Gene experts claim they identified human genes that can protect against Covid-19 – CNBC

COVID-19 Coronavirus molecule, March 24, 2020.

CDC | API | Gamma-Rapho via Getty Images

A team of CRISPR scientists at the New York Genome Center, New York University and Icahn School of Medicine at Mount Sinai said they have identified the genes that can protect human cells against Covid-19, a disease that has infected over 40 million and led to 1 million deaths worldwide.

The discovery comes after an eight-month screen of all 20,000 genes in the human genome led by Dr. Neville Sanjana at the New York Genome Center. Leading virologist at Mount Sinai, Dr. Benjamin tenOever, developed a series of human lung cell models for the coronavirus screening to better understand immune responses to the disease and co-authored the study.

Their study, published online last month by Cell, will appear in the scientific peer-reviewed journal's Jan. 7 print issue.

The goal was two-fold: to identify the genes that make human cells more resistant to SARS-CoV-2 virus; and test existing drugs on the market that may help stop the spread of the disease.

The breakthrough comes at a time when drug makers such as Pfizer, Oxford-AstraZeneca and Moderna are fast-forwarding vaccine and therapeutics to treat Covid-19. On Friday, Pfizer and BioNTech requested emergency authorization from the FDA for their Covid vaccine that contains genetic material called messenger RNA, which scientists expect provokes the immune system to fight the virus.

In order to better understand the complex relationships between host and virus genetic dependencies, the team used a broad range of analytical and experimental methods to validate their results. This integrative approach included genome editing, single-cell sequencing, confocal imaging and computational analyses of gene expression and proteomic datasets.

After intensive research, the scientists and doctors claim they have found 30 genes that block the virus from infecting human cells including RAB7A, a gene that seems to regulate the ACE-2 receptor that the virus binds to and uses to enter the cell. The spike protein's first contact with a human cell is through ACE-2 receptor.

"Our findings confirmed what scientists believe to be true about ACE-2 receptor's role in infection; it holds the key to unlocking the virus," said Dr. tenOever. "It also revealed the virus needs a toolbox of components to infect human cells. Everything must be in alignment for the virus to enter human cells."

The team discovered that the top-ranked genes those whose loss reduces viral infection substantially clustered into a handful of protein complexes, including vacuolar ATPases, Retromer, Commander, Arp2/3, and PI3K. Many of these protein complexes are involved in trafficking proteins to and from the cell membrane.

"We were very pleased to see multiple genes within the same family as top-ranked hits in our genome-wide screen. This gave us a high degree of confidence that these protein families were crucial to the virus lifecycle, either for getting into human cells or successful viral replication," said Dr. Zharko Daniloski, a postdoctoral fellow in the Sanjana Lab and co-first author of the study.

Using proteomic data, they found that several of the top-ranked host genes directly interact with the virus's own proteins, highlighting their central role in the viral lifecycle. The team also analyzed common host genes required for other viral pathogens, such as Zika or H1N1 pandemic influenza.

The research team also identified drugs that are currently on the market for different diseases that they claim block the entry of Covid-19 into human cells by increasing cellular cholesterol. In particular, they found three drugs currently on the market were more than 100-fold more effective in stopping viral entry in human lung cells:

The other five drugs that were tested called PIK-111, Compound 19, SAR 405, Autophinib, ALLN -- are used in research but are not yet branded and used in clinical trials for existing diseases.

Our findings confirmed what scientists believe to be true about ACE-2 receptor's role in infection; it holds the key to unlocking the virus.

Their findings offer insight into novel therapies that may be effective in treating Covid-19 and reveal the underlying molecular targets of those therapies.

The bioengineers in New York were working on other projects with gene-editing technology from CRISPR but quickly pivoted to studying the coronavirus when it swept through the metropolitan area last March. "Seeing the tragic impact of Covid-19 here in New York and across the world, we felt that we could use the high-throughput CRISPR gene editing tools that we have applied to other diseases to understand what are the key human genes required by the SARS-CoV-2 virus," said Dr. Sanjana.

Dr. Neville Sanjana and his team at the New York Genome Center used CRISPR to identify the genes that can protect human cells against Covid-19.

New York Genome Center

As he explained, "current treatments for SARS-CoV-2 infection currently go after the virus itself, but this study offers a better understanding of how host genes influence viral entry and will enable new avenues for therapeutic discovery."

Previously, Dr. Sanjana has applied genome-wide CRISPR screens to identify the genetic drivers of diverse diseases, including drug resistance in melanoma, immunotherapy failure, lung cancer metastasis, innate immunity, inborn metabolic disorders and muscular dystrophy.

"The hope is that the data from this study which pinpoints required genes for SARS-CoV-2 infection could in the future work be combined with human genome sequencing data to identify individuals that might be either more susceptible or more resistant to Covid-19," Dr. Sanjana said.

The New York team is not the first to use CRISPR gene editing techniques to fight Covid-19. Other bioengineering groups at MIT and Stanford have been using CRISPR to develop ways to fight the SARS-CoV-2 and develop diagnostic tools for Covid-19.

The potential for using CRISPR to eliminate viruses has already generated some enthusiasm in the research community. Last year, for example, Excision BioTherapeuticslicenseda technology from Temple University that uses CRISPR, combined with antiretroviral therapy, to eliminate HIV, the virus that causes AIDS.

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Gene experts claim they identified human genes that can protect against Covid-19 - CNBC

Genome Medical Reaches 90 Million Covered Lives in US – PRNewswire

As a nationwide telehealth medical practice, Genome Medical has assembled an extensive team of clinical genetic experts, including board-certified genetic counselors, medical geneticists and other specialists. This team delivers education, risk assessment, access to genetic testing and specialty care referrals -- all through virtual visits. During the COVID-19 pandemic, when two out of five Americans have avoided or delayed medical care1, access to safe virtual services is essential to ensure people at greatest risk are receiving the care they need. Genetic services support the diagnosis and care management of hereditary conditions and the identification of patients at an elevated risk for disease.

Some of the largest payers in the United States are recognizing the critical role geneticists and genetic counselors play. Their members can now self-refer and get in-network access to Genome Medical's genetic experts, and the payer's contracted providers can also make in-network referrals for their patients.

The 90 million covered lives are across multiple payers, including (in part):

"Genome Medical brings together telemedicine and genomics to tackle the rising need for genetic experts to guide patients and providers in making appropriate decisions around 1) who should get genetic testing, 2) which test is optimal and 3) how clinical care should be changed based on test results," said Steven B. Bleyl, M.D., Ph.D., chief medical officer of Genome Medical. "Patients can be seen sooner, and through telehealth, we extend the reach of genetic services to rural communities and underserved areas that have less access to in-person care. Genome Medical is a flexible and cost-effective solution for payers and their members."

Genome Medical can see 85% of cancer patients more quickly than in a traditional clinic setting.2 And in areas like pediatric genetics, where wait times of six months or more for an appointment are common, Genome Medical's growing clinical team can often see patients within a few days. The company's genetic experts are licensed in all 50 states and provide clinical genetics expertise across six major specialty areas: cancer, reproductive health, proactive health, pediatrics/rare disease, pharmacogenomics and cardiovascular genetics. Genome Medical's innovative services are trusted and utilized by health systems, hospitals, testing labs, payors, providers and employers.

Genome Medical is also committed to leveraging advanced technology-enabled solutions to transform the delivery of standard-of-care genetic health services. Beyond wider and accelerated access, the company's technology delivers a 5.5X return on investment in genetic services, while also reducing the cost of care by up to 75 percent.3,4 Its Genome Care DeliveryTM platform creates an efficient and comprehensive experience, including patient engagement and care navigation, risk assessment, self-directed education and informed consent through the Genome Care NavigatorTM, multi-modality patient support, and peer-to-peer provider consultations.

"We are pleased to see health plan partners continue to expand in-network coverage for our genetic health services," said Lisa Alderson, co-founder and CEO of Genome Medical. "It is estimated that tens of millions of patients in the United States meet medical management guidelines for referral to genetics, but most are still being missed. These patients could benefit from the advancements made in utilizing genomics for prevention, diagnosis and treatment. Giving their members access to Genome Medical and telegenetics is a significant step payers are taking in removing historical barriers."

About Genome MedicalGenome Medical is a national telegenomics technology, services and strategy company bringing genomic medicine to everyday care. Through our nationwide network of genetic specialists and efficient Genome Care DeliveryTM technology platform, we provide expert virtual genetic care for individuals and their families to improve health and well-being. We also help health care providers and their patients navigate the rapidly expanding field of genetics and utilize test results to understand the risk for disease, accelerate disease diagnosis, make informed treatment decisions and lower the cost of care. We are shepherding in a new era of genomic medicine by creating easy, efficient access to top genetic experts. Genome Medical is headquartered in South San Francisco. To learn more, visit genomemedical.com and follow @GenomeMed.

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Sarepta Therapeutics Named One of The Boston Globe’s Top Places to Work 2020 – GlobeNewswire

-- Sarepta is honored to be recognized for offering a range of benefits and work-life resources to employees and supporting the local community --

-- Rankings based on confidential survey information submitted by employees to independent research company --

CAMBRIDGE, Mass., Nov. 20, 2020 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, announced today that it has been named one of TheBoston Globes Top Places to Work in 2020 in the large company category.

The Boston Globes 2020 list recognizes 150 companies and organizations in Massachusetts based on surveys completed by their employees about the workplace, including 40 in the large company category. The survey measured opinions about company direction, execution, connection, management, work, pay and benefits, and engagement. Companies also provided supplemental information about responses to the global pandemic and changes implemented in how teams work.

This recognition reflects the quality of the Sarepta employees, who together have built a positive culture, navigated a challenging environment this year and, both at facilities and from home, remained focused on our daily race to save lives stolen or impacted by rare disease, said Doug Ingram, president and CEO, Sarepta. It is a testament to the resilience, tenacity and commitment of those who work at Sarepta.

Sarepta is committed to engineering precision genetic medicine to reclaim futures otherwise impacted or cut short by ushering in a new era of drug development, with the goal of shortening the time from lab to patient. The Company is building among the worlds largest gene therapy manufacturing capacity, and rethinking access and reimbursement models for revolutionary new treatments. Sareptas purpose-driven culture, where patient-focus is central to the values that shape how work is done, was resoundingly echoed by its people as a key attribute that contributed to its top ranking. Additionally, Sarepta fosters an environment that encourages its people to bring their whole selves to work and share ideas that support the entire workforce and the patient community it serves.

As the Company adjusted during the pandemic, several initiatives and new benefits were implemented as a result of employee feedback:

At Sarepta, a vision for the possibilities of pioneering science to redefine the future of medicine, and advance treatment options for patients, is shared by all. Individuals who are inspired by the opportunity to toss aside convention and break down barriers to radically change the future of medicine are encouraged to explore employment opportunities at http://www.sarepta.com.

About Sarepta TherapeuticsAt Sarepta, we are leading a revolution in precision genetic medicine and every day is an opportunity to change the lives of people living with rare disease. The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and in gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visitwww.sarepta.comor follow us onTwitter,LinkedIn,InstagramandFacebook.

Source:Sarepta Therapeutics, Inc.

Media and Investors:Sarepta Therapeutics, Inc. Investors: Ian Estepan, 617-274-4052, iestepan@sarepta.com Media: Tracy Sorrentino, 617-301-8566, tsorrentino@sarepta.com

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Sarepta Therapeutics Named One of The Boston Globe's Top Places to Work 2020 - GlobeNewswire

New Study Highlights the Importance of Genetic Testing for Pancreatic Cancer Patients – PRNewswire

SAN FRANCISCO, Nov. 19, 2020 /PRNewswire/ -- Invitae (NYSE: NVTA), a leading medical genetics company, today presented study findings that show nine percent of patients with pancreatic cancer had genetic changes in DNA damage repair (DDR) genes that would make them eligible for PARP inhibitor therapy or clinical treatment trials. Despite professional guidelines that recommend testing for all pancreatic cancer patients, it remains underutilized in routine care. The study was presented at the National Society of Genetic Counselors 39th Annual Conference.

"New therapeutics have recently become available to treat pancreatic cancer for patients with certain changes in genes such as BRCA1 and BRCA2. Yet despite the availability of these treatments and professional guidelines recommending testing, utilization is still lagging," said Robert Nussbaum, M.D., chief medical officer of Invitae and study author. "Pathogenic variants in these genes are associated with an increased risk of other cancers as well, such as breast, ovarian and prostate cancer, which means that a failure to test patients with pancreatic cancer impacts not only their treatment, but also the health of their families."

Importantly, the study of over 2,000 patients found that 15% of patients with actionable genetic changes reported no family history of cancer, which underscores the limitations of using testing criteria based on reported family history. National Comprehensive Cancer Network (NCCN) guidelines recommend genetic counseling and germline genetic testing for everyone diagnosed with pancreatic cancer as well as their first degree relatives -- approximately 3.5 million individuals in the United States.

In addition to evaluating the clinical relevance of genetic testing results, the study offered sponsored, no-charge testing to patients to evaluate the role of cost as a barrier to testing. Researchers found a small but significant increase (2%) in testing among African-American patients compared to typical rates among patients using health insurance, suggesting reducing cost may increase access to testing among this population.

The research was presented at the virtual annual meeting of the National Society of Genetic Counselors. The full research presentation from Invitae included:

Oral platform presentations:

Poster presentations:

In addition to its scientific presence, Invitae will again partner with NSGC to present the Heart of Genetic Counseling award, which honors excellence in genetic counseling and patient care as recognized by patients. Nominations include stories from patients that highlight both the clinical and personal impact a genetic counselor had on their lives and the lives of their families. This year's award will be presented during a virtual ceremony on Thursday, November 17th. The finalists include:

About Invitae

Invitae Corporation (NYSE: NVTA) is a leading medical genetics company, whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Safe Harbor Statement

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the implications of the company's study results; and the importance and potential benefits of genetic testing for pancreatic cancer patients. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's history of losses; the company's ability to compete; the company's failure to manage growth effectively; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2020. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:

Laura D'Angelo[emailprotected](628) 213-3283

SOURCE Invitae Corporation

http://www.invitae.com

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New Study Highlights the Importance of Genetic Testing for Pancreatic Cancer Patients - PRNewswire

Baylor Genetics Launches Combination Test for COVID-19 and Influenza A and B; Multi-Panel Test Seeks to Address Dilemma of "Overlapping symptoms…

HOUSTON, Nov. 17, 2020 /PRNewswire/ --With the arrival of flu season, Baylor Genetics, a pioneer of genetic testing and precision medicine, has launched the latest combination test for the novel coronavirus, SARS-CoV-2, and Influenza A and B.

"Baylor Genetics created the combination COVID-19 and flu test because the symptoms between the two are so similar, but the treatments are undeniably different," stated Kengo Takishima, President & Chief Executive Officer at Baylor Genetics. "This groundbreaking test, with results available in 48 hours or less, will result in better data and more accurate treatments for these similar, but distinct, viruses."

In response to the global pandemic, Baylor Genetics validated its first test for COVID-19 in June 2020. Once launched, the company continued to focus on innovative efforts to help prevent the spread of the disease. Some of these efforts include unique partnerships with the City of Houston and Rice University. With their latest COVID-19 (SARS-CoV-2) & Flu (Influenza A/B) RT-PCR test, individuals will be able todetermine if they are currently infected with COVID-19 or the flu.

"The clinical presentations of COVID-19 and influenza are similar, and it is difficult to differentiate the two entities on symptoms alone," stated Dr. Christine Eng, Chief Medical Officer and Chief Quality Officer at Baylor Genetics. "This combination test will identify if SARS-CoV-2 or influenza A/B is the culprit, thus helping you and your healthcare provider better direct your care. Of course, it's important to stay proactive this season and get your flu shot if you haven't already."

Since many are traveling during the holidays, it is imperative that individuals know whether they are infected with either COVID-19 or the flu and how to treat each virus. While these respiratory viruses have similar symptoms, their treatments are different. For COVID-19, potential treatment and vaccine options are emerging. For the flu, antiviral medications can help address symptoms and potentially shorten the time an individual is sick. Therefore, it is crucial for individuals to be able to confirm which virus they may be infected with to take the proper next steps to restore their health.

For the COVID-19 and flu combination test, all sample results will be sent to individuals securely and electronically within 48 hours of Baylor Genetics' receiving the sample. In addition, the results will be automatically reported to state officials to track and slow the spread of cases in the local community. With accepted sample types of nasal or nasopharyngeal swab, all of the supplies for testing and returning the kit is provided to the individual.

To learn more about Baylor Genetics' test for COVID-19, visit https://www.baylorgenetics.com/covid19/.

About Baylor GeneticsBaylor Genetics is a joint venture of H.U. Group Holdings, Inc. and Baylor College of Medicine, including the #1 NIH-funded Department of Molecular and Human Genetics. Located in Houston's Texas Medical Center, Baylor Genetics serves clients in 50 states and 16 countries.

To learn more about Baylor Genetics visit http://www.baylorgenetics.com.

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CHOP Researchers Reverse Severe Lymphatic Disorder in Patient with Noonan Syndrome by Targeting Genetic Pathway – BioSpace

Precise treatment leads to resolution of patient's debilitating symptoms and complete remodeling of her lymphatic system

PHILADELPHIA, Nov. 20, 2020 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) have resolved a severe lymphatic disorder in a girl with Noonan Syndrome that had led to upper gastrointestinal bleeding, fluid collection around the lungs, and numerous surgeries that had been unable to resolve her symptoms. By identifying a genetic mutation along a pathway related to lymphatic vessel development and function, the research team was able to target the pathway using an existing drug they had used in a previous case to remodel a patient's lymphatic system.

The case study, which was published today in Pediatrics, describes a resolution of the patient's symptoms within three months while on the medication.

"This study is quite significant," said first author Yoav Dori, MD, PhD, Director of the Jill and Mark Fishman Center for Lymphatic Disorders at CHOP. "Inhibiting this pathway seems to have sweeping, widespread effects on the lymphatic system. How this process occurs is not fully understood, but is remarkable in its speed and breadth. This gives us a lot of hope for treating other patients with genetic mutations along this same pathway in the future."

The patient described in the paper, Maria, first came to CHOP when she was 14, after experiencing severe anemia due to upper gastrointestinal bleeding, as well as other symptoms including fluid build-up in the cavity around her lungs, chronic fatigue, delayed puberty, and difficulty gaining weight. Maria had been born with Noonan Syndrome, a genetic disorder that prevents normal development in various parts of the body and often results in short stature, heart defects and other physical problems, including an abnormal lymphatic system. Despite aggressive medical therapy elsewhere, Maria continued to bleed internally, and she underwent multiple blood transfusions to try to stabilize her health.

Within two days of transferring to CHOP, the lymphatics team, led by Dori, determined Maria had many lymphatic irregularities, which were leading to internal bleeding and lung problems, so they scheduled Maria's first intervention, a lymphatic embolization procedure that would seal the leaky vessels in her gut.

However, within two months of the procedure, Maria's gastrointestinal bleeding recurred. Over the following 8 months, she underwent two additional procedures, as well as a cauterization procedure to close off some of the blood vessels in her gut, but the benefits of each procedure lasted only about three months before the bleeding and her symptoms returned.

Based on whole exome sequencing done at CHOP's Center for Applied Genomics, the research team learned that Maria had a genetic mutation in the SOS1 gene, which operates along the RAS-MAPK pathway. This pathway involves mitogen-activated protein kinase (MEK), and Maria's mutation caused an overproduction of MEK, which resulted in the uncontrolled proliferation of her lymphatic vessels.

The research team had previously used a MEK inhibitor in another patient with a severe lymphatic disorder with great success. That patient had a mutation in the ARAF gene, which is also on the RAS-MAPK pathway. Within months of beginning treatment with trametinib, a MEK inhibitor, the patient saw a resolution of his symptoms and a complete remodeling of his lymphatic system.

Given that SOS1 operates on the same pathway as ARAF, Jean Belasco, MD, an oncologist in CHOP's Cancer Center who co-led the study, applied for compassionate use of the drug in Maria's case, given the lack of other treatment options.

"The success of trametinib in another patient with a mutation on the RAS-MAPK pathway encouraged us to try this approach, since other procedures and therapies continued to be unsuccessful," Belasco said. "Although we are in the early days of this type of personalized medicine, the hope is that by looking at patients' mutations, we can find more drugs and better care for patients with genetic diseases."

Within three months of starting the drug, Maria's vital signs stabilized. The bleeding stopped, her electrolyte, hemoglobin, and albumin levels returned to normal, and she began to gain weight. Maria's mother noticed that Maria wasn't going through periods of exhaustion anymore, and her pallor improved.

"She looks better than she's ever looked," her mother said. "She looks like a normal teenager. It's like night and day. She's also a lot happier. I think she knew deep down she was dying. The medicine gave her hope."

Hakon Hakonarson, Director of the Center for Applied Genomics and co-author of the paper, said that although Maria's SOS1 mutation is distinctly different than the ARAF mutation seen in the other patient, the drug was equally effective because it targets and blocks the function of MEK. He likened the scenario to a pathway where 15 events need to occur for a cell to function. Maria's SOS1 mutation might occur at step nine, whereas the ARAF mutation might occur at step three, but both genes are on a chain that ultimately passes through a tunnel that leads to phosphorylation and overactivity of MEK. Since both mutations were so-called gain of function mutations, MEK and thus lymphatic activity was overexpressed in both patients. The MEK inhibitor put the brakes on a system in overdrive.

"Remarkable advances in genetics have allowed us to uncover these mutations and cluster them into selective pathways and determine effective therapies based on genetic mutations with very high precision," said Hakonarson. "No one could have guessed that this drug would have worked for Maria without knowing the underlying genetics. This discovery is extremely important because Noonan Syndrome has the biggest patient population with alterations in MEK signaling. Not all Noonan patients will have mutations that respond to this therapy, but a very good number of them will."

He added that the treatment could also benefit patients with other genetic defects, though he noted the ongoing use of the drug treats the symptoms caused by these mutations, but does not fix the gene or cure the underlying condition.

"MEK inhibition has the potential to have significant effects on other organ systems affected by RAS-MAPK gene defects, such as the heart, eyes, skin and the coagulation system," Hakonarson said.

Hakonarson is also part of CHOP's Comprehensive Vascular Anomalies Program (CVAP), a CHOP Frontier Program that uses state-of-the-art genomics and personalized research strategies to determine the causes of complex vascular conditions and identify targeted therapies. The program works closely with the Lymphatic Imaging and Interventions Frontier Program, which is led by Dori. CHOP's Frontier Programs conduct cutting-edge research that translates into advanced clinical care. The CVAP, in particular, draws on the extensive clinical and genomic research capacity within the Cancer Center and Center for Applied Genomics.

Even with the success of the breakthrough treatment pioneered by these programs, it is not entirely clear why MEK inhibitors not only resolve patients' symptoms but also completely remodel their lymphatic systems. Hakonarson said one possibility is that when mutated genes cause uncontrolled growth of the lymphatic system, the body's vessels leak fluid everywhere in the body. When you shut down the unregulated growth, other homeostatic mechanisms that are balancing the system come into effect, so the overreactive cells that were growing out of control die and are replaced by normal cells that gradually build up the lymphatic system.

Whatever the mechanism, Maria's mother said her daughter had no hesitation at being the first patient with Noonan Syndrome to try this treatment to resolve a lymphatic issue.

"Maria saw the value from the beginning," she said. "She saw the value for herself, but she was also thinking of other Noonan kids, some of whom have passed away from lymphatic issues. She was willing and eager."

Dori et al. "Severe Lymphatic Disorder Resolved with MEK Inhibition in a Noonan Patient with SOS1 Mutation," Pediatrics, published online November 20, 2020, doi: 10.1542/2020-000123

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Contact: Natalie SolimeoChildren's Hospital of Philadelphia267-426-6246solimeon@chop.edu

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Epigenetics and pulmonary diseases in the horizon of precision medicine: a review – DocWire News

This article was originally published here

Eur Respir J. 2020 Nov 19:2003406. doi: 10.1183/13993003.03406-2020. Online ahead of print.

ABSTRACT

Epigenetic mechanisms represent potential molecular routes which could bridge the gap between genetic background and environmental risk factors contributing to the pathogenesis of pulmonary diseases. In patients with chronic obstructive pulmonary disease (COPD), asthma, and pulmonary arterial hypertension (PAH), there is emerging evidence of aberrant epigenetic marks, mainly including DNA methylation and histone modifications which directly mediate reversible modifications to the DNA without affecting the genomic sequence. Post-translational events and microRNAs can be also epigenetically regulated and potentially participate to disease pathogenesis. Thus, novel pathogenic mechanisms and putative biomarkers may be detectable in peripheral blood, sputum, nasal and buccal swabs, or lung tissue. Besides, DNA methylation plays an important role during the early phases of fetal development and may be impacted by environmental exposures, ultimately influencing an individuals susceptibility to COPD, asthma, and PAH later in life. With the advances in omics platforms and the application of computational biology tools, modelling the epigenetic variability in a network framework, rather than as single molecular defects, is providing insights into the possible molecular pathways underlying the pathogenesis of COPD, asthma, and PAH. Epigenetic modifications may have clinical applications as non-invasive biomarkers of pulmonary diseases. Moreover, combining molecular assays with network analysis of epigenomic data may aid in clarifying the multi-stage transition from a pre-disease to disease state, with the goal of improving primary prevention of lung diseases and its subsequent clinical management.We describe epigenetic mechanisms known to be associated with pulmonary diseases and discuss how network analysis could improve our understanding of lung diseases.

PMID:33214212 | DOI:10.1183/13993003.03406-2020

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Myriad Genetics Announces Global Expansion of Myriad myChoice Tumor Testing in Europe and China – GlobeNewswire

SALT LAKE CITY, Nov. 16, 2020 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc. (NASDAQ: MYGN), a global leader in molecular diagnostics and precision medicine, announced today the expansion of Myriad myChoice tumor testing in several European markets and China.

Myriad myChoice CDx is the industrys most clinically-validated genomic instability test. The test enables physicians to identify patients with tumors that have lost the ability to repair double-stranded DNA breaks, resulting in potentially increased susceptibility to DNA-damaging drugs such as platinum drugs or PARP inhibitors, including Lynparza (olaparib). A biomarker subgroup analysis of the PAOLA-1 Phase III trial (Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer, 2019) of Lynparza included patients with advanced ovarian cancer and homologous recombination deficient (HRD)-positive tumors as detected by the myChoice test, including those with BRCA gene mutations. The trial showed that Lynparza in combination with bevacizumab maintenance treatment improved progression-free survival to a median of 37.2 months versus 17.7 months for bevacizumab alone in patients with HRD-positive advanced ovarian cancer. Recently, the European Commission authorized use of Lynparza for the first-line maintenance treatment with bevacizumab of patients with HRD-positive advanced ovarian cancer. Lynparza is jointly developed and commercialized by AstraZeneca (LSE/STO/Nasdaq: AZN) and Merck.

As part of the expansion in Europe, Myriad will license and provide technological support to leading pathology institutes in Germany and France. Additionally, Myriad will support European customers by performing testing out of its clinical laboratory at the companys global headquarters in Salt Lake City. Also, the institutes in Europe will perform the tests with Myriads myChoice CDx PLUS assay. Myriad myChoice CDx PLUS is CE-marked in accordance with the In-Vitro Diagnostic Devices Directive (98/79/EC).

Another collaboration in China provides that Myriad will partner with Burning Rock Biotech, a leader in next generation sequencing technology for precision oncology, to provide myChoice for HRD testing in Phase III clinical studies and clinics throughout China. Myriad will provide Burning Rock with access to its proprietary myChoice technology. The partnership with Burning Rock expands global access to myChoice and positions the test as a preferred developmental companion diagnostic in this important drug development category.

These new strategic partnerships with leading companies dedicated to advancing the power of precision medicine, reinforce Myriads commitment to expanding access to genetic insights for more patients than ever before, said Nicole Lambert, president of Myriad Genetic Laboratories. Through close collaboration with innovative laboratories in Europe and with Burning Rock in China, we are bringing the clinical benefits of myChoice testing to additional markets and patients, advancing personalized treatment for patients around the world.

In August 2020, myChoice was exclusively cited and the only named commercial companion diagnostic by the American Society of Clinical Oncology in new recommendations on the use of PARP inhibitors for the treatment and management of certain patients with advanced ovarian cancer. The new recommendations, based on clinical trial results, were published in the Journal of Clinical Oncology.

AboutMyriad myChoice Myriad myChoice is the most comprehensive homologous recombination deficiency (HRD) test, enabling physicians to identify patients with tumors that have lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum drugs or PARP inhibitors. The myChoice test comprises tumor sequencing of the BRCA1 and BRCA2 genes and a composite of three proprietary technologies (loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions). For more information, visit: https://myriad-oncology.com/mychoice-cdx/

About Myriad Genetics Myriad Genetics Inc., is a leading personalized medicine company dedicated to being a trusted advisor transforming patient lives worldwide with pioneering molecular diagnostics. Myriad discovers and commercializes molecular diagnostic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across six major medical specialties where molecular diagnostics can significantly improve patient care and lower healthcare costs. Myriad is focused on three strategic imperatives: transitioning and expanding its hereditary cancer testing markets, diversifying its product portfolio through the introduction of new products and increasing the revenue contribution from international markets. For more information on how Myriad is making a difference, please visit the Company's website:www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, Vectra, Prequel, Foresight, GeneSight, riskScore and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Safe Harbor Statement This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to the Companys new international collaborations on the myChoice CDx test, including offering the test to European patients, and partnering with pathology institutes in Europe and Burning Rock in China; and the Companys strategic directives under the caption "About Myriad Genetics." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties associated with COVID-19, including its possible effects on our operations and the demand for our products and services; our ability to efficiently and flexibly manage our business amid uncertainties related to COVID-19; the risk that sales and profit margins of our molecular diagnostic tests and pharmaceutical and clinical services may decline; risks related to our ability to transition from our existing product portfolio to our new tests, including unexpected costs and delays; risks related to decisions or changes in governmental or private insurers reimbursement levels for our tests or our ability to obtain reimbursement for our new tests at comparable levels to our existing tests; risks related to increased competition and the development of new competing tests and services; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that we may not successfully develop new markets for our molecular diagnostic tests and pharmaceutical and clinical services, including our ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying our molecular diagnostic tests and pharmaceutical and clinical services and any future tests and services are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating our laboratory testing facilities and our healthcare clinic; risks related to public concern over genetic testing in general or our tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to our ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to our ability to successfully integrate and derive benefits from any technologies or businesses that we license or acquire; risks related to our projections about our business, results of operations and financial condition; risks related to the potential market opportunity for our products and services; the risk that we or our licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying our tests; the risk of patent-infringement claims or challenges to the validity of our patents or other intellectual property; risks related to changes in intellectual property laws covering our molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries, such as the Supreme Court decisions in Mayo Collab. Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012), Assn for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), and Alice Corp. v. CLS Bank Intl, 573 U.S. 208 (2014); risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that we may be unable to comply with financial operating covenants under our credit or lending agreements; the risk that we will be unable to pay, when due, amounts due under our credit or lending agreements; and other factors discussed under the heading "Risk Factors" contained in Item 1A of our most recent Annual Report on Form 10-K for the fiscal year ended June 30, 2020, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

Media Contact: Jared Maxwell (801) 505-5027 jmaxwell@myriad.comInvestor Contact: Scott Gleason(801) 584-1143sgleason@myriad.com

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Myriad Genetics Announces Global Expansion of Myriad myChoice Tumor Testing in Europe and China - GlobeNewswire

Four years after landing in US, graduating ISU senior is on his way to medical school – Iowa State University News Service

Mohamed Elrashed Shogar, graduating in genetics, stands inside a Molecular Biology Building laboratory where he has conducted much of his undergraduate research. Photo by Christopher Gannon. Larger image. All photos and videos were shot following physical distancing guidelines, and with staff wearing face coverings.

AMES, Iowa A headache started Mohamed Shogars journey to a career in medicine.

His mothers relentless headaches forced her to travel more than 900 miles from their home to Sudans capital, Khartoum, for treatment. She never found relief, and it frustrated Shogar, who is graduating from Iowa State University next weekend with a bachelors degree in genetics.

Shes the reason, Shogar said. She motivated me to pursue a career in medicine.

He was also bothered by the physician shortage in his hometown of Al Fashir. Shogar noticed the same physician shortage when he arrived in the United States and again thought, Why not pursue a career in medicine to help them out?

Shogars mother has a Ph.D. and his father is a high school principal. Education was the biggest priority for his family. So, after graduating high school, Shogar came to the U.S. in 2016.

After traveling to Egypt to meet with the U.S. ambassador and receive a green card, Shogar was on his way.

The first time, when I landed in Chicago, I was so overwhelmed, he said. I didnt know what to expect. I didnt know the language or the culture. I had just finished high school, and the future wasnt clear to me.

He headed to Cedar Rapids, where he lived with his cousin for a few months and talked to newfound friends about his educational options in the state. One friend suggested starting out at a community college before heading to a four-year university. So, Shogar enrolled at Kirkwood Community College and took English as a Second Language classes while working full time at the Nordstrom warehouse. He gained medical experience as a phlebotomist at Mercy Medical Center in Cedar Rapids before taking some courses at the University of Iowa.

In 2018, he transferred to Iowa State to finish his genetics degree. At the same time, hes worked as a phlebotomist at Mary Greeley Medical Center.

I wouldnt have done it without the people who helped me out, he said. Im so grateful for them.

During his first semester in Ames, Shogar had to take organic chemistry considered one of the most difficult courses at Iowa State. He struggled during the first exam and felt defeated. But he went to the office of chemistry professor Arthur Winter for help. They talked about college courses generally, and how to study. On Shogars next organic chemistry exam, he received a near-perfect score.

Shogar found community and friendship in his classes as well as student organizations, such as the Sudan United Association and the Minority Association for Pre-Health Students.

He typically travels back to Sudan every winter to visit his family, but with the ongoing COVID-19 pandemic and his post-graduation plans, that visit is on hold. Right now, hes in the midst of the nerve-wracking process of applying to medical schools.

Shogar said going to school and working through the pandemic has been mentally and emotionally draining.

It also had an impact on my education journey, he said. I was not able to shadow and volunteer, which is a very important part in medical school applications.

He also found a mentor in Mark Hargrove, Morrill Professor of biochemistry, biophysics and molecular biology (BBMB), who talked with Shogar about his plans after graduation. To build his research experience, Gordon connected Shogar with Alan DiSpirito, professor of BBMB, whose lab works with methanobactin to study its effects on Wilsons disease, a genetic disorder that causes excessive copper build-up in the body.

This has been an amazing experience, honestly, Shogar said. Its been such a welcoming environment.

The opportunities that I got here, I dont think I would be able to get in Sudan. In terms of the quality of education, I cant even compare it.

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Four years after landing in US, graduating ISU senior is on his way to medical school - Iowa State University News Service

Lethal brain infections in mice thwarted by decoy molecule – Washington University School of Medicine in St. Louis

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Discovery of receptor, generation of decoy could help contain outbreaks of Venezuelan equine encephalitis virus

Researchers at Washington University School of Medicine in St. Louis have identified a molecule that protects mice from brain infections caused by Venezuelan equine encephalitis virus (VEEV), a mosquito-borne virus notorious for causing fast-spreading, deadly outbreaks in Mexico, Central America and northern South America.

Researchers at Washington University School of Medicine in St. Louis have identified a molecule that protects mice from brain infections caused by Venezuelan equine encephalitis virus (VEEV), a mosquito-borne virus notorious for causing fast-spreading, deadly outbreaks in Mexico, Central America and northern South America. As the climate changes, the virus is likely to expand its range and threaten more countries in the Americas, including the U.S.

Public health officials have struggled to contain such outbreaks in the absence of effective drugs and vaccines. As a potential drug, the molecule described in a paper published Nov. 18 in the journal Nature could serve as a much needed tool to control the deadly virus.

This virus can infect many species of wild mammals, and every few years it jumps from animals to humans via mosquitoes and causes thousands of infections and many deaths, said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and a professor of molecular microbiology, and of pathology and immunology. Theres concern that with global warming and population growth, well get more outbreaks.

Once injected under the skin by mosquitoes, the virus homes in on neurons. People start experiencing symptoms such as headache, muscle pain, fatigue, vomiting, nausea, diarrhea, sore throat and fever within a week. In the most serious cases, the virus gets past the blood-brain barrier, causing encephalitis brain inflammation that can be fatal in up to a quarter of patients.

To find the potential drug, Diamond and colleagues including first authors Hongming Ma, PhD, an instructor in medicine, and Arthur S. Kim, PhD, a postdoctoral researcher began by searching for the protein handle on the surface of animal cells that the virus attaches to and uses to get inside cells. A drug that stops the virus from grabbing that handle, the scientists reasoned, could stymie infection and prevent disease.

But first they had to make a form of the virus they could work easily with. During the Cold War, the U.S. and the Soviet Union attempted to weaponize the virus, and it is still classified as a select agent, meaning only certain high-security labs are allowed to work with it. So instead, the researchers and their colleagues took Sindbis virus, a related virus that causes mild fever and rash, and swapped out some of its genes for some from VEEV. The resulting hybrid virus, called Sindbis-VEEV, infects cells like authentic VEEV but is unable to cause severe disease.

Using a genetic engineering technique known as genome-wide CRISPR screening, the researchers deleted genes in mouse neuronal cells until they found one called Ldlrad3 whose absence kept Sindbis-VEEV from infecting cells. The missing gene codes for a little-studied surface protein.

Further experiments verified the importance of Ldlrad3. Adding the gene back to neuronal cells restored the viruss ability to infect cells. The human LDLRAD3 gene is almost identical to its mouse equivalent, and knocking out the human gene also reduced infection in multiple cell lines. When the researchers added Ldlrad3 to a different cell type that is normally resistant to infection, the virus was able to infect the cell. Co-author William Klimstra, PhD, at the University of Pittsburgh, separately replicated the findings using authentic, highly virulent VEEV.

Ldlrad3 doesnt appear to be the only way the virus gets inside cells, since a small amount of virus is able to infect cells lacking the protein. But it is clearly the primary way in. Since Ldlrad3 is naturally on our cells and cant be removed, the scientists decided to create a decoy handle using a piece of the Ldlrad3 protein. Any virus particles that mistakenly latch onto the decoy handle would fail to infect cells and instead would get destroyed by the immune system.

To test their decoy in a living animal, the researchers injected mice with authentic virulent VEEV in two different ways: under the skin to mimic a mosquito bite, or directly into the brain. They gave the mice the decoy handle or a placebo molecule for comparison, either six hours before or 24 hours after infection. In all experiments, all of the mice that received the placebo died within a week. In most cases, all of the mice that received the decoy molecule survived, although in the most stringent experiment in which the virus was injected into the brain two of the 10 mice died despite receiving the decoy.

In an outbreak situation, you may be able to use a drug like this as a countermeasure to prevent transmission and further spread, Diamond said.

A major advantage to an antiviral drug based on a human rather than a viral protein is that it is unlikely the virus could evolve resistance to it. Any mutation that enables the virus to avoid the decoy probably would make it unable to attach to cells, too, the researchers said.

Ma H, Kim AS, Kafai NM, Earnest JT, Shah A, Case JB, Basore K, Gilliland TC, Sun C, Nelson CA, Thackray LB, Klimstra WB, Fremont DH, Diamond MS. LDLRAD3 is a receptor for Venezuelan equine encephalitis virus. Nature. Nov. 18, 2020. DOI: 10.1038/s41586-020-2915-3

This study was supported by the National Institutes of Health (NIH), grant numbers R01AI143673, U19AI142790, R01AI095436 and T32 AI007172 and contract number HHSN272201700060C; and the Defense Reduction Threat Agency, grant numbers HDTRA1-15-1-0013 and HDTRA1-15-1-0047.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Lethal brain infections in mice thwarted by decoy molecule - Washington University School of Medicine in St. Louis

Reducing barriers to mainstream gene therapy – BioPharma-Reporter.com

The company is to invest 3.4m (around US$4.5m) alongside the grant.

The funds will support research into the manufacturing challenges associated with scaling gene therapies for widespread patient access, to further develop technologies to improve the safety and efficacy of current therapies, and to enable the treatment of genetic diseases with more complicated disease pathways the industry is not yet able to address.

Along with the creation of 11 new jobs in Edinburgh, the developer said it will further enhance its Pro10 platform, an AAV manufacturing process that can be scaled and applied throughout the group.

The grant will also advance development of the tool kit of inducible, repressible, tunable and responsive expression cassettes to be adopted in the current clinical pipeline and new disease targets.

Gene therapy has the potential to treat a wide range of diseases including certain forms of muscular dystrophy, congestive heart failure and some diseases of the central nervous system but, at present, only two market-approved therapies are available.

David Venables, president, AskBio Europe, commented: The grant awarded by Scottish Enterprise supports AskBio in working towards developing even safer and more effective gene therapies through improved development and manufacturing techniques. Science and innovation keep progressing, and that makes this an exciting time to develop this type of therapeutic agent.

AskBios technology is inside both currently approved AAV gene therapies, which include Luxturna, developed by Spark Therapeutics, for the treatment of patients with inherited retinal disease, and Zolgensma, developed by AveXis, for the treatment of patients with spinal muscular atrophy (SMA).

AveXis licenses AskBios self-complementary DNA technology for Zolgensma.

While the promise of such therapies is being shown, significant barriers remain before gene therapies can become more broadly impactful, according to AskBio.

With global headquarters in Research Triangle Park, North Carolina, and European headquarters in Edinburgh, UK, AskBio has generated hundreds of proprietary third generation AAV capsids and promoters, several of which have entered clinical testing.

BioPharma-Reporter (BPR) spoke to Ken Macnamara, (KM), PhD, chief operating officer, AskBio Europe,to get the AAV developers take on the factors preventing gene therapy going mainstream.

BPR: What criteria did AskBio have to fulfill to be awarded this grant?

KM: The research must be highly novel with significant risk from which a successful outcome will accelerate business growth within Scotland and globally.

BPR: What are the current manufacturing challenges associated with scaling gene therapies for widespread patient access?

KM: As we see growing evidence that gene therapy is a viable, transformational medicine, along with an acceleration in the number of AAV therapeutics moving towards regulatory approval, the ability to manufacture these therapies for diseases with large patient populations does not exist today and costs are extremely high.

Many companies can manufacture small batches of therapeutics for clinical applications, but as they approach commercialization, the challenges of production costs and timelines remain an issue. We recognized this more than a decade ago and focused on creating robust, scalable manufacturing capabilities.

Today, the challenges for manufacturing gene therapy are being met by simply adding large amounts of capacity, which is not the long-term answer. There is a significant amount of innovation taking place that will no doubt shape the future of manufacturing AAV gene therapeutics. This work continues today in our Edinburgh and US facilities to further improve the technology.

BPR: What are some of the typical safety and efficacy issues linked to current therapies?

KM: Currently approved gene therapies have provided effective therapy by targeting tissues in the body with an administered gene that produces a new, effective protein. This new gene replaces the defective or missing gene causing the patients underlying disease.

Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible.

AAV is not known to cause human disease, and it cannot make more of itself without outside help, so it will not replicate in the body like normal viruses do. AAV is engineered to carry therapeutic genes by removing some of its genetic cargo and replacing it with human gene sequences. This results in an AAV vector, a therapeutic genetic medicine.

Risks associated with AAV gene therapy vector administration include unwanted immune system reactions. The body's immune system may see the newly introduced AAV vectors as intruders and attack them, which may cause inflammation and, in severe cases could be local and mild or throughout a greater area of the body and be more serious. AAV vectors can also target tissues other than the intended tissue. Thus, it's possible that AAV vectors may affect additional cells, not just the targeted cells containing mutated genes. These are called off-target effects. If this happens, healthy cells may be damaged.

BPR: Can you indicate the other significant barriers that remain before gene therapies can become more broadly impactful?

KM: Therapies need to express the gene in the right tissue, at the right level, for the right amount of time. There is a great deal of research happening throughout the gene therapy field to identify the best means of delivering and controlling activation of the genetic material. Furthermore, the response of the patients immune system also needs to be considered based on the therapy. Additional funding, like that from Scottish Enterprise, can help speed up the development process of promising therapies.

BPR: How does AskBio envisage exploring the treatment of genetic diseases with more complicated disease pathways that the industry is not yet able to address?

KM: One of the most exciting advances in modern medicine has been the discovery of how AAV vectors can be used as an effective delivery system for therapeutic genetic material into living tissue. AAV gene therapy has broad therapeutic implications for a vast array of diseases.

Some genetic diseases are caused by mutations in a single gene, while others are a result of mutations in multiple genes, for example, cancer. Additionally, environmental factors, such as smoking and diet, can play a role in diseases. The complexity of these disease characteristics creates variables in developing and testing potential treatments. Currently the gene and cell therapy options that exist today are limited to treating diseases caused by a single gene mutation.

AskBios Edinburgh team leads the gene therapy field in the design and development of synthetic gene expression cassettes. The technology is essential for controlling the expression of AAV therapeutics, thereby improving their safety and efficacy. This R&D project will enable AAV therapeutics to be turned on and off and dialed up or down depending on the amount of drug needed at any given time. This technology provides a desired safety switch and level of variable dosing that previously did not exist. Before this breakthrough, AAV therapeutics could only express at one constant level and could not be turned off, which limited the type of therapeutics for which AAV could be used and may hold the key to treating pathway diseases where multiple genes are affected.

BPR: On the job creation front, is the talent already hired or are you starting a recruitment drive?

KM: The grant allows us to make some positions permanent and bring in new talent.

Ken Macnamara joined AskBio in 2019 with a wealth of R&D, business operations, financial planning, intellectual property and quality/compliance experience gained from start-up to multinational firms. He most recently was COO at Synpromics.

Dr Macnamara began his career at the University of Edinburgh, where he earned a PhD in chemistry before helping to start Lab901 (Scottish SME). There, he was a product development manager responsible for developing the TapeStation and ScreenTape technologies from concept to market success. Lab901 was acquired by Agilent Technologies in 2011. Dr Macnamara then served as R&D director for the Microfluidics business at Agilent.

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Reducing barriers to mainstream gene therapy - BioPharma-Reporter.com

Mapping Genetic Diversity of Lung Tumors Over Time May Lead to More Effective Therapies – UCSF News Services

Lung cancer cells invade surrounding tissues and start to spread.Image courtesy of the National Cancer Institute

A malignant tumor is a bustling metropolis populated by many different kinds of cancer cells. This cellular diversity, however, is what makes cancer so difficult to treat, as each type of cell in a tumor responds differently and sometimes not at all to cancer therapies. This is especially true for lung cancer, which often responds to an initial course of treatment, only to remerge after becoming drug-resistant, making it the deadliest form of cancer worldwide.

A better understanding of the diversity that exists within a lung tumor would likely lead to more effective treatments. Today, clinicians generally rely on tests that generate genetic profiles of biopsied tumors in bulk rather than one cell at a time. Unfortunately, this usually fails to capture the full extent of cellular diversity within tumors and ends up obscuring clinically significant information. This has led scientists to search for ways to assemble a census of the many types of cells that comprise a malignant tumor. Even better would be a more complete picture of how these cell populations evolve during the course of treatment. However, figuring out exactly how to conduct this survey has proven to be a major technical barrier for scientists.

But this hurdle, once thought to be nearly insurmountable, was recently cleared by a research team led by UC San Francisco and Chan Zuckerberg Biohub scientists. The researchers figured out how to assemble genetic profiles of individual lung cancer cells obtained from patients at different times during the course of their treatment. In doing so, they revealed a vast cornucopia of cellular diversity in both lung tumors and the tissue surrounding the tumor as they evolved during the course of treatment clinically significant information that had previously eluded scientists. The findings are detailed in a paper published Aug. 20 in the journal Cell.

This study is among the first of its kind, said Trever Bivona, MD, PhD, professor of medicine and senior author of the study. We observed features of lung cancer cells and the tumor microenvironment that no one had seen before. This gave us a window into the evolution of individual cells within the tumors ecosystem.

Starting with 49 biopsies obtained from 30 lung cancer patients, the researchers used single-cell sequencing to map the landscape of gene activity in over 23,000 individual lung cancer cells at three time points: before treatment, after the tumors stabilized or went into remission during treatment, and after the cancer, despite continuous treatment, had fully re-grown and become treatment resistant.

These single-cell profiles revealed the presence of tumor cells that harbored cancer-driving genetic mutations distinct from those that were identified by the various clinical tests that the patients received during the course of their treatment. Though these mutations were present in only a fraction of cells in each tumor, they had a significant effect on patient outcomes. Patients whose tumors carried two or more of these mutations had significantly lower overall survival rates than patients with fewer than two.

The researchers also found that when lung tumors stabilized or went into remission in response to treatment, some malignant cells were able to cling to life by switching on genes associated with injury repair and survival that are normally only active in healthy lung cells. When these genes are active, the cancer cells enter a repair and survival state that, according to Bivona, puts the cells into hibernation mode so that the cell death machinery doesnt get activated.

But these survival genes have an Achilles heel. They rely on whats known as the Wnt/beta-catenin signaling pathway, which can be targeted with existing drugs. In fact, laboratory tests demonstrated that when administered at the appropriate time, drugs targeting the Wnt/beta-catenin pathway, combined with a common lung cancer therapy, reduced the number of cancer cells that survived.

Our results suggest that we could target specific cell states in lung tumors and improve patient survival by constraining tumor evolution and preventing drug resistance and tumor survival and re-growth, Bivona said.

The study also provides key insights into how the cells and tissue that surround a lung malignancy the tumor microenvironment create conditions that prevent the immune system from taking up arms against the tumor.

Single-cell profiling revealed that the tumor microenvironment was hostile to immune activity both before treatment and after a tumor had evolved drug resistance. However, during treatment, when the cancer is in the hibernation mode revealed in the study, the researchers found that immune cells were able to infiltrate the tumor microenvironment and appeared to be switched on, suggesting there may be a limited window of opportunity during which conventional cancer therapies can be combined with immunotherapies a class of cancer treatments that has proven effective against some cancers, but has largely failed against the types of lung tumors profiled in this study to produce better overall survival rates.

Putting tumor heterogeneity front and center would better equip clinicians with information that allows for a high-resolution window into the evolution of tumors during therapy, and help us use such a roadmap to intervene more proactively to better control tumors and help patients, said Bivona. The single-cell analysis that we proved is feasible in real-life clinical tumors may help usher in a new era in the clinical management of tumors during therapy by strengthening our molecular diagnostic toolkit.

Authors: Additional authors include Caroline E. McCoach, Franziska Haderk, D. Lucas Kerr, Elizabeth A. Yu, Philippe Gui, Tasha Lea, Wei Wu, Anatoly Urisman, Kirk Jones, Pallav K. Kolli, Eric Seeley, Yaron Gesthalter, Sourav Bandyopadhyay, Khyati Shah, Lauren Cech, Nicholas J. Thomas, Anshal Gupta, Mayra Gonzalez, Hien Do, Lisa Tan, Bianca Bacaltos, Matthew Gubens, Thierry Jahan, Johannes R. Kratz, David Jablons, Jonathan Weissman, and Collin M. Blakely of UCSF; Ashley Maynard, Lincoln Harris, Weilun Tan, Alexander Zee, Michelle Tan, Rene Sit, Daniel D. Le, Kevin A. Yamauchi, Rafael Gomez-Sjoberg, Norma Neff, and Spyros Darmanis of Chan Zuckerberg Biohub; Julia K. Rotow of Dana-Farber Cancer Institute; and Erin L. Schenk, David M. Naeger and Robert C. Doebele of the University of Colorado.

Funding: This research was supported by NIH awards U54CA224081, R01CA204302, R01CA211052, R01CA231300, R01CA169338, U01CA217882, R01CA227807, T32 HL007185, and K12 CA086913; the Van Auken Foundation; Novartis Pharmaceuticals; Pfizer; the University of California Cancer League; AstraZeneca; The Damon Runyon Cancer Research Foundation award P0528804; Doris Duke Charitable Foundation award P2018110; V Foundation award P0530519l; and the Mildred Scheel postdoctoral fellowship from the German Cancer Aid.

Disclosures: See manuscript for a full list of disclosures.

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Mapping Genetic Diversity of Lung Tumors Over Time May Lead to More Effective Therapies - UCSF News Services

Multi-site study to evaluate the role of testing guidelines in ensuring access to genetic information for men with prostate cancer – PRNewswire

SAN FRANCISCO, Sept. 3, 2020 /PRNewswire/ --Invitae (NYSE: NVTA), a leading medical genetics company, today announced enrollment has begun for a nationwide study to better understand the role of current genetic testing guidelines in ensuring prostate cancer patients receive testing to identify clinically relevant genetic variants that can inform prognosis and support access to targeted therapies. The study is supported by Invitae and is part of the company's ongoing work to increase access to genetic information for men with prostate cancer.

"Currently, germline testing guidelines for patients with prostate cancer have evolved from more than one set of NCCN guidelines and some may still find these guidelines difficult to implement in everyday practice," said Neal D. Shore, M.D., F.A.C.S. from the Carolina Urologic Research Center in Myrtle Beach, South Carolina, and the principal investigator of the study. "Guidelines were established when testing was both more expensive and less accessible and don't address newer therapeutic approvals and trial literature for expanding therapeutic options, missing many patients whose clinical care and treatment choices could benefit from genetic information. Our study is intended to provide a deeper understanding of how these issues impact the care of men with prostate cancer so that we might improve how genetic information can be assessed and utilized for their cancer care and potentially inform their family members."

The use and importance of genetic information in the diagnosis and treatment of prostate cancer has been growing, particularly as the development of targeted treatments continues to accelerate. Despite its utility, guidelines governing testing among prostate cancer patients remain restrictive, and genetic information is underutilized in prostate cancer care. The study will determine whether guidelines are adequate in identifying patients who may benefit from genetic testing.

"Simplifying and possibly expanding current testing guidelines would provide benefits for medical management of men with prostate cancer and offer opportunities for targeted therapies, including PARP inhibitors and qualification for clinical trials," said Robert Nussbaum, M.D., chief medical officer of Invitae. "In addition, the genes involved in prostate cancer include BRCA1 and 2, which as we all know also play an important role in breast and ovarian cancer, and MSH6 and other genes involved in hereditary colon cancer. Widespread testing among men with prostate cancer could have an important role in not only improving their care but also the health of their relatives."

The study will enroll men across the country who have been diagnosed with prostate cancer. Both men who meet and don't meet current testing guidelines will be included to gather data on whether genetic testing results change treatment and recommendations. In addition, the study will also gather data on the patient's experience with genetic testing.

A study presented recentlyby Invitae at the American College of Medical Genetics and Genomics (ACMG) underscored the frequency of actionable variants expanded testing can help uncover. The study of 2,252 men found an overall positive rate of 13% with no statistical differences in rates among stages of disease. Only half of patients with an actionable variant reported a family history suggestive of increased risk. Nearly three-quarters (71%) of positive patients were eligible for management guidelines and/or potentially eligible for approved precision therapies or clinical trials.

An estimated three million men are living with prostate cancer in the U.S., and just under 200,000 are newly diagnosed each year.

Contact [emailprotected] for more information about the study.

About InvitaeInvitae Corporation(NYSE: NVTA) is a leading medical genetics company whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the use and importance of genetic testing and information; and the benefits of simplifying and possibly expanding current testing guidelines for men with prostate cancer. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's history of losses; the company's ability to compete; the company's failure to manage growth effectively; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended June 30, 2020. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:Laura D'Angelo[emailprotected](628) 213-3283

SOURCE Invitae Corporation

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Multi-site study to evaluate the role of testing guidelines in ensuring access to genetic information for men with prostate cancer - PRNewswire

Global Prime Editing Market to Witness Heightened Growth During the Period 2020 2030 – The Daily Chronicle

Prime editing is the gene-editing method that can insert, delete and do base swapping accurately. Prime editing also termed as genetic word processor precisely select the target DNA and replace genetic code. Targeting 75,000 different mutations and correcting 89% of genetic defects will drive the demand for prime editing. In 2017, the first gene editing in the human body was attempted. Gene editing in a patient with Hunters syndrome was tested for safety and concluded reliable shreds of evidence. Superior target flexibility and editing precision with minimal errors make Prime editing first preference over the other conventional technique such as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). Application of prime editing in reversing Genetic disease will be a milestone in gene editing.

Increasing prevalence of genetic disease creates a huge opportunity for prime editing market. Successful preliminary results with a genetic disease like Tay Sachs and Sickle cell anaemia will drive the prime editing market. Technological advancements providing minimal error with this technique will fuel the growth of prime editing. Decreased cost of DNA sequencing will propel prime editing market for research and commercialization. Arising ethical and safety concerns will make prime editing highly regulated sector. This may limit the scope and can restraint the growing market. Detrimental effect on Genetic diversity due to genetic engineering in one way may limit the market scope.

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The global Prime Editing market is classified on the basis of application and end user:

Based on application, Prime Editing Market is segmented into following:

Based on end user, Prime Editing Market is segmented into following:

Prime Editing is the most recent invention has created a buzz in the market. Firms accessing conventional genome engineering technologies have rolled plans of transitioning to this new technology. The restructuring by the firms is either by building upon the technological capabilities or by merging or acquiring the firms which hold expertise in prime editing. Inscripta, one of the most innovative company has launched the worlds first benchtop platform for digital genome engineering. Inscriptas Onyx device that was launched in October 2019, will enable genome editing at an unprecedented scale and cheaper rate. In 2019, Beam Therapeutics collaborated with a premium start-up in prime editing segment Prime Medicine for Prime Editing Technology. Beam therapeutics holds expertise in precision genetic medicine using base editing technology. The market consolidation activities my giants depict that genome editing will be the largest revenue-generating segment for prime editing market.

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North America will drive the market for Prime Editing due to high prevalence of genetic disease and technological advancement in the U.S. and Canada. One in every 27 Jews, is carrying Tay Sachs disease gene. After North America, Europe is leading in patient pool for genetic diseases such Hemophilia and Cystic fibrosis. The genetic disease pool will drive the adoption for Prime editing treatments in this region. Asia-Pacific will remain at steady growth for Prime Editing market due less disease prevalence and focus on other therapies. Latin America and Middle East and Africa region will boost the market owing to the disease prevalence.

Examples of some of the market participants in Prime Editing market identified across the value chain Beam Therapeutics Inc., Precision BioSciences, Inscripta, Inc, Horizon Discovery Ltd., Sangamo Therapeutics, Inc., CRISPR Therapeutics., Intellia Therapeutics, Inc., and others

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Global Prime Editing Market to Witness Heightened Growth During the Period 2020 2030 - The Daily Chronicle

Liquid biopsies to disrupt the oncology testing market – Medical Device Network

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Obtaining sufficient tumour tissue for oncology testing can be challenging, particularly when there is an insufficient biopsy sample, and invasive procedures pose a health risk to the patients. This is especially true for non-small cell lung carcinoma (NSCLC), where 27%31% of patients are unable to provide a suitable specimen upon diagnosis. One area of active research in oncology testing has been the evaluation of alternative sources of testing material. Liquid biopsy refers to the analysis of any tumour-derived material, circulating in the blood or any other body fluid. The detection of mutations via circulating tumour DNA (ctDNA) found in plasma has been rising in popularity due to its minimal invasiveness.

On 7 August, Guardant Health announced the Food and Drug Administration (FDA) approval of its novel liquid biopsy comprehensive tumour mutation profiling test across all solid cancers. This is a landmark approval for cancer testing as Guardant Healths liquid biopsy is the first of its kind to genetically profile tumours anywhere in the body from a single blood draw. The FDA approval of this test includes its approval as a companion diagnostic for identifying patients with metastatic NSCLC based on the presence of mutations in the EGFR gene. Lung cancer is the current leading cause of cancer-related deaths worldwide with NSCLC comprising 80%90% of all lung cancers. As such, the need for this test is very high.

On 27 August, Foundation Medicine, a Roche company, received FDA approval for its FoundationOne Liquid CDx, a multi-cancer comprehensive liquid biopsy test. Foundation Medicines test is broader than Guardant Healths, covering more than 300 cancer-related genes. In addition to single-gene alterations, Foundation Medicines test also reports on the presence of multi-gene signatures namely microsatellite instability and blood tumour mutational burden, which can help guide the use of cancer immunotherapies.

The genomic analysis of ctDNA has the potential to offer insight across multiple metastatic sites. This is particularly valuable in settings with increased genomic heterogeneity such as in patients with treatment resistance. Some key opinion leaders (KOLs) interviewed by GlobalData have indicated that despite the fact that the test has some sensitivity issues, liquid biopsies are a cheaper alternative and the minimally invasive aspect of the technique improves patient satisfaction. Other KOLs noted the potential for liquid biopsies to integrate the overall cancer burden in patients with numerous metastases in different locations. GlobalData predicts an increased usage of liquid biopsies in the future due to the benefits they offer patients with metastatic recurrence.

Liquid biopsy is revolutionising cancer tests as it is non-invasive, precise and provides faster turnaround time for results compared to traditional solid tumour biopsy. While DNA sequencing methods such as Sanger sequencing have been considered the gold standard for detecting many genetic mutations associated with cancer, these techniques have lower sensitivity, and thus, require samples with a higher percentage of mutated DNA. As such, the use of ctDNA will be important for detecting cancerous mutations where tumours are hard to resect. Furthermore, the use of highly sensitive assays such as next-generation sequencing (NGS) will aid in the detection of cancerous mutations. As sequencing technology like NGS becomes more developed and its costs decrease, GlobalData expects these techniques to be more frequently used to test for mutations in cancer.

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Liquid biopsies to disrupt the oncology testing market - Medical Device Network

Global RNA-interference (RNAi) Market Growth, Trends and Forecasts to 2025: Focus on Key Players Alnylam Pharmaceuticals, Arrowhead, Quark…

DUBLIN, Sept. 2, 2020 /PRNewswire/ -- The "RNA-interference (RNAi) Market - Growth, Trends, and Forecast (2020 - 2025)" report has been added to ResearchAndMarkets.com's offering.

The RNA-interference (RNAi) market is expected to witness a CAGR of 10.12% during the forecast period. Certain factors that are driving the market growth include the increasing number of applications in molecular diagnostics, particularly in cancer and improving synthetic delivery carriers and chemical modifications to RNA.

Cancer diagnosis and treatment is currently undergoing a shift with the incorporation of RNAi techniques in personalized medicine and molecular diagnostics. The availability of high throughput techniques for the identification of altered cellular molecules and metabolites allows the use of RNAi techniques in various cancer diagnosis and targeting approaches. For diagnostic purposes, small interfering RNAs (siRNA) or microRNAs (miRNA) can be utilized. The commercial availability of siRNAs to silence virtually any gene in the human genome is dramatically accelerating the pace of molecular diagnosis and biomedical research. Thus, increasing the application of RNAi in molecular diagnosis and its viability as a therapeutic technique is expected to drive the growth of the RNAi market during the forecast period.

However, in recent years, there has been a decline in FDA drug approval rates. Getting FDA approval for a new drug has become extremely challenging. It approved less than half the number of new drugs in 2016 (19 so far) when compared to 2015 (45 total) and 2014 (41 total). Hence, despite the large investments, there has been a decline in the number of innovative drugs manufactured. FDA explains manufacturing standards and other complying issues as the major reasons for this declining trend. This can impede the growth of the RNAi therapeutics, especially since the miRNAs and siRNAs fall into the relatively new field of genetic medicine, wherein they may require more intensified clinical trials. The highly extensive clinical trials effectively result in low approval rates of drugs. This would mean that the stringent guidelines will be a major restraint for the growth of the market.

Key Market Trends

Oncology is Expected to Hold Significant Market Share in the Therapeutics Type

According to the World Health Organization, cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer. The number of new cases is expected to rise by about 70% over the next two decades.

Recent advancements, such as the development of small interfering RNA (siRNA) tolerant to nucleases and the development of non-viral vectors, such as cationic liposomes and nanoparticles, can overcome this obstacle and facilitate the clinical use of RNAi-based therapeutics in the treatment of cancer.

Substantial pipeline for cancer therapies by companies and institutes such as Enzon Pharmaceuticals (Santaris Pharma), University of Texas, OncoGenex, Isarna Therapeutics, Astrazeneca (Ionis Pharmaceuticals), and INSYS Therapeutics, Inc. are expected to drive the market. In addition, many companies have invested in R&D for nanocarriers to deliver oligonucleotides for cancer treatment, which is expected to contribute to the oncology verticle.

North America Dominates the Market and Expected to do the Same in the Forecast Period

The U.S. has a number of RNAi therapeutics that are in developmental pipelines. A number of biotechnology companies have made considerably high investments for RNAi therapeutic development. Big pharmaceutical developers have entered into collaboration agreements or licensing deals with a number of smaller firms in an attempt to capitalize on the expected growth in revenue that this market can have over the forecast period. For instance, AstraZeneca's agreement with Ionis pharmaceuticals is one of the big deals that are investing heavily into RNA-interference technology

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS4.1 Market Overview4.2 Market Drivers4.2.1 Increasing Number of Applications in Molecular Diagnostics, Particularly in Cancer4.2.2 Improving Synthetic Delivery Carriers and Chemical Modifications to RNA4.3 Market Restraints4.3.1 Stringent FDA Regulations and Changing Reimbursement Environment4.3.2 Unstable Potentially Immunogenic Nature of RNA4.4 Porter's Five Forces Analysis4.4.1 Threat of New Entrants4.4.2 Bargaining Power of Buyers/Consumers4.4.3 Bargaining Power of Suppliers4.4.4 Threat of Substitute Products4.4.5 Intensity of Competitive Rivalry

5 MARKET SEGMENTATION5.1 Application5.2 Geography

6 COMPETITIVE LANDSCAPE6.1 Company Profiles6.1.1 Alnylam Pharmaceuticals6.1.2 Arcturus Therapeutics6.1.3 Arrowhead6.1.4 Dicerna Pharmaceuticals6.1.5 Quark Pharmaceuticals Inc.6.1.6 Ionis Pharmaceuticals Inc.6.1.7 Merck & Co. Inc. (Sigma Aldrich)6.1.8 Silence Therapeutics PLC6.1.9 Qiagen NV6.1.10 Phio Pharmaceuticals Corp.6.1.11 Thermo Fisher Scientific Inc.

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

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Global RNA-interference (RNAi) Market Growth, Trends and Forecasts to 2025: Focus on Key Players Alnylam Pharmaceuticals, Arrowhead, Quark...

Fusion Genes Associated With More Aggressive Papillary Thyroid Cancer in Pediatric Patients – Targeted Oncology

The most common genetic cause of alterations in pediatric patients with papillary thyroid cancer (PTC) were fusion genes, which were associated with more aggressive disease, according to a study published in Thyroid.

In this study, several novel rearrangements were identified, and the fusion genes seemed to be a molecular marker number one in this patient population.

Overall, the study included 93 pediatric patients who had undergone thyroid surgery between 2003 and 2019 at the Department of Ear, Nose, and Throat, Second Faculty Medicine, Charles University, and Motol University Hospital in Prague. The mean age of patients at diagnosis was 14.5 3.4 years, and the female to male ratio was 2.6 to 1. Eighty-two patients had a total thyroidectomy and 11 had a subtotal thyroidectomy, where 10 were completed to total thyroidectomy.

The mean tumor size was 22.1 13.7 mm, and the investigators noted that 17 patients had microcarcinoma. Twenty-six patients (29.9%) had PTC of classical variant, 20 (23.0%) had classical and follicular variant, 29 (33.3%) had follicular variant, 3 (3.4%) had solid variant, 3 (3.4%) had a mixture of classical/follicular/solid variant, 2 (2.3%) had diffuse sclerosing variant, 2 (2.3%) had columnar variant, 1 (1.1%) had tall cell variant, and 1 (1.1%) had case clear cell variant.

After a median follow-up was 72 months (range, 2-198), 11 (19.3%) patients had persistent or recurrent disease at least 1 year after surgery or patients who were in remission and later had a malignant object thyroid tissue formed. Sixteen (19.3%) patients only had biochemical evidence of persistent disease, while 56 (67.5%) remained in remission with no evidence of disease. One patient died due to advanced disease. Additionally, 10 patients were not classified because of short-term follow-up, 84 received radioactive iodine (RAI) treatment, and 8 did not receive RAI because of low-risk disease.

More than half (55.9%) of the patients had fusion genes, which included RET, NTRK1, NTRK3, ALK, BRAF, and MET. Additionally, 10 different types of RET fusions were observed in 26 patients, 4 types of NTRK3fusions in 14 patients, 1 ALK fusion in 6 patients, 2 types of NTRK1 fusions in 3 patients, 2 types of BRAFfusions in 2 patients, and 1 type of MET fusions in 1 patient. Overall, 20 types of fusion genes were identified in the study, 11 of which were interchromosomal and 9 were intrachromosomal rearrangements.

Investigators detected 2 co-existing RET fusions in 1 PTC nodule, which included ACBD5/RET fusion with juxtaposition of exon 11 of the ACBD5 gene and exon 12 of RET gene in the first and BBIP1/RET fusion with a juxtaposition of exon 1 of the BBIP1 gene and exon 8 of the RET gene. CCDC6/RET rearrangement was the most common fusion gene, which was observed in 13 patients (14%), while 1 of these patients had a novel isoform including a part of exon 9 of RET gene. Other rearrangements that were observed more commonly included ETV6/NTRK3 in 10 patients (10.8%), NCOA4/RET, and STRN/ALK both in 6 patients (6.5%) and RBPMS/NTRK3 found in 2 patients (2.2%). The remaining fusions were not recurrent.

BRAF fusions with partner genes, CUL1, and OPTN were reciprocal, and the IRF2BP2/NTRK1 fusion gene has 2 isoforms, 1 being a fusion of exon 1 and the second of exon 2 of the IRF2BP2 gene with exon 10 of the NTRK1 gene. Every isoform was found in a different patient, and no patients with fusion genes had a prior history of radiation exposure before their PTC diagnosis.

The investigators also compared the samples positive for the fusion gene to those that did not harbor this mutation. Positive samples were associated significantly with the mixture of classical and follicular types of PTC (P =.025), and the fusion-positive samples were also significantly associated with extrathyroidal extension (P <.001), higher T classification (P =.009), lymph node metastases (P <.001), distant metastases (P =.021), chronic lymphocytic thyroiditis (P =.001), and frequent occurrence of psammoma bodies (P =.004). Patients who were positive for the fusion gene has also received more frequent multiple doses of RAI therapy (P=.008). Borderline statistically significant associations were observed for features such as tumor size larger in fusion gene-positive tumors (P =.057), number of microcarcinomas higher in fusion gene-negative tumors (P=.052), and a higher number of patients who were not given RAI treatment (P =.058).

Samples that were positive for the fusion genes were different from each other as well, according to the fused oncogene involved. A statistical analysis was only able to be performed between RET and NTRK3 fusion gene-positive samples because of the low number of samples in the other fusion groups. RET fusions were significantly associated with lower mean age of patients at diagnosis (P =.035), lymph node metastases (P =.033), distant metastases (P =.020), and frequent occurrence of psammoma bodies (P =.006). The NTRK3fusions were significantly associated with follicular variant PTC (P =.013).

In RET fusion gene-positive group, 11 patients (42.3%) were of prepubertal age (up to age 12) compared with only 1 patient (7.1%) in the NTRK3 fusion-positive group (P =.021).

All patients with distant metastases (n = 10) had the genetic cause of PTC detected, which was HRAS Q61R point mutation in 1 patient, NCOA4/RET in 4, CCDC6/RET in 2, RASAL2/RET in 1, EML4/MET in 1, and co-occurrence of ACBD5/RET with BBIP1/RET in 1.

Point mutations in BRAF, HRAS, KRAS, NRAS, and TERT genes were assessed in all patients, in which 18 (19%) had the BRAF V600E mutation, and the HRAS Q61R and NRAS Q61K was found in 1 patient each. No mutations were found in the KRAS gene or in the promoter region of TERT. Patients with HRAS-positive PTC (n = 1) underwent radiation treatment for Hodgkins lymphoma. The co-occurrence of fusion gene and somatic point alternation was not identified in the study.

These findings demonstrated a point mutation or fusion gene was observed in 72 pediatric patients (77.4%) with PTC, and the oncogenic alteration was unidentified in 21 patients (22.6%). Most tumors were follicular variants of PTC and T1/T2 classification predominated the tumor samples in this study. No patients had experienced recurrence or persistence of structural disease, but 1 patient had biochemical persistence of their disease while almost all of the other patients remained in remission.

Overall, this study demonstrated that fusion genes occurred in 56% of pediatric patients with PTC, and point mutations in the BRAF and RAS genes were observed in 77% of patients. Patients who harbored a fusion gene had more aggressive forms of the disease, which included more frequent extrathyroidal extension, lymph node metastases, distant metastases, and consequently had received more doses of RAI than those without the fusion gene mutations.

Reference

Pekova B, Sykorova V, Dvorakova S, et al.RET, NTRK, ALK, BRAF,andMETfusions in a large cohort of pediatric papillary thyroid carcinomas.Thyroid.Published Online July 1, 2020. doi: 10.1089/thy.2019.0802

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‘Coming into their own’: FDA approval of liquid biopsy tests puts early, less invasive cancer detection in broader reach – USA TODAY

In the past, in order to get tumor cells from a patient, a doctor had to do surgery or biopsy. Now a nurse draws blood from the arm, like what happens in a routine blood test. (Sept. 2017) Video Elephant

Cancer patients often have to endure months of anxiety and side effects before they can schedule a scan or painful biopsy to learn if their treatment is working.

Liquid biopsy tests, which have won federal approval in recent weeks, could make that process faster and less miserable.

The Food and Drug Administration approved Guardant360 CDxin early August for use in a range of solid tumors; Foundation Medicine's FoundationOne Liquid CDx, became available for widespread use as of late last month.

The tests aren't brand new, but the federal approvals will make them more accessible, as Medicare and more insurance companies cover the costs, which can run as much as $6,000.

"I think that liquid biopsies now are coming into their own," said Dr. Matthew Freedman, an oncologist and researcher at the Dana-Farber Cancer Institute in Boston.

The newly approved liquid biopsies can identify the genetic signature of tumors, which then can be used to match patients to treatments or research trials with experimental therapies.

Lung cancer patients who have certain genetic mutations in their tumors, for instance, can double or triple their life expectancy when given a drug targeted to those mutations.

Doctors can also use liquid biopsies a few weeks after starting treatment to see how a tumor is evolving, and perhaps gain insights into why a treatment isn't working, said Helmy Eltoukhy, CEO of Guardant Health, of Redwood City, California, which makes Guardant360 CDx.

"It's better care for patients at lower cost if you test appropriately," he said.

Today, many cancer patients, particularly those with hard-to-reach tumors, get one biopsy with all future treatment decisions based on that one sample. But tumors change over time. "There's almost no other area of medicine where you'd use an old clinical specimen to decide treatment," Eltoukhy said.

Because blood is so easy to access, a liquid biopsy can be done several times to see how the tumor evolves, he said. And patients who live far from an academic medical center can still get cutting-edge recommendations without traveling.

So-called liquid biopsies, recently approved by the FDA, may make it easier for oncologists to track their patients' cancers.(Photo: Guardant Health)

Liquid biopsies are generally seen as not as precise as more typical biopsies, where a needle is inserted directly into a solid tumor. "If one had a choice, the choice would be to look at the biopsies," said Dr. Bert Vogelstein, who has spent years developing liquid biopsy tests as a professor at Johns Hopkins University in Baltimore.

But with some cancers, it's not easy to access the tumor, or there's very little cancerous material that can be withdrawn or seen.

As a tumor begins to spread its tentacles,it's initially invisible on scans. And after successful surgery, there may be no obvious tumor, but residual disease could still be lurking.

Liquid biopsies can fill those crucial gaps.

Scientific advances in recent years have made it possible to identify cancer DNA in the bloodstream tiny needles in the haystack of the bloodstream.

This opens up a lot of possibilities for treatment and diagnosis, Vogelstein said.

Guardant Health is one of two companies that recently received approval for its liquid biopsy tests, intended to make it easier to track cancers.(Photo: Guardant Health)

In colon cancer, for instance, roughly half of Stage 3 patients who otherwise would die can be cured with so-called adjuvant therapy, Vogelstein said. But nearly everyone who has enough metastatic cancer to be visible on an X-ray will die from their disease. "You cure close to 0% with adjuvant therapy," he said.

Adjuvant therapy is terribly toxic, though, so doctors don't want to use it unless they believe the patient is likely to have metastatic disease.

"So, this is a decision that virtually every patient goes through: Should I undergo adjuvant therapy?" said Vogelstein.

Until now, they've only beenable to guess and play the odds. But early research suggests using liquid biopsy to identify if there's residual diseasecan help make that decision easier, Vogelstein said.

Although studies proving the clinical usefulness of liquid biopsies have yet to be completed, he added, "Patients with positive liquid biopsies after surgery nearly always recur, and many that don't have positive liquid biopsy tests don't recur."

Dr. Neal Shore, medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, said he uses liquid biopsies to help him find clinical trials for patients with advanced cancer.

One patient, who only wanted to be identified by his first name, Joel, has been on a clinical trial of a double-drug therapy for two years, after a liquid biopsy identified a genetic mutation in his advanced prostate cancer.

"He looks great," Shore said on a call with Joel and his wife Tracey. "He's done exceptionally well."

Joel said the treatment has been challenging at times. He has trouble swallowing some days, suffers from back pain, and the hormone therapy he still takes gives him hot flashes.

But his wife said his issues are largely manageable with Tylenol and heating pads. "For the most part, he feels pretty good," she said.

Shore, who treats patients with kidney, bladder and prostate cancers, said liquid biopsies are particularly useful when a tissue sample is old or unusable.

"It expands our treatment armamentarium," he said. "This is really exciting for me as a urologist."

The next step, said Cindy Perettie, CEO of Cambridge, Massachusetts-based Foundation Medicine, will be to use liquid biopsies early in the course of someone's treatment.

"We're really focused on taking it from the metastatic setting and moving it to the early setting," she said. "That's where we're going to have the opportunity to really impact (patients)."

Breast cancer patients on maintenance therapy with tamoxifen, for instance, usually have to wait five years to know if their cancer has advanced, she said, but a liquid biopsy could let them know much faster and more often.

"We can look every six months whether they've progressed or not," Perettie said.

Even further into the future, the real potential for liquid biopsies lies in early detection.

For kidney cancer, as well as many other tumors, the earlier the diagnosis, the better the chance of survival, said Freedman of Dana-Farber. He, along with colleagues including Dr. Toni Choueiri, showed in a paper published earlier this summerthey could identify kidney cancer cells in urine at all stages of disease.

If such tumors could be identified when they're just beginning, the prognosis for kidney cancer would vastly improve.

"You want to cure cancer. You don't cure it with third-line chemo. You want to cure it before it happens," Choueiri said.

Today, about 20% of cancers are diagnosed via screening tools like mammography, colonoscopies or stool-based tests. Add liquid biopsies and that figure could jump to 75%. "I think that will be possible within five years or so," said Vogelstein, who is involved in a company, Thrive Earlier Detection, based in Cambridge, Massachusetts, that is working on such a test.

The challenge: the smaller the tumor, the less DNA released from the cancer cells, so the harder it is to detect.

Metastatic cancers that have spread throughout the body might account for 5-10% of the DNA floating in the bloodstream; but DNA from very early tumors may make up just 1-in-10,000 or 1-in-100,000 DNA molecules in blood, Vogelstein said.

Studies have shown it's feasible to find these few needles in a haystackbut not whether it's useful to doctors or patients.

There is also a risk to using liquid biopsies as a screening tool for early tumors, Vogelstein warned. False positives telling people they have cancer when they don't could do a lot of harm.

And a liquid biopsy can only say there's a high likelihood someone has cancer somewhere and that further testing is warranted, he said. Sometimes, something might look like cancer on a CT scan, but it isn't.

"It is essential," he said, "to show that the benefits of early detection outweigh the risks."

Contact Karen Weintraub at kweintraub@usatoday.com

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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'Coming into their own': FDA approval of liquid biopsy tests puts early, less invasive cancer detection in broader reach - USA TODAY

Yale researchers find a cause and possible treatment for Fragile X – Yale News

Yale scientists have discovered an underlying mechanism for Fragile X syndrome a leading cause of autism and the primary genetic driver of intellectual disability as well as a drug that reversed the underlying abnormality and autism-like behaviors in mice. Their research appears in the Sept. 3 edition of the journal Cell.

Fragile X, a genetic disorder linked to the X chromosome, leads to learning disabilities, cognitive impairment, and many features of autism, including social difficulties.Approximately one in 7,000 males and one in 11,000 females have the syndrome, according to the Centers for Disease Control and Prevention. Fragile Xtypically becomes evident in children by age 2.

The new Yale study deepens basic understanding of the syndrome and demonstrates early promise for a previously unexplored avenue for treatment.

In the study, led by Dr. Elizabeth Ann Jonas, professor of internal medicine (endocrinology) and neuroscience, researchers focused on a protein called adenosine triphosphate synthase, which is present in nearly all cells in the body. It uses energy from food to generate adenosine triphosphate (ATP), a molecule that is a major energy source for cells.

In Fragile X syndrome, cells ATP-making function is abnormal, Jonas team found. Specifically, the cells mitochondria which process fuel to make ATP have a leaky inner membrane.

This leaky membrane is making the process of ATP production inefficient, said Jonas, who studies synapses, the junctions that help pass messages between the brain cells known as neurons. In Fragile X neurons, the synapses fail to mature during development. The synapses remain in an immature state and this seems to be related to their immature metabolism.

When a leak in the cells mitochondria short-circuits efficient functioning of the synapse, memory, learning and typical brain development are all compromised, Jonas said.

As part of the study, the Yale researchers tested a drug on mouse models with Fragile X to see if it would close the leaks and improve brain function. They found that Dexpramipexole, an ATP synthase modulator previously tested as a treatment for ALS, reversed two autistic-like behaviors in mice with Fragile X: excessive grooming and compulsive shredding of their nests.

Jonas said she is now interested in testing the effectiveness of this and other leak-closing drugs for improving learning. She has a separate study underway intended to ascertain the role of leaky membranes in memory formation. This could yield a pathway for treating Alzheimers disease as well as for Fragile X and autism.

Mitochondria are making ATP in synapses all throughout life, Jonas said. We think mitochondrial leak closure may be one of the first responses to neuronal activity when you form a memory and this could be required for the changes that lead to long-term memory formation.

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Yale researchers find a cause and possible treatment for Fragile X - Yale News

Existing Class of Drugs May Improve Neurological Function in Patients with Rare, Aggressive Genetic Disorder – Newswise

Philadelphia, September 3, 2020 New findings from Childrens Hospital of Philadelphia (CHOP) show that some patients with a rare and aggressive form of leukodystrophy may benefit from receiving treatment with a class of targeted therapy drugs that could improve their neurological function. A correspondence about these findings was published today in the New England Journal of Medicine.

Aicardi-Goutires syndrome (AGS) is a rare genetic disorder and type of leukodystrophy that affects the brain and immune system. In patients with AGS, the bodys immune system turns on itself in a destructive way, targeting the brains white matter, causing most children with the disorder to experience mild to severe intellectual or physical impairments. Most children with AGS are unable to walk or talk and have multisystemic complications, including skin inflammation.

Prior studies have linked the activation of interferons signaling proteins that respond to various immune disruptions to exacerbated symptoms in AGS. Researchers at CHOP wanted to explore whether a class of small molecule inhibitor drugs called janus kinase (JAK) inhibitors could be used to block interferon activation in a way that helped these patients.

Because treatment options for AGS are limited and the symptoms that these patients experience are so severe, there is a need to explore a wide variety of options, said senior author Adeline Vanderver, MD, an attending physician in the Division of Neurology, Program Director of the Leukodystrophy Center, and Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at CHOP.

The study was conducted at CHOP with 35 international patients with genetically confirmed AGS. These patients received baricitinib, an oral JAK1 and JAK2 inhibitor, with doses based on each patients renal function, age and symptoms. Patients had their developmental histories evaluated from the onset of the disease to the end of the study, which ranged from 7.4 months to 41.5 months. The study team analyzed a variety of developmental milestones, including head control, sitting, rolling, smiling, babbling, and the use of single words and word combinations.

Before the patients in this study received treatment, 26 of the 35 had stable or declining neurologic function, and 9 of the 35 patients gained one or two of these developmental skills after disease onset. However, during the study, 20 patients met new milestones, and 12 patients gained between two to seven new skills. The improvements were typically observed within three months into the study and persisted. Children who received higher doses of the therapy appeared to achieve more of these milestones.

Some of the AGS patients who received baricitinib were at risk for developing thrombocytosis, leukopenia, and infection and therefore should be monitored closely while taking the drug.

Measuring neurologic improvements in these patients is a complex process, but the results of this study are encouraging, especially because we observed improvements even in patients with severe and long-standing disease, Vanderver said.

Eli Lilly provided the medication for the study and performed the safety laboratory tests. This work was supported by grants NINDS U01 NS106845 and NICHD U01HD082806 and the State of Pennsylvania, Commonwealth Universal Research Enhancement Program, the J.A. Kamens Chair in Translational Neurotherapeutics from CHOP; grant KL2TR001879 from the National Center for Advancing Translational Sciences of the NIH, K23NS114113 the National Institute of Neurological Disorders and Stroke of the NIH, and K08-HL140129 from the Parker B. Francis Foundation; and funding from the Department of Pediatrics at CHOP.

Vanderver et al, Janus Kinase Inhibition in the AicardiGoutires Syndrome. N Engl J Med, online September 3, 2020. DOI: 10.1056/NEJMc2001362.

About Childrens Hospital of Philadelphia: Childrens Hospital of Philadelphia was founded in 1855 as the nations first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Childrens Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

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Existing Class of Drugs May Improve Neurological Function in Patients with Rare, Aggressive Genetic Disorder - Newswise