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University of Warwick Researchers Identity Blood Protein Biomarkers That Can Predict Dementia Onset Years in Advance

With further study, this research may provide clinical laboratories with a new proteomic biomarker for dementia screenings that identifies risk more than 10 years before symptoms appear

Researchers at the University of Warwick in the UK and Fudan University in Shanghai, China, identified four protein biomarkers in blood that they say can predict dementia up to 15 years before diagnosis. They say these biomarkers may lead to clinical laboratory blood tests that offer alternatives to costly brain scans and lumbar punctures for diagnosis of dementia.

The scientists “used the largest cohort of blood proteomics and dementia to date,” according to a University of Warwick news release. This included taking blood from 52,645 “healthy” people without dementia who participated in the UK Biobank—a population-based study cohort, the new release noted.

“The proteomic biomarkers are [easy] to access and non-invasive, and they can substantially facilitate the application of large-scale population screening,” said neurovegetative disease specialist Jin-tai Yu, MD, PhD, a professor at Fudan University and co-author of the study, in the news release.

The scientists published their findings in the journal Nature Aging titled, “Plasma Proteomic Profiles Predict Future Dementia in Healthy Adults.”

“The advent of proteomics offers an unprecedented opportunity to predict dementia onset,” the researchers wrote.

“This is a well-conducted study that adds to what we know about changes in blood that occur very early in diseases that cause dementia, which will be important for early diagnosis in the future,” said Tara Spires-Jones, PhD, in a post from the Science Media Center in the UK. “However,” she added, “it is important to note that these are still scientific research studies and that there are currently no blood tests available for routine use that can diagnose dementia with certainty.

Jones, who was not involved in the study, is President of the British Neuroscience Association (BNA) and group leader of the UK Dementia Research Institute at the University of Edinburgh.

“Based on this study, it does seem likely that blood tests will be developed that can predict risk for developing dementia over the next 10 years, although individuals at higher risk often have difficulty knowing how to respond,” Suzanne Schindler, MD, PhD (above), told Reuters. Schindler, an Associate Professor of Neurology at Washington University in St. Louis, was not involved in the research. Clinical laboratories may soon have a new blood test for dementia. (Photo copyright: VJDementia.)

Predicting Onset of Dementia with 90% Accuracy

The researchers analyzed 52,645 blood samples from the UK Biobank (UKBB). The samples were collected between 2006 and 2010 from healthy individuals who at that time were without dementia.

By March 2023, 1,417 of the study participants had developed Alzheimer’s disease or some other form of dementia. The researchers looked at 1,463 proteins and identified four that were present in high levels among those people:

“Individuals with higher GFAP levels were 2.32 times more likely to develop dementia,” the researchers wrote in Nature Aging. “Notably, GFAP and LTBP2 were highly specific for dementia prediction. GFAP and NEFL began to change at least 10 years before dementia diagnosis.”

When adding known risk factors such as age, sex, and genetics, the researchers said they could predict onset of dementia with 90% accuracy, according to the University of Warwick news release.

“Our findings strongly highlight GFAP as an optimal biomarker for dementia prediction, even more than 10 years before the diagnosis, with implications for screening people at high risk for dementia and for early intervention,” the researchers wrote.

The news release also noted that smaller studies had already identified some of the proteins as potential biomarkers, “but this new research was much larger and conducted over several years.”

Further Validation Needed

Amanda Heslegrave, PhD, of the UK Dementia Research Institute, University College London described the UKBB as “an excellent resource” in the Science Media Center (SMC) post. However, she noted, it’s “a highly curated biobank and may not capture all populations that we need to know the risk for. The new biomarkers identified will need further validation before being used as screening tools.”

Another expert raised additional questions about the University of Warwick/Fudan University study in the SMC post.

“These results may help researchers understand the biological systems involved in the development of dementia,” said David Curtis, MD, PhD, of the UCL Genetics Institute at University College London. “However in my view the strengths of the reported associations are not really strong enough to say that these would form a useful test for predicting who will get dementia in the future.”

Conversely, Curtis pointed to other studies suggesting that phosphorylated tau (p-tau) proteins are better candidates for developing a simple blood test.

P-tau “provides a very good indicator of whether the pathological processes leading to Alzheimer’s disease are present in the brain,” he said. “When effective treatments for Alzheimer’s disease are developed it will be very helpful indeed to have simple blood tests—such as measuring phosphorylated tau—available in order to identify who could benefit.”

At least two blood tests based on the p-tau217 variant—from ALZpath and C2N—are currently available to US clinicians as laboratory developed tests (LDT).

In “University of Gothenburg Study Findings Affirm Accuracy of Clinical Laboratory Blood Test to Diagnose Alzheimer’s Disease,” Dark Daily reported on a study from the University of Gothenburg in Sweden which found that the ALZpath test was as good or better than lumbar punctures and brain scans as a diagnostic tool for Alzheimer’s.

UK Biobank

The UK Biobank continues to be used by researchers both in the UK and abroad because of the full sets of data on large numbers of patients over many years. There are few other sources of such data elsewhere in the world. The UK Biobank is a large-scale biomedical database and research resource. It contains de-identified genetic, lifestyle and health information, and biological samples from 500,000 UK participants.

On its website, the UK Biobank states, “It is the most comprehensive and widely-used dataset of its kind and is globally accessible to approved researchers who are undertaking health-related research that is in the public interest, whether they are from academic, commercial, government or charitable settings.”

Thus, clinical laboratory managers and pathologists can expect a continuing stream of published studies that identify biomarkers associated with different health conditions and to see where the data used in these analyses came from the UK’s biobank.

—Stephen Beale

Related Information:

Protein Biomarkers Predict Dementia 15 Years Before Diagnosis, According to New Study

Plasma Proteomic Profiles Predict Future Dementia in Healthy Adults

Proteins May Predict Who Will Get Dementia 10 Years Later, Study Finds

Expert Reaction to Study of Potential Protein Biomarkers for Dementia Risk

Two New p-Tau217 Blood Tests Join a Crowded Field

Plasma p-Tau-217 Assays Work Well, But No Home Run for Diagnosis

Dementia Can Be Predicted More than a Decade Before Diagnosis with These Blood Proteins

Dementia Predicted 10 Years Before Diagnosis

Early Blood Test to Predict Dementia Is Step Closer as Biological Markers Identified

Validating Blood Tests as A Possible Routine Diagnostic Assay of Alzheimer’s Disease

Washington University School of Medicine Researchers Find Accelerated Aging May be Contributing to an Increase in Early-onset Cancers among Young People

More research into accelerated aging may lead to new clinical laboratory and anatomic pathology testing biomarkers for early-onset cancer

Could accelerated aging be contributing to the rise in early-onset cancer rates among younger individuals? A recent study conducted at the Washington University School of Medicine in St. Louis (WUSTL) claims the condition may be partially to blame for the increase in cancer diagnoses among young people. But what is accelerated aging, and what tests will clinical laboratories be required to perform to help physicians diagnose early-onset cancer in that age group?

“Accelerated aging—when someone’s biological age [how old one’s cells are] is greater than their chronological age [how long one has existed]—could increase the risk of cancer tumors,” Fox News reported.

In their presentation at the 2024 American Association for Cancer Research (AACR) annual meeting, the WUSTL researchers noted that “individuals born in or after 1965 had a 17% higher likelihood of accelerated aging than those born between 1950 and 1954,” according to an AACR news release.

The scientists studied “the association between accelerated aging and the risk of early-onset cancers,” and found that “each standard deviation increase in accelerated aging was associated with a 42% increased risk of early-onset lung cancer, a 22% increased risk of early-onset gastrointestinal cancer, and a 36% increased risk of early-onset uterine cancer.”

“Multiple cancer types are becoming increasingly common among younger adults in the United States and globally,” said Ruiyi Tian, MPH, a PhD candidate at WUSTL, in the news release. “Understanding the factors driving this increase will be key to improve the prevention or early detection of cancers in younger and future generations.”

Tian was part of the team conducting the study at the Cao Lab at WUSTL. The primary function of this lab is to uncover risk factors for various cancers and develop precision medicine protocols for cancer prevention and treatment. 

“Historically, both cancer and aging have been viewed primarily as concerns for older populations,” Ruiyi Tian, MPH (above), a graduate student at Washington University School of Medicine in St. Louis and one of the study’s researchers, told Fox News. “The realization that cancer, and now aging, are becoming significant issues for younger demographics over the past decades was unexpected.” Clinical laboratories and anatomic pathologists will likely be performing cancer testing on younger populations as incidences of early-onset cancer increase. (Photo copyright: Washington University School of Medicine in St. Louis.)

Biological versus Chronological Aging

A study published last year in BMJ Oncology titled, “Global Trends in Incidence, Death, Burden and Risk Factors of Early-Onset Cancer from 1990 to 2019,” stated that early onset of 29 cancers increased by almost 79% globally between 1990 and 2019. Early-onset cancer deaths rose by almost 28% during that time period. 

The WUSTL researchers set out to prove that both chronological age and biological age could be determining factors in early-onset cancers. Chronological age refers to the amount of time an individual has been alive, while biological age refers to the age of cells and tissues based on physiological evidence.

“We all know cancer is an aging disease. However, it is really coming to a younger population,” said Yin Cao, MPH, Associate Professor of Surgery at WUSTL and senior author of the study, told CNN. “So, whether we can use the well-developed concept of biological aging to apply that to the younger generation is a really untouched area.”

To perform the research, the scientists examined data of 148,724 individuals between the ages of 37 and 54 located in the UK Biobank database. They calculated each person’s biological age by examining nine biomarkers found in blood:

They then input the data into the PhenoAge algorithm which estimated the biological age of each person.

“Individuals whose biological age was higher than their chronological age were defined as having accelerated aging,” the AACR news release noted.

The next step was to calculate each person’s level of accelerated aging by comparing biological and chronological ages. They then looked at how many of the individuals studied had been diagnosed with early-onset cancers.

For the WUSTL study, early-onset cancers were defined as cancers that were diagnosed before age 55. The researchers found 3,200 cases where such cancers had been discovered. 

Faster Agers Twice as Likely to Develop Early-onset Cancer

The scientists then compared the data of people who showed slower aging to those showing faster aging based on the biobank samples. They found that individuals who had the highest accelerated aging were twice as likely to be diagnosed with early-onset lung cancer, had a 60% higher risk of gastrointestinal tumors, and had a more than 80% higher risk of uterine cancer.

“By examining the relationship between accelerating aging and the risk of early-onset cancers, we provide a fresh perspective on the shared etiology of early-onset cancers,” Tian said in the news release. “If validated, our findings suggest that interventions to slow biological aging could be a new avenue for cancer prevention, and screening efforts tailored to younger individuals with signs of accelerated aging could help detect cancers early.”

More clinical studies and research are needed to determine if accelerated aging truly is causing a rise in early-onset cancers. The fact that all of the participants in this study were from the United Kingdom indicates that future studies should include more diverse populations.

Studying accelerated aging’s influence on early-onset cancer may lead to new biomarkers that clinical laboratories and anatomic pathologists can use to help physicians diagnose the condition. Laboratory scientists and pathologists will want to follow any ongoing research and studies on the trend, as ‘accelerated aging’ might be identified as a new disorder to look for when diagnosing and treating cancers. 

—JP Schlingman

Related Information:

Accelerated Aging May Increase the Risk of Early-onset Cancers in Younger Generations

Cancer Rates Rising in Young People Due to ‘Accelerated Aging,’ New Study Finds: ‘Highly Troubling’

Global Trends in Incidence, Death, Burden and Risk Factors of Early-onset Cancer from 1990 to 2019

Accelerated Aging Linked to Cancer Risk in Younger Adults, Research Shows

Accelerated Aging May be a Cause of Increased Cancers in People under 55

Utah Cancer Researcher Says New Accelerated Aging Study Needs More Examination

What to Know about Rising Rates of ‘Early-Onset’ Cancer

Chronological vs. Biological Age

Early-onset Cancer: Faster Biological Aging May be Driving Rates in Young Adults

Rise in Cancer Rates among Young People Contributes to New Phenomenon of ‘Turbo Cancers’ as a Cause for Concern

American Cancer Society Annual Report Shows Cervical Cancer Rate Increasing, but Only among 30- to 40-Year-Olds

Australian Company Launches At-Home Genetic Test in the US That Claims to Identify a Person’s ‘Risk’ for Contracting the SARS-CoV-2 Coronavirus. But What Science Supports the Test’s Ability to Accurately Assess Risk?

Since all Americans have access to free COVID-19 vaccines, many pathologists and clinical lab managers will ask if this test is even necessary. Some experts say “maybe”

Here’s another example of genetic test developers who are willing to push boundaries and sell a diagnostic test directly to consumers that has some diagnostic experts and pathologists challenging its clinical validity.

The test was developed by molecular diagnostics company Genetic Technologies Ltd. (NASDAQ:GENE) of Melbourne, Australia, and, according to an article in Science, is an at-home saliva test that “combines genetic data with someone’s age, sex, and pre-existing medical conditions to predict their risk of becoming extremely ill from COVID-19.”

In a non-peer-reviewed preprint, titled, “Development and Validation of a Clinical and Genetic Model for Predicting Risk of Severe COVID-19,” Genetic Technologies’ Chief Scientific Officer Richard Allman, PhD, and Senior Biostatistician and the study’s first author, Gillian Dite, PhD, wrote, “Using SARS-CoV-2 positive participants from the UK Biobank, we developed and validated a clinical and genetic model to predict risk of severe COVID-19. … Accurate prediction of individual risk is possible and will be important in regions where vaccines are not widely available or where people refuse or are disqualified from vaccination, especially given uncertainty about the extent of infection transmission among vaccinated people and the emergence of SARS-CoV-2 variants of concern.”

But since every American already has access to free COVID-19 vaccines, one wonders why this test would be launched in the US?

Determining Risk for COVID-19 Infection

Can a genetic test predict an individual’s risk of contracting a SARS-CoV-2 infection that would require hospitalization or cause death? Genetic Technologies and its US partner, Infinity BiologiX (IBX) of Piscataway, N.J., believe so.

According to a Genetic Technologies news release, the saliva test, which reportedly costs $175, enables a “leading-edge risk assessment that estimates your personal risk of severe disease,” IBX says on its website.

The at-home saliva-based test, which is intended for people age 18 and older, gives a risk score for contracting a serious COVID-19 case based on genetic and clinical information, IBX stated in its own news release.

The two companies partnered with Vault Health, a “virtual platform for telemedicine and diagnostics” developer, to distribute, and sell the COVID-19 Serious Disease Risk Test in the US.

Genetic Technologies’ COVID-19 Risk Test

In the IBX news release, IBX’s Chief Executive Officer, Robin Grimwood, said, “We see this initial agreement for the sale and distribution of Genetic Technologies’ COVID-19 Risk Test (above) as a critical collaboration in line with our mission to understand the genetic causes of common, complex diseases and to discover diagnoses, treatments and, eventually, cures for these diseases.” However, as Dark Daily’s sister publication The Dark Report previously reported, some geneticists, epidemiologists, and clinical laboratory professionals have expressed concerns. (Photo copyright: Infinity BiologiX.)

Is There a Place for Genetic COVID-19 Risk Test in the US?

“Alongside existing treatment options and vaccines, we believe this test will enable more insightful decisions for states, workplaces, and individuals,” said Simon Morriss, Genetic Technologies’ CEO, in the news release.

Meanwhile, some experts are uncertain about predictive types of testing for the SARS-CoV-2 coronavirus. “I think it’s premature to use a genetic test to predict a person’s likely COVID-19 severity. We don’t understand exactly what these genetic variants mean or how they affect disease,” epidemiologist Priya Duggal PhD, a professor in the Genetics Epidemiology Division at the Johns Hopkins University School of Public Health, told Science.

Launched without FDA Clearance?

A recent Intelligence Briefing from Dark Daily’s sister publication The Dark Report, noted that the companies introduced the test in the US without a US Food and Drug Administration (FDA) review.

According to Science, “The test debuts in a regulatory gray zone …. The two companies did not seek [FDA] approval for validity because, [Genetic Technologies Chief Scientific Officer Richard Allman] says, the test is not a direct-to-consumer product that falls under its review. After a customer receives results from IBX’s federally-approved labs, they can consult with a ‘telehealth’ physician.”

“We are uniquely and strategically positioned with our partners to deliver the test and provide remote telehealth services and reporting, utilizing our extensive array capability and capacity across a number of platforms,” Grimwood said in the IBX news release.

However, Science reported that “Several geneticists who reviewed the company’s preprint” said “the test needs to be validated in other, more diverse populations than one detailed in the UK Biobank, and they wonder whether its predictions are reliable for people infected with new SARS-CoV-2 variants.”

“It’s a good start, but by no means is it calibrated or validated sufficiently to say this is a test I would take, or my wife should take,” cancer geneticist Stephen Chanock, MD, Director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health, told Science.

The question remains unanswered as to why a genetic risk test for SARS-CoV-2 and its variants is needed in the United States. Nevertheless, clinical laboratory leaders and pathologists may want to monitor these developments for new biomarkers and COVID-19 diagnostics.

—Donna Marie Pocius

Related Information

Test Improves COVID-19 Prevention and Management Capabilities for Employers, Governments, and Public Health Decision Makers; Gene’s COVID-19 Risk Test Released for Sale in the US

Infinity BiologiX, Genetic Technologies, and Vault Health Launch New Test to Assess Severity of COVID-19 in Individuals

Intelligence Briefing: The Dark Report

Would You Have Your DNA Tested to Predict How Hard COVID-19 Would Strike? Should You?

Development and Validation of a Clinical and Genetic Model for Predicting Risk of Severe COVID-19

Mapping the Human Genetic Architecture of COVID-19 Using Worldwide Meta-Analysis

Common DNA Testing Method Using SNP Chips Struggles to Find Rare Variants Associated with BRCA Test, UK Researchers Find

Results of the UK study confirm for clinical laboratory professionals the importance of fully understanding the design and function of SNP chips they may be using in their labs

Here is another example of a long-established clinical laboratory test that—upon new evidence—turns out to be not as accurate as once thought. According to research conducted at the University of Exeter in Devon, UK, Single-nucleotide polymorphism (SNP) chips (aka, SNP microarrays)—technology commonly used in commercial genetic testing—is inadequate at detecting rare gene variants that can increase breast cancer risk.  

A news release announcing the results of the large-scale study states, “A technology that is widely used by commercial genetic testing companies is ‘extremely unreliable’ in detecting very rare variants, meaning results suggesting individuals carry rare disease-causing genetic variants are usually wrong.”

Why is this a significant finding for clinical laboratories? Because medical laboratories performing genetic tests that use SNP chips should be aware that rare genetic variants—which are clinically relevant to a patient’s case—may not be detected and/or reported by the tests they are running.

UK Researchers Find ‘Shockingly High False Positives’

The objective of the Exeter study published in British Medical Journal (BMJ), titled, “Use of SNP Chips to Detect Rare Pathogenic Variants: Retrospective, Population Based Diagnostic Evaluation,” was “To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population.”

The conclusion reached by the Exeter researchers, the BMJ study states, is that “SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.”  

Leigh Jackson, PhD, Lecturer in Genomic Medicine at University of Exeter and co-author of the BMJ study, said in the news release, “The number of false positives on rare genetic variants produced by SNP chips was shockingly high. To be clear: a very rare, disease-causing variant detected using [an] SNP chip is more likely to be wrong than right.” 

Caroline Wright, PhD, Professor in Genomic Medicine at the University of Exeter Medical School
In the news release, Caroline Wright, PhD (above), Professor in Genomic Medicine at the University of Exeter Medical School and senior author of the BMJ study, said, “SNP chips are fantastic at detecting common genetic variants, yet we have to recognize that tests that perform well in one scenario are not necessarily applicable to others.” She added, “We’ve confirmed that SNP chips are extremely poor at detecting very rare disease-causing genetic variants, often giving false positive results that can have profound clinical impact. These false results had been used to schedule invasive medical procedures that were both unnecessary and unwarranted.” (Photo copyright: University of Exeter.)

Large-Scale Study Taps UK Biobank Data

The Exeter researchers were concerned about cases of unnecessary invasive medical procedures being scheduled by women after learning of rare genetic variations in BRCA1 (breast cancer type 1) and BRCA2 (breast cancer 2) tests.

“The inherent technical limitation of SNP chips for correctly detecting rare genetic variants is further exacerbated when the variants themselves are linked to very rare diseases. As with any diagnostic test, the positive predictive value for low prevalence conditions will necessarily be low in most individuals. For pathogenic BRCA variants in the UK Biobank, the SNP chips had an extremely low positive predictive value (1-17%) when compared with sequencing. Were these results to be fed back to individuals, the clinical implications would be profound. Women with a positive BRCA result face a lifetime of additional screening and potentially prophylactic surgery that is unwarranted in the case of a false positive result,” they wrote.

Using UK Biobank data from 49,908 participants (55% were female), the researchers compared next-generation sequencing (NGS) to SNP chip genotyping. They found that SNP chips—which test genetic variation at hundreds-of-thousands of specific locations across the genome—performed well when compared to NGS for common variants, such as those related to type 2 diabetes and ancestry assessment, the study noted.

“Because SNP chips are such a widely used and high-performing assay for common genetic variants, we were also surprised that the differing performance of SNP chips for detecting rare variants was not well appreciated in the wider research or medical communities. Luckily, we had recently received both SNP chip and genome-wide DNA sequencing data on 50,000 individuals through the UK Biobank—a population cohort of adult volunteers from across the UK. This large dataset allowed us to systematically investigate the performance of SNP chips across millions of genetic variants with a wide range of frequencies, down to those present in fewer than 1 in 50,000 individuals,” wrote Wright and Associate Professor of Bioinformatics and Human Genetics at Exeter, Michael Weedon, PhD, in a BMJ blog post.

The Exeter researchers also analyzed data from a small group of people in the Personal Genome Project who had both SNP genotyping and sequencing information available. They focused their analysis on rare pathogenic variants in BRCA1 and BRCA2 genes.

The researchers found:

  • The rarer the variant, the less reliable the test result. For example, for “very rare variants” in less than one in 100,000 people, 84% found by SNP chips were false positives.
  • Low positive predictive values of about 16% for very rare variants in the UK Biobank.
  • Nearly all (20 of 21) customers of commercial genetic testing had at least one false positive rare disease-causing variant incorrectly genotyped.
  • SNP chips detect common genetic variants “extremely well.”

Advantages and Capabilities of SNP Chips

Compared to next-gen genetic sequencing, SNP chips are less costly. The chips use “grids of hundreds of thousands of beads that react to specific gene variants by glowing in different colors,” New Scientist explained.

Common variants of BRCA1 and BRCA2 can be found using SNP chips with 99% accuracy, New Scientist reported based on study data.

However, when the task is to find thousands of rare variants in BRCA1 and BRCA2 genes, SNP chips do not fare so well.

“It is just not the right technology for the job when it comes to rare variants. They’re excellent for the common variants that are present in lots of people. But the rarer the variant is, the less likely they are to be able to correctly detect it,” Wright told CNN.

SNP chips can’t detect all variants because they struggle to cluster needed data, the Exeter researchers explained.

“SNP chips perform poorly for genotyping rare genetic variants owing to their reliance on data clustering. Clustering data from multiple individuals with similar genotypes works very well when variants are common,” the researchers wrote. “Clustering becomes more difficult as the number of people with a particular genotype decreases.”

Clinical laboratories Using SNP Chips

The researchers at Exeter unveiled important information that pathologists and medical laboratory professionals will want to understand and monitor. Cancer patients with rare genetic variants may not be diagnosed accurately because SNP chips were not designed to identify specific genetic variants. Those patients may need additional testing to validate diagnoses and prevent harm.

—Donna Marie Pocius

Related Information:

Large-scale Study Finds Genetic Testing Technology Falsely Detects Very Rare Variants

Use of SNP Chips to Detect Rare Pathogenic Variants: Retrospective, Population-Based Diagnostic Evaluation

The Home DNA Kits “Falsely Warning of High Risk of Cancer”: DIY Genetic Tests are “Extremely Unreliable” at Detecting Rare Genetic Variants, Major New Study Warns

SNP Chips Perform Poorly for Detecting Rare Genetic Variants

Chip-based DNA Testing Wrong More than Right for Very Rare Variants

Common Genetic Tests Often Wrong When Identifying Rare Disease-Causing Variants Such as BRCA1and BRCA2, Study Says

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

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