Unlike most other CRISPR/Cas-9 therapies that are ex vivo treatments in which cells are modified outside the body, this study was successful with an in vivo treatment
Use of CRISPR-Cas9 gene editing technology for therapeutic purposes can be a boon for clinical laboratories. Not only is this application a step forward in the march toward precision medicine, but it can give clinical labs the essential role of sequencing a patient’s DNA to help the referring physician identify how CRISPR-Cas9 can be used to edit the patient’s DNA to treat specific health conditions.
Most pathologists and medical lab managers know that CRISPR-Cas9 gene editing technology has been touted as one of the most significant advances in the development of therapies for inherited genetic diseases and other conditions. Now, a pair of biotech companies have announced a milestone for CRISPR-Cas9 with early clinical data involving a treatment delivered intravenously (in vivo).
As with other therapies, determining which patients are suitable candidates for specific treatments is key to the therapy’s success. Therefore, clinical laboratories will play a critical role in identifying those patients who would most likely benefit from a CRISPR-delivered therapy.
Such is the goal of precision medicine. As methods are refined that can correct unwelcome genetic mutations in a patient, the need to do genetic testing to identify and diagnose whether a patient has a specific gene mutation associated with a specific disease will increase.
Cleveland Clinic describes ATTR amyloidosis as a “protein misfolding disorder” involving transthyretin (TTR), a protein made in the liver. The disease leads to deposits of the protein in the heart, nerves, or other organs.
According to Intellia and Regeneron, NTLA-2001 is designed to inactivate the gene that produces the protein.
The interim clinical trial data indicated that one 0.3 mg per kilogram dose of the therapy reduced serum TTR by an average of 87% at day 28. A smaller dose of 0.1 mg per kilogram reduced TTR by an average of 52%. The researchers reported “few adverse events” in the six study patients, “and those that did occur were mild in grade.”
Current treatments, the companies stated, must be administered regularly and typically reduce TTR by about 80%.
“These are the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR,” said Intellia President and CEO John Leonard, MD, in a press release. “The interim results support our belief that NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR amyloidosis with a single dose.”
He added that “solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline.”
“It’s an important moment for the field,” MIT biomedical engineer Daniel Anderson, PhD (above), told Nature. Anderson is Professor, Chemical Engineering and Institute for Medical Engineering and Science at the Koch Institute for Integrative Cancer Research at MIT. “It’s a whole new era of medicine,” he added. Advances in the use of CRISPR-Cas9 for therapeutic purposes will create the need for clinical laboratories to sequence patients’ DNA to help physicians determine the best uses for a CRISPR-Cas9 treatment protocol. (Photo copyright: Massachusetts Institute of Technology.)
In Part 2 of the Phase 1 trial, Intellia plans to evaluate the new therapy at higher doses. After the trial is complete, “the company plans to move to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis,” the press release states.
Previous clinical trials reported results for ex vivo treatments in which cells were removed from the body, modified with CRISPR-Cas9 techniques, and then reinfused. “But to be able to edit genes directly in the body would open the door to treating a wider range of diseases,” Nature reported.
How CRISPR-Cas9 Works
On its website, CRISPR Therapeutics, a company co-founded by Emmanuelle Charpentier, PhD, a director at the Max Planck Institute for Infection Biology in Berlin, and inventor of CRISPR-Cas9 gene editing, explained that the technology “edits genes by precisely cutting DNA and then letting natural DNA repair processes take over.” It can remove fragments of DNA responsible for causing diseases, as well as repairing damaged genes or inserting new ones.
The therapies have two components: Cas9, an enzyme that cuts the DNA, and Guide RNA (gRNA), which specifies where the DNA should be cut.
Charpentier and biochemist Jennifer Doudna, PhD, Nobel Laureate, Professor of Chemistry, Professor of Biochemistry and Molecular Biology, and Li Ka Shing Chancellor’s Professor in Biomedical and Health at the University of California Berkeley, received the 2020 Nobel Prize in Chemistry for their work on CRISPR-Cas9, STAT reported.
It is important to pathologists and medical laboratory managers to understand that multiple technologies are being advanced and improved at a remarkable pace. That includes the technologies of next-generation sequencing, use of gene-editing tools like CRISPR-Cas9, and advances in artificial intelligence, machine learning, and neural networks.
At some future point, it can be expected that these technologies will be combined and integrated in a way that allows clinical laboratories to make very early and accurate diagnoses of many health conditions.
Of interest to clinical pathologists is the finding that sequencing the genomes of Humans and Neanderthals revealed a link between severity of COVID-19 infections and Neanderthal DNA
Genetic scientists from the University of California Santa Cruz have learned that just 7%—or less—of our DNA is unique to the human species, with the remainder of our genomes coming from other archaic species, such as Neanderthal and Denisovan.
Why should this matter to pathologists and clinical laboratories? Because a broader knowledge of how DNA evolves may help researchers and healthcare providers better understand how a modern family’s DNA can change over generations. In turn, these insights may lead to precision medicine tools for personalized diagnosis and treatment.
“We find that a low fraction, 1.5 to 7%, of the human genome is uniquely human, with the remainder comprising lineages shared with archaic hominins from either ILS [incomplete lineage sorting] or [genetic] admixture,” wrote the paper’s authors.
To complete their study, the researchers used DNA extracted from fossils of Neanderthals and Denisovans, as well as genetic information from 279 people from various locations around the world.
One goal was to determine what part of a modern human’s genome is truly unique. Though only a small percentage of our entire genome, those portions are important.
“We can tell those regions of the genome are highly enriched for genes that have to do with neural development and brain function,” Richard Green, PhD, Associate Professor of Biomolecular Engineering at the University of California Santa Cruz and co-author of the paper, told the Associated Press (AP).
In addition to highlighting what makes modern humans unique as a species, the study also suggests, “That we’re actually a very young species. Not that long ago, we shared the planet with other human lineages,” said Joshua Akey, PhD, Professor of Ecology and Evolutionary Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University. Akey co-authored the Science Advances research paper.
Human/Neanderthal Genetic Overlap
The genetic research being conducted at the University of California Santa Cruz is just the most recent in a flurry of studies over the past decade investigating the Neanderthal genome. Most of these studies point to the vast similarities between humans and Neanderthals, but also to how similar humans are to each other.
“Humans have more than three billion letter pairs of DNA in their genome: It turns out less than 2% of that spells out around 20,000 specific genes, or sets of instructions that code for the proteins that make our tissues,” wrote zooarcheologist Anna Goldfield, PhD (above), Adjunct Instructor Cosumnes River College in Sacramento, Calif., and at the University of California, Davis, in Sapiens. “All humans share the same basic set of genes (we all have a gene for earwax consistency, for example), but there are subtle variations in the DNA spelling of those genes from individual to individual that result in slightly different proteins (sticky earwax versus dry earwax) … Overall, any given human being is about 99.9% similar, genetically, to any other human being,” she added. It is those variations that could lead to precision medicine treatments, personalized drug therapies, and clinical laboratory tests that inform physicians about relevant genetic variations. (Photo copyright: Boston University.)
Practically Everyone Has Neanderthal DNA
Understanding that humans and Neanderthals are 93-98.5% similar genetically may—or may not—come as a surprise. In delving into those similarities and differences researchers are making interesting and potentially important discoveries.
For example, researchers have studied a gene that occurs in both modern humans and Neanderthal fossils that has to do with how the body responds to carcinogenic hydrocarbons, such as smoke from burning wood. Neanderthals were far more sensitive to the carcinogens, but also had more genetic variants, such as single-nucleotide polymorphisms, that could neutralize their effects.
Most modern humans carry some Neanderthal DNA. For some time, scientists thought that Africans likely did not carry Neanderthal DNA, since ancient people tended to migrate out of Africa and met Neanderthals in Europe. More recent research, however, shows that migration patterns were more complex than previously thought, and that the ancient people migrated back to Africa bringing Neanderthal DNA with them.
“Our results show this history was much more interesting and there were many waves of dispersal out of Africa, some of which led to admixture between modern humans and Neanderthals that we see in the genomes of all living individuals today,” Akey told CNN.
Neanderthal DNA and COVID-19
Researchers have found that having Neanderthal DNA may affect the health of modern people who carry it. Perception of pain, immune system function, and even hair color and sleeping patterns have been associated with having Neanderthal DNA.
Scientists have even found a potential link between severe COVID-19 infection and Neanderthal DNA, CNN reported.
The researchers added, “It turns out that this gene variant was inherited by modern humans from the Neanderthals when they interbred some 60,000 years ago. Today, the people who inherited this gene variant are three times more likely to need artificial ventilation if they are infected by the novel coronavirus SARS-CoV-2.”
Of course, these links and associations are preliminary science. John Capra, PhD, Research Associate Professor of Biological Sciences and Associate Professor of Biomedical Informatics at the University of California, San Francisco says, “We can’t blame Neanderthals for COVID. That’s a damaging response, and that’s why I want to emphasize so much [that] the social and environmental factors are the real things that people should be worrying about,” he told CNN.
“That said,” he continued, “as a geneticist, I think it is important to know the evolutionary history of the genetic variants we find that do have effects on traits. The effects of Neanderthal DNA traits are detectable, but they’re modest.”
Nevertheless, genetic scientists agree that understanding the genetic roots of disorders could lead to breakthroughs that result in new types of clinical laboratory tests designed to guide precision medicine treatments.
23andMe executives say they plan to leverage their database of millions of customer genotypes ‘tohelp accelerate personalized healthcare at scale,’ a key goal of precision medicine
In what some financial analysts believe may be an indication that popularity of direct-to-consumer (DTC) genetic testing among customers who seek info on their ethnic background and genetic predisposition to disease is waning, personal genomics/biotechnology company 23andMe announced it has completed its merger with Richard Branson’s VG Acquisition Corp. (NYSE:VGAC) and is now publicly traded on NASDAQ.
According to a 23andMe news release, “The combined company is called 23andMe Holding Co. and will be traded on The Nasdaq Global Select Market (“NASDAQ”) beginning on June 17, 2021, under the new ticker symbol ‘ME’ for its Class A Common shares and ‘MEUSW’ for its public warrants.”
Now that it will file quarterly earnings reports, pathologists and clinical laboratory managers will have the opportunity to learn more about how 23andMe serves the consumer market for genetic types and how it is generating revenue from its huge database containing the genetic sequences from millions of people.
After raising $600 million and being valued at $3.5 billion, CNBC reported that 23andMe’s shares rose by 21% during its first day of trading.
“23andMe is more than just a genetics company. We are an activist brand that is approaching healthcare and drug discovery with the individual at the center, as our partner,” said Anne Wojcicki (above), 23andMe’s co-founder and Chief Executive Officer, during remarks she gave after ringing the opening bell on the company’s first day of public trading, a 23andMe blog post noted. “We are going to continue pioneering a consumer-centered personalized healthcare world. We are going to show that drug discovery can be more efficient when you start with a human genetic insight,” she continued. (Photo copyright: TechCrunch.)
Might the quick rise in its stock price be a sign that 23andMe—with its database of millions of human genotypes—has found a lucrative path forward in drug discovery?
23andMe says that 80% of its 10.7 million genotyped customers have consented to sharing their data for research, MedCity News reported, adding that, “The long-term focus for 23andMe still remains using all of its accumulated DNA data to strike partnerships with pharmaceutical companies.”
Time for a New Direction at 23andMe
While 23andMe’s merger is a recent development, it is not a surprising direction for the Sunnyvale, Calif.-based company, which launched in 2006, to go.
Even prior to the COVID-19 pandemic, both 23andMe and its direct competitor Ancestry had experienced a decline in direct-to-consumer testing sales of at-home DNA and genealogy test kit orders. This decline only accelerated during the pandemic.
Meanwhile, 23andMe Therapeutics, a division focused on research and drug development, has been on the rise, Bloomberg News reported. On its website, 23andMe said it has ongoing studies in oncology, respiratory, and cardiovascular diseases.
“It’s kind of an ideal time for us,” Wojcicki told Bloomberg News.
“There are huge growth opportunities ahead,” said Richard Branson, founder of the Virgin Group, which sponsors the special-purpose acquisition company (SPAC) VG Acquisition Corp., in the 23andMe news release.
In a VG Acquisition Corp. news release, Branson said, “Of the hundreds of companies we reviewed for our SPAC, 23andMe stands head and shoulders above the rest.”
“As an early investor, I have seen 23andMe develop into a company with enormous growth potential. Driven by Anne’s vision to empower consumers, and with our support, I’m excited to see 23andMe make a positive difference to many more people’s lives,” he added.
Report Bullish on Consumer Genetic Testing
Despite the apparent saturation of the direct-to-consumer (DTC) genetic testing market, and consumers’ concerns about privacy, Infiniti Research reported that worldwide sales of DTC tests “are poised to grow by $1.39 bn during 2021-2025, progressing at a CAGR [compound annual growth rate] of over 16% during the forecast period.”
“This study identifies the advances in next-generation genetic sequencing as one of the prime reasons driving the direct-to-consumer genetic testing market growth during the next few years. Also, reduction in the cost of services and growing adoption of online service platforms will lead to sizable demand in the market,” the report states.
Clinical laboratory leaders will want to stay abreast of 23andMe rise as a publicly-traded company. It will be interesting to see if Wojcicki’s vision about moving therapies into clinics in five years comes to fruition.
New biomarkers for cancer therapies derived from the research could usher in superior clinical laboratory diagnostics that identify a patient’s suitability for personalized drug therapies and treatments
Once approved for clinical use, not only would these biomarkers become targets for specific cancer therapies, they also would require development of new diagnostic tests that anatomic pathologists could use to determine whether a biomarker was present in a patient.
If yes, the drug can be administered. If no, the patient is not a candidate for that drug. Thus, this research may produce both diagnostic biomarkers and therapeutic targets.
Relevance of In-Depth Tumor Profiling to Support Clinical Decision-Making
In the Swiss “Tumor Profiler” (TuPro) project, the research team is examining the cellular composition and biology of tumors of 240 patients with melanoma, ovarian cancer, and acute myeloid leukemia. Recruitment for the study began in 2018. Today, the melanoma cohort is fully enrolled, and the ovarian cancer and acute myeloid leukemia cohorts are nearing complete enrollment.
“The Tumor Profiler Study is an observational clinical study combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making (“fast diagnostic loop”) with an exploratory approach to improve the biological understanding of disease (“exploratory science loop”),” the TuPro website states.
The graphic above taken from the Tumor Profiler project paper illustrates how the TuPro study’s workflow entails patient enrollment, sample collection, analysis by different technology platforms, and data integration, creation and discussion of molecular research and summary reports, discussion of treatment options in pre-tumor boards and the final treatment decision in tumor boards. (Photo copyright: Cancer Cell.)
In their published paper, the Swiss researchers say these three cancers were selected for the study “based on the potential clinical benefit and availability of sufficient tumor material for simultaneous analysis across all technologies.”
According to a University Hospital Basel blog post, the TuPro project examination of each cancer tumor goes “much further than the limited use of molecular biological methods” used by leading hospitals. “This results in huge amounts of data per patient, which we process and analyze using data science methods,” stated data scientist Gunnar Rätsch, PhD (above), Professor for BiomedicalInformatics at ETH Zurich and one of the study’s corresponding authors, in the blog post. This research could lead to new precision medicine biomarkers for clinical laboratory cancer diagnostics and therapies. (Photo copyright: ETH Zurich.)
The TuPro Project’s findings are available to doctors who analyze them at interdisciplinary tumor board meetings and generate treatment options, creating a “fast diagnostic loop” with an estimated four-week turnaround time from surgery to tumor board. “This approach has the potential to alter current diagnostics and paves the way for the translation of comprehensive molecular profiling into clinical decision-making,” the study’s authors wrote in Cancer Cell.
Could Oncologists Be Making Better Precision Medicine Decisions?
In its writeup on the TuPro Project’s research, Precision Oncology News concluded that the Swiss study “is rooted in the researchers’ notion that oncologists are not making the best personalized treatment decisions for patients by relying just on targeted DNA profiling using next-generation sequencing and digital pathology-based tests.
“The researchers within the TuPro consortium hypothesized that integrating a more comprehensive suite of omics tests could lead to a more complete understanding of patients’ tumors, including providing insights into the tumor microenvironment, heterogeneity, and ex vivo responses to certain drugs. This, in turn, could help inform the best course of treatment,” Precision Oncology News added.
“With the Tumor Profiler study, we want to show that the widespread use of molecular biological methods in cancer medicine is not only feasible, but also has specific clinical benefits,” said TuPro consortium member Viola Heinzelmann-Schwarz, MD, Head of Gynecological Oncology at University Hospital Basel, in an ET Zurich news release.
New Precision Medicine Biomarkers from TuPro’s Molecular Analysis
Researchers in the study also are investigating whether and what influence the molecular analysis had on doctors’ therapy decisions.
The University Hospital Basal blog notes the long-term benefits of the Tumor Profiler approach is to expand the personalized-medicine therapy options for patients, including determining whether patients would benefit in certain cases “if they were not treated with drugs from standard therapy, but with drugs that have been approved for other types of cancer.”
Anatomic pathologists and clinical laboratory scientists will want to take note of the TuPro project’s ultimate success or failure, since it could usher in changes in cancer treatments and bring about the need for new diagnostic tests for cancer biomarkers.
As many clinical laboratory scientists know, gene sequencing technology continues to become faster, more accurate, and less expensive per whole human genome sequenced
In February, Dark Daily reported that Personalis, Inc. (NASDAQ:PSNL) had delivered its 100,000th whole human genome sequence to the US Department of Veterans Affairs Million Veterans Program (VA MVP). Now, the Menlo Park, Calif.-based cancer genomics company has topped that achievement by delivering its 125,000 whole human genome sequence!
“This represents another important landmark for both the program and for Personalis,” said John West, Chief Executive Officer, Personalis, in a news release. “We congratulate the VA MVP for reaching this important milestone.
“We strongly believe that the research projects being performed today will enable precision medicine in healthcare systems in the future across a wide range of disease areas,” he added. This is a positive development for clinical laboratories, as personalized medicine services require a lab to sequence and interpret the patient’s DNA.
Personalis was contracted with the US federal government to perform genetic research in 2012 and has delivered 50,000 genomes to the VA MVP during the past twelve months.
The Personalis and VA MVP researchers seek to gain a better understanding of how genetic variants affect health. Before the COVID-19 pandemic hit the US, the VA was enrolling veterans in the Million Veterans Program at 63 VA medical centers across the country. There are currently about 830,000 veterans enrolled in the venture and the VA is expecting two million veterans to eventually sign up for the sequencing project.
“As a global leader in genomic sequencing and comprehensive analytics services, Personalis is uniquely suited to lead these population-scale efforts and we are currently in the process of expanding our business operations internationally,” West added.
According to the press release, “the VA MVP provides researchers with a rich resource of genetic, health, lifestyle, and military-exposure data collected from questionnaires, medical records, and genetic analyses. By combining this information into a single database, the VA MVP promises to advance knowledge about the complex links between genes and health.”
NIH All of Us Research Program Supports Precision Medicine Goals Another genetic research project being conducted by the US National Institutes of Health (NIH) is the All of Us Research Program. Using donated personal health information from thousands of participants, the NIH researchers seek to “learn how our biology, lifestyle, and environment affect health,” according to the program’s website.
“We’re changing the paradigm for research,” said Josh Denny, MD (above), Chief Executive Officer of the All of Us Research Program, in an NIH news release. “Participants are our most important partners in this effort, and we know many of them are eager to get their genetic results and learn about the science they’re making possible. We’re working to provide that valuable information in a responsible way,” he added. Clinical laboratories may soon see new precision medicine biomarkers derived from this type of research. (Photo copyright: Vanderbilt University.)
The All of Us Research Program intends to have at least one million US participants take part in the research. The researchers hope to help scientists discover new knowledge regarding how biological, environmental, and behavioral factors influence health, and to learn to tailor healthcare to patients’ specific medical needs, a key component of precision medicine.
Participants in the project share personal information via a variety of methods, including surveys, electronic health records, and biological samples.
A Better Sampling of Under-Represented Communities
Since opening enrollment in 2018, more than 270,000 people have contributed blood, urine, and saliva samples to the All of Us Research Program. More than 80% of the participants come from communities that are traditionally under-represented in biomedical research.
“We need programs like All of Us to build diverse datasets so that research findings ultimately benefit everyone,” said Brad Ozenberger, PhD, Genomics Program Director, All of Us, in the NIH news release. “Too many groups have been left out of research in the past, so much of what we know about genomics is based mainly on people of European ancestry. And often, genomic data are explored without critical context like environment, economics, and other social determinants of health. We’re trying to help change that, enabling the entire research community to help fill in these knowledge gaps.”
The All of Us Research Project’s analysis of the collected data includes both whole-genome sequencing (WGS) and genotyping and is taking a phased approach in returning genetic data to participants.
Participants initially receive data about their genetic ancestry and traits. That is followed later by health-related results, such as how their genetic variants may increase the risk of certain diseases and how their DNA may affect their reaction to drug therapies.
Genetic researchers hope programs like these will lead to improved in vitro diagnostics and drug therapies. Genetic sequencing also may lead to new diagnostic and therapeutic biomarkers for clinical laboratories.
