mutations that are deadly to cells only when combined with other — in his case, cancer-causing — mutations. A previous startup that Jackson launched, KuDOS Pharmaceuticals, applied this approach to develop a drug called olaparib, which sabotages a DNA repair mechanism that cancer cells with particular driver mutations rely on for survival. AstraZeneca acquired KuDOS in 2006 and has subsequently shepherded olaparib into the clinic as a treatment for multiple cancer indications.

Steve Jackson, co-founder Adrestia Therapeutics

The synthetic rescue interactions sought by Adrestia represent the flip side of the coin: genes that, when disabled, buffer the detrimental effects of other gene mutations. Jackson’s academic team has described at least one example of this kind of interaction, in which mutations in the USP48 gene mitigate the pathological effects of gene mutations that cause the blood disease Fanconi’s anemia, which commonly gives rise to leukemia. He notes that studies by others in large patient cohorts have identified individuals that are surprisingly ‘resilient’ against the otherwise-detrimental effects of known disease mutations. “These patients probably have variants in their genetic background in modifier genes,” says Jackson.

The possibility of discovering and drugging those modifier genes led Jackson to launch Adrestia in 2017, in partnership with Cambridge colleagues Gabriel Balmus and Yaron Galanty, Delphine Larrieu of the Cambridge Institute for Medical Research, Raphaël Rodriguez at the Institut Curie in Paris and Rafael Carazo Salas, now at the University of Bristol. Three years later, the company would draw series A funding from Ahren Innovation Capital and GlaxoSmithKline (GSK), the latter of which is collaborating with Adrestia on up to 5 programs, with the promise of $230 million in milestone payments per successful program. GSK is also working in close collaboration with Adrestia on multiple drug development programs. “They are a super partner,” says CEO Robert Johnson. “And I think GSK, like many companies in the industry, are struggling to find high-quality validated targets.”

Rob Johnson, CEO Adrestia Therapeutics.

The core of Adrestia’s strategy is high-throughput screening — taking human cells carrying a known disease-causing gene mutation, systematically perturbing other sites in the genome and observing the phenotypic outcome. The details of this process can vary depending on the disease; in some cases, the company might use patient-derived induced pluripotent stem cells, whereas other projects might use CRISPR-based genome manipulation to inactivate a gene or introduce selected point mutations. But the key question is always the same, says Jackson: “Which of the 20,000 human genes will allow you to modulate that phenotype in the right direction?” He adds that the methods themselves are not the key ingredient here, but rather the experience and knowhow of a research team with many years of gene network research.

Jolanda van Leeuwen, a functional genomics researcher at the University of Lausanne in Switzerland, sees promise in this approach based on her own large-scale analyses of gene–gene interactions that enable synthetic rescue. For example, her group has repeatedly shown that the loss of many so-called essential genes in yeast and human cells can be countered by secondary mutations in ‘suppressor’ genes. “It is still so surprising to me how common this is,” says van Leeuwen. The work to date in this field leads her to suspect that “for almost every disease allele in humans, there must be a way to ameliorate the disease.”

Adrestia is also planning to bolster their screening results with complementary data from large patient cohorts and resources like the UK Biobank, which contains clinical and genomic data from half a million individuals. Showing that people possessing rescue mutations exist in these populations could provide evidence for the safety of targeting those genes therapeutically.

These cohort data could even offer direct, real-world confirmation that these apparent rescue mutations mitigate the effects of other disease-causing mutations. However, van Leeuwen cautions that the complexity of the genome can confound the interpretation of these results. “You can identify a suppressor in one patient population or cell line,” she says, “but it may not actually work as a suppressor in different genetic backgrounds.” Thus, extensive validation in a variety of animal models and other experimental systems will also be essential.

The company is also building out its computational capabilities and recently brought on board John Perry — Jackson’s colleague and long-time collaborator at Cambridge — as VP of human genetics. Among Perry’s tasks will be building out the analytical capabilities needed to sift through tremendous amounts of experimental and human data. “We’re delving into datasets in a more systematic way now,” says Jackson.

The company has yet to announce its clinical pipeline, but has disclosed exploratory research in areas including cardiac disease and Huntington’s disease. For the latter indication, Adrestia is working closely with Cambridge and University College London researchers to develop strategies for inducing protection against the inevitable neurodegenerative decline experienced by patients with Huntington’s disease. The idea would be to find genetic modifiers to counter the effect of the loss of DNA repair mechanisms in Huntington’s disease that leads to the expansion of triplet repeats.

Johnson believes their approach should be suitable for identifying targets in many disorders and tissue types. “We've done nearly 30 screens, and all of them have identified at least one target that could be druggable with a small molecule,” he says. “And furthermore, none of the targets that have been identified by the screens have yet failed in validation.” His ultimate vision is for Adrestia to grow into a fully integrated drug company, covering the entire spectrum of pharmaceutical development from target discovery to drug manufacturing. In the nearer term, partnerships are likely to be critical to make the most of the company’s approach, and talks are currently underway with a number of potential industry partners in addition to GSK.

But Jackson is excited about the discovery opportunities, including the opportunity to find hidden threads that contribute to the pathology of multiple disease states. This information could in turn dramatically accelerate the discovery of more broadly useful drugs, as well as the repurposing of existing agents that might offer previously unrecognized value for other conditions. “Each disease is distinct, but we're already seeing crossover between the hits that we're getting,” he says. “I think an ultimate direction of travel is generating a ‘synthetic rescue atlas’, which would be a network model that would allow one to discover these connections in a more systematic way.”