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Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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Maze Therapeutics Uses CRISPR to Identify Genetic Modifiers That Could Lead to Precision Medicine Companion Diagnostics for Clinical Laboratories

With $191 million in startup capital, the genomics startup will draw on existing genetic databases to create personalized medicine therapies for chronic diseases

Why do some people get sick while others do not? That’s what genetic researchers at Maze Therapeutics want to find out. They have developed a new approach to using tools such as CRISPR gene editing to identify and manipulate proteins in genetic code that may be the key to providing personalized protection against specific diseases.

If viable, the results of Maze’s research could mean the development of specific drugs designed to mimic genetic code in a way that is uniquely therapeutic to specific patients. This also would create the need for clinical laboratories to sequence and analyze patients’ DNA to determine whether a patient would be a candidate for any new therapies that come from this line of research.

Such developments are at the heart of precision medicine. It promises to bring companion diagnostics to clinical laboratories that will help anatomic pathologists employ disease therapies keyed to each patient’s unique physiology.

Natural Protection Against Disease

Based in San Francisco, Maze Therapeutics (Maze) is studying modifier genes—genes that affect the phenotype or physical properties of other genes—and attempting to create drugs that replicate them, reported MIT Technology Review. Maze believes that genetic modifiers could afford a “natural form of protection” against disease.

“If you have a disease-causing gene, and I have the disease-causing gene, why is it that you may be healthy and I may be sick? Are there other genes that come into play that provide a protective effect? Is there a drugging strategy to recover normal phenotype and recover from the illness?” Maze Chief Executive Officer Jason Coloma, PhD, asked in an interview with FierceBiotech.

In 2019, Maze received $191 million in financing from Third Rock Ventures, ARCH Venture Partners, and others, to find ways to translate their findings into personalized medicines, according to a news release. And with the availability of international public genetic databases and CRISPR gene editing, now may be good timing.

“This was the perfect time to get into this space with the tools that were being developed and the amount of data that has been accumulated on the human genetic side,” Charles Homcy, MD, Third Rock Ventures Partner and Maze Scientific Founder, told Forbes, which noted that Maze is tapping existing population-wide genetic databases and large-scale studies, including the United Kingdom’s Biobank and Finland’s Finngen.

To help find genetic modifier drug targets, Maze is accessing CRISPR gene editing capabilities. Jonathan Weissman, PhD, Maze Scientific Founder and Professor of Cellular Molecular Pharmacology at University of California, San Francisco (UCSF), told MIT Technology Review: “You take a cell with a disease-causing gene and then see if you can turn it back to normal. We can do 100,000 experiments at once because each cell is its own experiment.”

“At Maze, we are focused on expanding our understanding of the natural disease protection provided by genetic modifiers through an integrated approach that combines studying natural human genetic variation across the globe and conducting large-scale experiments of gene perturbations,” Charles Homcy, MD (above), Founder and interim CEO of Maze and a partner at Third Rock Ventures, said in a news release. “Through our integrated approach, we believe we will create novel medicines based around those modifiers to treat a number of diseases.” (Photo copyright: Forbes.)

Using CRISPR to Identify the Cause of Disease

One drug research program reportedly progressing at Maze involves developing gene therapy for the neurogenerative disease amyotrophic lateral sclerosis (ALS). The program borrows from previous research conducted by Aaron Gitler, PhD, Professor of Genetics at Stanford University and Maze co-founder, which used CRISPR to find genetic modifiers of ALS. The scientists found that when they removed the protein coding gene TMX2 (Thioredoxin Related Transmembrane Protein 2), the toxicity of proteins building the disease was reduced, reported Chemical and Engineering News.

“We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells,” Gitler and colleagues wrote in Nature Genetics. “Together, our results demonstrate the promise of using CRISPR-Cas9 screens in defining the mechanisms of neurodegenerative diseases.”

In 2020, Maze plans to advance elements of its ALS research to a Food and Drug Administration Investigational New Drug (IND) application. Maze also intends to work next year on drugs targeting metabolism, kidney, and glaucoma, FierceBiotech reported.

“We have the flexibility to think differently. We like to think of ourselves as part of this new breed of biotech companies,” Coloma told FierceBiotech.

It’s an exciting time. Clinical laboratories can look forward to new precision medicine diagnostic tests to detect disease and monitor the effects of patient therapies. And the research initiatives by Maze and other genetic companies represent a new approach in the use of genetic code to create specific drug therapies targeted at specific diseases that work best for specific patients.

The companion diagnostics that may come from this research would be a boon to anatomic pathology.

—Donna Marie Pocius

Related Information:

The Secret to a New Drug Could be Hiding in Your Genes: Companies are Searching Gene Databases for People Whose DNA Says They Should be Very Sick, But Who Aren’t

Special Report: Maze Therapeutics

Maze Therapeutics Launches with $191 Million to Focus on Translating Genetic Insights into New Medicines

Third Rock and ARCH-Backed Genetics Startup Launches with Nearly $200 Million

Maze Therapeutics Raises $191 Million

CRISPR Screen Identifies Genetic Modifiers of ALS

CRISPR-Cas9 Screens in Human Cells and Primary Neurons Identify Modifiers of C90RF72 Dipeptide-Repeat-Protect Toxicity

Targeted Cancer Therapies Bring New Precision Medicine Tools to Anatomic Pathologists and Clinical Laboratories

FDA is streamlining how new diagnostic tests are approved; encourages IVD companies to focus on ‘qualifying biomarkers’ in development of new cancer drugs

It is good news for the anatomic pathology profession that new insights into the human immune system are triggering not only a wave of new therapeutic drugs, but also the need for companion diagnostic tests that help physicians decide when it is appropriate to prescribe immunotherapy drugs.

Rapid advances in precision medicine, and the discovery that a patient’s own immune system can be used to suppress chronic disease, have motivated pharmaceutical companies to pursue new research into creating targeted therapies for cancer patients. These therapies are based on a patient’s physiological condition at the time of diagnosis. This is the very definition of precision medicine and it is changing how oncologists, anatomic pathologists, and medical laboratories diagnose and treat cancer and other chronic diseases.

Since immunotherapy drugs require companion diagnostic tests, in vitro diagnostic (IVD) developers and clinical laboratory and pathology group leaders understand the stake they have in pharma companies devoting more research to developing these types of drugs.

New cancer drugs combined with targeted therapies would directly impact the future of anatomic pathology and medical laboratory testing.

Targeted Therapies Cost Less, Work Better

Targeted therapies focus on the mechanisms driving the cancer, rather than on destroying the cancer itself. They are designed to treat cancers that have specific genetic signatures.

One such example of a targeted therapy is pembrolizumab (brand name: Keytruda), a humanized antibody that targets the programmed cell death 1 (PD-1) receptor. The injection drug was primarily designed to treat melanoma. However, the FDA recently expanded its approval of Keytruda to include treatment of tumors with certain genetic qualities, regardless of the tumor’s location in the body. It was the first time the FDA has expanded an existing approval.

In a Forbes article, David Shaywitz, MD, PhD, noted that pembrolizumab had “an unprecedented type of FDA approval … authorizing its use in a wide range of cancers.” Shaywitz is Chief Medical Officer of DNAnexus in Mountain View, Calif.; Visiting Scientist, Department of Biomedical Informatics at Harvard Medical School; and Adjunct Scholar, American Enterprise Institute.

Cancers with high mutational burdens respond to the therapy because they are more likely to have what Shaywitz calls “recognizable novel antigens called mutation-associated neoantigens, or MANAs.” Such cancers include melanomas, non-small cell lung cancer, some rare forms of colorectal cancers, and others.

Such therapies require genetic sequencing, and because sequencing is becoming faster and less expensive—as is the analysis of the sequencing—the information necessary to develop targeted therapies is becoming more accessible, which is part of what’s motivating pharma research.

Biomarkers and Traditional versus Modern Drug Testing and Development

At the same time pharma is developing new immunotherapies, the FDA is recognizing the benefit of faster approvals. In an FDA Voice blog post, Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research (CDER) at the FDA, wrote, “In the past three years alone, [we have] approved more than 25 new drugs that benefit patients with specific genetic characteristics … and we have approved many more new uses—also based on specific genetic characteristics—for drugs already on the market.”

In his Forbes article, Shaywitz notes that pembrolizumab’s development foreshadows a “More general trend in the industry,” where the traditional phases of drug testing and development in oncology are becoming less clear and distinct.

Along with the changes to drug development and approval that precision medicine is bringing about, there are also likely to be changes in how cancer patients are tested. For one thing, biomarkers are critical for precision medicine.

However, pharmaceutical companies have not always favored using biomarkers. According to Shaywitz, “In general, commercial teams tend not to favor biomarkers and seek to avoid them wherever possible.” And that, “All things being equal, a doctor would prefer to prescribe a drug immediately, without waiting for a test to be ordered and the results received and interpreted.”

In July, just weeks after expanding its approval for Keytruda, the FDA approved a Thermo Fisher Scientific test called the Oncomine Dx Target Test. A Wired article describes it as “the first next-generation-sequencing-based test” and notes that it “takes a tiny amount of tumor tissue and reports on alterations to 23 different genes.”

Thermo Fisher’s Oncomine DX Target Test (above) is the first multi-drug next-generation sequencing test approved by the FDA. The test is a companion diagnostic for lung-cancer drugs made by Novartis and Pfizer. (Caption and photo copyright: Thermo Fisher Scientific.)

Unlike pembrolizumab, however, the Oncomine Dx Target Test did not enjoy fast-track approval. As Wired reported, “Getting the FDA’s approval took nearly two years and 220,000 pages of data,” in large part because it was the first test to include multiple genes and multiple drugs. Thus, according to Joydeep Goswami, PhD, President of Clinical Next Generation Sequencing at Thermo Fisher, “That put the technology under extraordinary scrutiny.”

FDA Encouraging Use of Biomarkers in Precision Medicine Therapies

The FDA, however, is taking steps to make that process easier. Woodcock noted in her FDA Voice blog post that the agency is actively encouraging drug developers to “use strategies based on biomarkers.” She added that the FDA currently “works with stakeholders and scientific consortia in qualifying biomarkers that can be used in the development of many drugs.”

Additionally, in a column he penned for Wired, Robert M. Califf, MD, former Commissioner of the FDA, states that the organization has “begun to lay out a flexible roadmap for regulatory approval.” He notes, “Given the complexity of NGS [next-generation-sequencing] technology, test developers need assurance as well, and we’ve tried to reduce uncertainty in the process.”

Regulations that assist IVD developers create viable diagnostics, while ensuring the tests are accurate and valid, will be nearly as important in the age of precision medicine as the therapies themselves.

All of these developmental and regulatory changes will impact the work done by pathologists and medical laboratories. And since precision medicine means finding the right drug for the individual patient, then monitoring its progress, all of the necessary tests will be conducted by clinical laboratories.

Faster approvals for these new drugs and tests will likely mean steep learning curves for pathologists. But if the streamlined regulation process being considered by the FDA works, new immunoassay tests and targeted therapies could mean improved outcomes for cancer patients.

—Dava Stewart

Related Information:

How Precision Medicine, Immunotherapy Are Influencing Clinical Trial Design for Cancer Drugs

Pharma Cooperates to Achieve Precision Medicine

The Startling History Behind Merck’s New Cancer Blockbuster

Two Recent Scientific Advances Underscore an Encouraging Future for Precision Medicine at FDA

Fast, Precise Cancer Care Is Coming to a Hospital Near You

Biomarker Trends Are Auspicious for Pathologists and Clinical Laboratories

Precision Healthcare Milestone Reached as Food and Drug Administration Clears New Multi-Marker Medical Laboratory Test to Detect Antibiotic-Resistant Bacteria

Genetic Tests and Precision Medicine Start to Win Acceptance by Some Payers; Pathologists and Clinical Laboratories Have Opportunity as Advisors

University of Texas Researchers Develop New Techniques in Genetic Testing to Improve Clinical Laboratory Results through RNA

Innovative technological advances could potentially provide clinical laboratories, pathology groups, and medical researchers with improved methodologies for designing, performing, and analyzing lab tests that use genetic information

Researchers at the University of Texas at Austin (UT Austin) have developed an innovative new enzyme that promises to improve the methods and tools used by pathology groups and clinical laboratories when conducting genetic testing.

The enzyme enables the reproduction of large quantities of Ribonucleic acid (RNA) to be accurately duplicated. It also can perform reverse transcription and scrutinize itself while copying genetic information, which will enable both researchers and clinical laboratories to improve the accuracy of gene sequencing where RNA is involved.

The team published their findings in Science, the academic journal of The American Association for the Advancement of Science (AAAS) and filed for a provisional patent for the new sequence of the discovered enzyme. (more…)

Pathologists and Physicians in United Kingdom Comment on How Shortage of Medical Laboratory Professionals Could Soon Delay Essential Diagnostic, Therapeutic Testing

As chronic disease and aging populations strain the UK’s medical systems, staffing shortages at pathology laboratories contribute to lengthening delays of critical diagnostic services

In the United Kingdom (UK), pathologists and other physicians are going public with their concerns that a growing shortage of pathologists and medical laboratory scientists will soon contribute to delays in performing the lab tests needed to diagnose patients—particularly those with cancer—and identify which therapies will work best for them.

Thanks to vast improvements to both medical laboratory capabilities and treatment options, the cancer survival rate in the UK doubled over the past four decades. However, early diagnosis is a critical component to a successful outcome. As further strain is placed on medical laboratories and diagnostic providers, wait times continue to increase beyond the thresholds created by the UK’s National Health Service (NHS).

Worsening an already dire situation, a November 2016 report from Cancer Research UK, “Testing Times to Come? An Evaluation of Pathology Capacity Across the UK,” predicts a critical shortage in laboratory staffing within the next decade. Data on Provider-based Cancer Waiting Times for August 2016 from National Health Service England shows that 17.2% of patients with an urgent referral for suspected cancer fail to start treatment within two months of the referral. (more…)

Molecular Information Management Systems (MIMS) Are Newest Tools to Help Clinical Laboratories Perform and Report Molecular and Genetic Test Results

Some experts consider MIMS to be the classic LIS on steroids because they are designed to handle the vast amounts of data generated by the latest generation of genetic tests

Steady improvements to next-generation genetic sequencing, lab-on-a-chip technologies, and lab automation are triggering substantial increases in the volume of data generated at medical laboratories and pathology groups. The future of personalized medicine lies just as much in the analysis of the data generated by these tests as it does in how labs perform these procedures.

Laboratory Information Systems (LIS) help to manage and organize much of this data. However, over the past decade, the volume of data generated by molecular and genetic testing has outpaced the organization, reporting, and interfacing features of popular LISs. With more than 3-billion base pairs of DNA in the human genome, each sample analysis has the potential to generate huge amounts of data. (more…)

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