Drugs based on knockout genes are expected to trigger the need for companion diagnostic tests that will be performed by pathologists and medical laboratory scientists

Pharmaceutical companies and other research programs are developing a new opportunity to use information from human genome sequencing to create a new class of therapeutic drugs. These drugs target “knockout genes” and those same genes are expected to be used as diagnostic biomarkers for clinical laboratory testing as a new field of companion diagnostics emerges.

In simplest terms, large-scale DNA sequencing of the human genome is enabling researchers to identify individuals with “knockout” genes and then develop therapeutic drugs based on that knowledge.

The first commercial success story from this partnership of geneticists and the pharmaceutical industry is expected to be a new class of drugs that lowers cholesterol. These drugs may reach pharmacy shelves this year, reported an October 24 Nature article.

Identifying Rare Genetic Knockouts Could Lead to New Diagnostic Tools/Therapies

People missing a particular gene are known as “knockouts.” This is a term originally coined by scientists who inactivated, or “knocked out,” an existing gene in a laboratory mouse by replacing it or disrupting it with an artificial piece of DNA.

The development of powerful whole-genome sequencing platforms such as the Illumina HiSeq X Ten System—which can sequence a human genome in two hours and at a cost of less than $1,000 in consumables—is fueling the search for genetic outliers among healthy people.

A 2012 Science magazine study, showed that human genomes typically contain 100 genuine loss-of-function variants, and in 20 of those cases, both the maternal and paternal copies of the gene are missing, creating a knockout. Yet knockout mutations in any particular gene are so rare that large populations are needed to study them. Regeneron Pharmaceuticals, for example, has begun a five-year project to sequence the genomes of as many as 100,000 volunteers recruited from East Coast hospitals in order to identify rare genetic knockouts among them, Nature reports.

By uncovering how these mutations affect health, researchers expect to discover new biomedical treatments for disease. This is expected to also include new diagnostic tools (including medical laboratory tests), therapeutic drugs, and other therapies.

Experts Agree: Study of Human Knockout Genes Could Lead to Important Discoveries

MIT Technology Review Business Editor Antonio Regalado describes why large-scale genetic research eventually could supplant animal-based testing as the major model of human disease research. “Drug companies bet millions on drugs that cure animals or work in a lab dish,” he wrote in a November 19, 2014, feature article. “But 90% of drugs tested in human studies show no beneficial effect, or prove toxic. It’s guesswork at a staggering scale.”

Daniel MacArthur, Ph.D

Daniel MacArthur, Ph.D., a Group Leader at the Analytic and Translational Genetics Unit (ATGU) within the Department of Medicine at Harvard University in Boston, believes human “knockouts” will provide researchers with invaluable information. (Photo copyright ATGU.)

Daniel MacArthur, Ph.D., a Group Leader at the Analytic and Translational Genetics Unit (ATGU) within the Department of Medicine at Harvard Medical School in Boston, was lead author of the 2012 Science study that quantified how frequently genomes with knockouts occur. He predicts human knockouts will continue to provide researchers with invaluable information. “So much of what we know is based on mice and rats, and not humans,” MacArthur told Nature. “Now we can find people who actually have a particular gene inactivated and somehow modified, and that allows us to test hypotheses directly.”

Pharmaceutical Companies Capitalizing on Discoveries

The study of human knockouts already has paid dividends. For example,  scientists discovered a small number of people who were missing the gene known as PCSK9 had only tiny traces of low-density lipoprotein (LDL), or “bad” cholesterol, in their blood. Based on this discovery, pharmaceutical companies raced to create a drug that could mimic effects of the mutation.

Results from clinical trials of PCSK9-inhibiting drugs, suggests LDL cholesterol levels could be lowered by 57%. Amgen, Regeneron Pharmaceuticals, Roche, Alnylam Pharmaceuticals, and Pfizer are all looking to get a piece of what Nature in April 2013 estimated could be a $25 billion drug market.

In the 2013 Nature article, Elias Zerhouni, M.D., former director of the National Institutes of Health in Bethesda, Maryland, and an executive at the French drug firm Sanofi, is quoted as describing the development and discovery of PCSK9 as a “beautiful story” in which researchers combined detailed physical information about patients with shrewd genetics to identify a medically important gene that has made “super-fast” progress to the clinic. “Once you have it, boy, everything just lines up,” he stated.

Eric Topol, M.D., Director of the Scripps Translational Science Institute in La Jolla, California, believes the study of human knockout genes has the potential to unleash a barrage of new discoveries.

“I think there are hundreds more stories like PCSK9 out there, maybe even thousands,” in which a drug can mimic an advantageous loss-of-function mutation, Topol told Nature.

Eric Topol, M.D

Eric Topol, M.D., Director of the Scripps Translational Science Institute in La Jolla, California, believes the study of human knockout genes has the potential to unleash a barrage of new discoveries. (Photo copyright Scripps Translational Science Institute.)

Not all scientists, however, see an uninterrupted path from identifying human knockouts to the creation of blockbuster drugs or companion diagnostics to identify patients who would benefit from specific drugs.

Kári Stefánsson, M.D., is CEO of deCODE Genetics, an Icelandic genetics company that is building its own knockout catalog. “We couldn’t scan for these mutations before for a very simple reason,’ Stefánsson told MIT Technology Review. “Before, we didn’t have the data.” But he does not anticipate the discovery of the next PCSK9 to be quite so straightforward. “It’s not an argument without virtues,” he says, “but it’s an incredible simplification. Most of these scenarios are more complicated.”

Clinical Laboratories Could See New Companion Diagnostic Tests

The significance for pathologists is that the same molecular biomarker that works for a therapeutic drug can lead to medical laboratory tests that identify patients who would benefit from that therapeutic drug. Thus, this field of research may lead to more clinical laboratory tests—companion diagnostics—tied to the decision to prescribe specific prescription drugs.

—Andrea Downing Peck

Related Information:

The Search for Exceptional Genomes

Genetics: A Gene of Rare Effect

The Hunt for Missing Genes

Geneticists Tap Human Knockouts

It’s a Knockout

Whole Gene Sequencing for Diagnosis Is Goal of Beth Israel Deaconess Medical Center and GenomeQuest in a New Collaboration

Whole Human Gene Sequencing Technology Is Poised to Be the Next Big Thing for Clinical Pathology Laboratories