After years of fanfare and a few false starts, the era of genomic medicine has finally arrived.

Across the country, thousands of patients are being treated, or having their treatment changed, based on information gleaned from their genome. Its a revolution that has been promised since the human genome was first published in 2001. But making it real required advances in information technologyinfrastructure and a precipitous drop in price.

Today, the cost of whole exome sequencing, which reveals the entire protein-coding portion of DNA, is now roughly equivalent to an MRI exam in many parts of the country, says Louanne Hudgins, M.D., president of the American College of Medical Genetics and Genomics and director of perinatal genetics at Lucile Packard Children'sHospital Stanford, Palo Alto, Calif.

Genomic sequencing is a tool like any other tool in medicine, and its a noninvasive tool that continues to provide useful information for years after it is performed, she says.

Nowhere is this genomic transformation more apparent than in the realm of cancer treatment.

Companies like Menlo Park, Calif.-based Grail Inc. are forging ahead with large-scale genomic sequencing projects in collaboration with both academic medical centers and community health systems. Grails Circulating Cell-free Genome Atlas study aims to identify genomic fingerprints shed from tumors that can be identified in a blood sample. The goal is to help identifycancers early when they are more treatable and to match a patients tumors to individualized treatment.

We are finding great enthusiasmas people want to participate in this effort, both patients and physicians, says Mark Lee, M.D., a practicing oncologist at Stanford and head of clinical development and medical affairs at Grail. Right now, he says, health systems and patients have an opportunity to participate in shaping the future of this genome-based medicine.

Supporting article:Maine Genomics Project Rethinks Cancer Care

Backed by investing giants like Amazon and Bill Gates, Grail has partnered with the Mayo Clinic, the Cleveland Clinic, the U.S. Oncology Networkand others to collect de-identified data from consenting patients for large-scale genomic studies.

And they have lots of company. The biotech company Regeneron has partnered with Pennsylvania-based Geisinger Health System to enroll interested patients in a project dubbed MyCode Community Health Initiative. A discovery-focused initiative, MyCode is also using genomic data to guide treatment decisions today. Currently, the project has enrolled more than 150,000 consenting patients and has returned what are considered actionable results to 340 patients and providersand counting.

For example, MyCode participant Barbara Barnes chose to have her reproductive organs removed after an analysis of her DNA determined that she was at increased risk for developing breast and ovarian cancer. The surgeryrevealed that she already had a fallopian tube tumor that required treatment, and the early intervention may have saved her life. She shared her story in a Facebook video produced by Geisinger.

While anecdotal success stories provide a taste of whats possible, the Geisinger-Regeneron collaboration is aimed more toward matching genotypes with treatment on a population level, and that effort is starting to yield results.

In July, the group published a report in the New England Journal of Medicine describing a variant of the gene ANGPTL3 associated with a reduced risk of cardiovascular disease detected in some MyCode participants. The gene variant codes for a protein that seems to lower cholesterol, and the company has developed a targeted treatment, evinacumab, that mimics the action of this protein. Evinacumab earned breakthrough therapy designation by the Food and Drug Administrationin April and is now in Phase 3 clinical trials for patients with an inherited tendency that manifests early in life to have high cholesterol levels, leading to deadly cardiovascular disease.

Another goal of Geisingers population-based study, says Andy Faucett, a principal investigator of MyCode and genomics researcher at Geisinger, is to determine how to scale the program and make it possible for more health systems to implement genomic screening for their patients.

We probably have a health system a week call us and ask us for help [setting up a genomics program], he says. We think its something that should be offered to every patient.

Genomic medicine has advanced to the point that genes and their variants now can be targets for drug treatments. Case in point: In May, the FDA approved pembrolizumab (Keytruda) to treat any unresectable or metastatic solid tumor with a specific genetic biomarker, irrespective of its location in the body.

This is an important first for the cancer community, Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDAs Center for Drug Evaluation and Research, said in a statement made at the time of the approval. We have now approved a drug based on a tumors biomarker without regard to the tumors original location.

Clinical trials matching genomic markers with targeted treatment are well underway and are only expected to increase, making identification of genomic targets an essential part of care.

Targeted therapies got another advance in July when an advisory panel convened by the FDA gave its unanimous recommendation for approval of the first gene-based medical treatment in the U.S. Chimeric antigen receptor T, or CAR-T,cell therapy, expected to be approved in November for a particularly aggressive form of leukemia, is the first in a wave of living drugs engineered to seek out and destroy cancerous tumors.

CAR-T cell therapy represents the culmination of decades of research to identify genetic features that are unique to each specific form of cancer that can be targeted by the immune system. The approach, coaxing a patients own immune system to recognize and attack cancerous cells, also delivers on the promise of personalized medicine, as T cells are harvested from each patient, re-engineered to recognize and attack cancer, and returned to the patient.

In the case of Novartis CTL019, the treatment on the cusp of FDA approval, complete response rates in clinical trials for acute lymphoblastic leukemia patients whohad relapsed despite multiple conventional treatments, reached 80-90%.

Physician-scientists like Brian Till of Seattles Fred Hutchinson Cancer Research Center, who has been working on CAR-T for years but was not involved in the development of CTL019, say these early results are encouraging.

We have enough data right now to be optimistic that this could become standard of care for some cancers, says Till.

He quickly added that there will likely always be a role for chemotherapy or other standard treatments and that CAR-T will probably be limited in its early days to centers that have experience managing potential toxicities. But, he added, CAR-T has the potential to be given as an outpatient treatment with careful management of side effects.

Many questions remain about whether it makes sense for healthy people to learn the secrets hidden in their DNA, but those concerns are likely to be overshadowed by a cavalcade of genomic sequencing projects and targeted therapies now hitting clinics nationwide. Simply put, genomic sequencing will be part of standard care within the next decade.

In the realm of rare-disease diagnoses and treatment, genomics already has been transformative. As recently as five years ago, patients with myriad vague symptoms, mostly infants and children, could bounce from doctor to doctor and invasive procedure to invasive procedure without ever receiving a definitive diagnosis. While some disorders still do evade diagnosis, whole genome sequencing has dramatically reduced that number.

Our ability to diagnose genetic conditions has improved dramatically, says Hudgins. And we are gaining a much better understanding of the biology behind these genetic changes. Because of these advances, therapy and management of these diseases are much improved. So the idea that there is no treatment for genetic disorders is just not true anymore.

The speed of DNA sequencing and analysis now permits near real-time diagnosis, moving it into the clinical workflow.

At Rady Childrens HospitalSan Diego, an array of Illumina sequencing machines churns through clinical samples in as few as 37 hours, according to Stephen Kingsmore, M.D., director of its Institute forGenomic Medicine.

The rapid sequence analysis has resulted in almost half of patients receiving a genomic diagnosis, while 80 percent had their care altered as a result of sequencing.

Kingsmore is consulting with a dozen other childrens hospitals that want to offer real-time genomic testing to their patients within the next year. Every hospital should have access to rapid sequencing and analysis within a few years, he says.

For prospective parents, prenatal and perinatal diagnosis has entered a new realm as well.

Cell-free DNA prenatal screening has dramatically decreased the number of invasive procedures such as amniocentesis and chorionic villus sampling that pregnant women undergo, Hudgins says. In the last few years, it has decreased fivefold in many areas of the U.S.

Even the granddaddy of all genomic medicine, gene therapy, is enjoying a renaissance. Early efforts to treat disease by replacing defective genes suffered many setbacks over the years, mainly due to the difficulty of efficiently delivering genes to affected tissues and organs. But next-generation modified viral delivery systems have shown they can get the job done safely and efficiently.

Philadelphia-based Spark Therapeutics' biologics license application for voretigene neparvovec (Luxturna)for inherited retinal disease has been accepted for review by the FDA with a decision expected early next year. The experimental treatment of 31 patients was the first successful randomized, controlled Phase 3gene therapy clinical trial, leading to FDA orphan drug designation in July.

Spark is one of several companies developing gene-based treatment for vision loss in the U.S. and Europe.

Similarly, Bluebird Bio Inc.'s gene-therapy treatment for thalassemia and sickle cell disease has shown promise. Results presented at the European Hematology Association meeting in Vienna in June suggested that a child treated for severe sickle cell disease in France might have been cured.

The company is running clinical trials to treat severe sickle cell disease at six hospitals in the U.S., including the Medical University of South Carolina. Julie Kanter, M.D., director of sickle cell research at MUSC and a primary investigator on the U.S. trial, says the new generation of gene-delivery systems is more efficient with fewer side effects.

I think weve made incredible headway and we are going to see some great things coming, she says.

Amid tumbling genomic sequencing costs, more people are having their DNA sequenced to match an underlying genetic defect withan increasing variety of targeted treatment options. From an estimated 1,000 genetic tests available only five years ago, the field has exploded to more than 52,000 available in the U.S., and that number grows daily. To find out more about what's out there, visit the National Center for Biotechnology Information's Genetic Testing Registry website at http://www.ncbi.nlm.nih.gov/gtr.

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Genomic Medicine Has Entered the Building - Hospitals & Health Networks

What happened

Shares of gene editing pioneer Editas Medicine (NASDAQ: EDIT) dropped nearly 16% today after a new study published in Nature Methods drew attention to unintended effects of using the highly touted genetic engineering tool known as CRISPR. Shares of genome-editing peers CRISPR Therapeutics (NASDAQ: CRSP) and Intellia Therapeutics (NASDAQ: NTLA) were down as much as 6.9% and 14.9%, respectively, on the news.

The study, conducted by a team from Columbia University Medical Center, provided data showing that the technology can "introduce hundreds of unintended mutations into the genome," according to Genetic Engineering & Biotechnology News. That contradicts one of the better-known characteristics of CRISPR: precision.

Simply put, it's not sitting well with investors, who are (in knee-jerk fashion) adjusting the value placed on early-stage platforms, especially Editas Medicine, which will be the first of the group to enter clinical trials. As of 3:31 p.m. EDT, the stock had settled to a 11.3% loss.

Image source: Getty Images.

The study is among the first to quantify the specificity of CRISPR tools, which work by delivering gene editing enzymes to specific parts of the genome through the use of synthetic guide RNAs. Or that's how they're supposed to work. The authors of the study show that although intended edits can be made with respectable efficiency, such as correcting a mutation in a gene that causes blindness in mice, there are also unintended secondary edits made to the genome.

This may seem like a bombshell report, but it's a matter of optics. Researchers have never shied away from the reality that CRISPR gene editing tools can stray off target and make unintended edits to genomes in mammalian cells (i.e., humans). Many labs -- including Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics -- are working on increasing the efficiency and specificity of the technology. This is how science works. By quantifying these off-target mutations, which the paper attempted to do, researchers can begin to better understand how to improve the technology.

Investors and traders did not take the same cool-headed approach to the news, instead giving into a knee-jerk reaction to adjust the value of each pre-clinical technology platform. While off-target edits could prove troublesome for a CRISPR therapeutic used in humans, it's important to remember that there are currently no clinical trials underway in the United States. Editas Medicine will become the first to initiate a clinical trial later this year.

The sharp contrasts in reactions from researchers and investors is likely driven by how CRISPR is perceived by the media. Unfortunately, there is a generous amount of hyped-up science journalism that sticks to simple narratives -- "CRISPR has arrived and will cure all diseases!" -- instead of more nuanced takes that give equal weight to each current obstacles and future potential facing an emerging technology. Just remember: Biology is never quite so simple.

The results from the study don't really change anything, except for bringing more attention to the already existent clinical risk inherent to the development of early-stage CRISPR therapeutics. There is still plenty of work and new technology left to be developed before gene editing fulfills its promise in treating and curing human diseases. Hopefully, this can be a long-term positive for investors in CRISPR stocks by forcing them to listen to the fundamental hurdles for the technology. Hopefully.

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Here's Why Editas Medicine Fell as Much as 15.7% Today - Madison.com

Genetic Variation and Drug Response

Imagine taking a patients skin cells, using them to derive induced pluripotent stem cells [iPSCs], differentiating the stem cells to produce cells of a particular type, and then exposing the differentiated cells to drugs that the patient might be given, suggests Russ B. Altman, M.D., Ph.D., professor of bioengineering, genetics, medicine, and biomedical data science at Stanford University. Such procedures might detect the potential for drug-induced toxicity and reduce the incidence of serious side-effects in the clinical setting.

The ability to predict adverse effects is particularly important for therapeutic agents that are associated with a high likelihood of failure or adverse effects. Predicting adverse effects could also help tailor treatments in a more rational manner.

An example of a drug with a challenging adverse effect profile is doxorubicin. This chemotherapeutic agent is known to be cardiotoxic in some patients, but predicting which patients are at risk is difficult. In fact, no reliable means of predicting doxorubicin-induced cardiotoxicity (DIC) exists, so the drug cannot be administered with confidence.

In a recent study conducted in collaboration with Dr. Paul Burridge from Northwestern University School of Medicine and Dr. Joseph Wu from Stanford Cardiovascular Institute, and other colleagues, bioinformatics analyses performed by Dr. Altmans group were critical to show that patient-specific human induced pluripotent stem cell-derived cardiomyocytes can recapitulate at the single-cell level the predilection to develop doxorubicin-induced cardiotoxicity.

It was pretty straightforward, on the informatics side, to show a correlation between the cellular responses and the clinical responses, asserts Dr. Altman. This correlation is incredibly exciting.

Human iPSCs obtained from female patients with breast cancer and matched with healthy volunteers were differentiated into cardiomyocytes. RNA-Seq and microarray analyses were subsequently used to profile and compare gene-expression changes in the cardiomyocytes derived from the healthy volunteers and in those from the breast cancer patients with and without clinical DIC. Cells derived from patients presenting clinical DIC were more sensitive to therapy, exhibited increased metabolic stress and reactive oxygen species, and had impaired intracellular calcium signaling, as compared to cells derived from patients who did not show clinical DIC.

Using microarray analyses to examine gene-expression perturbations in response to various doxorubicin concentrations, this study revealed that in vitro, the cardiomyocytes recapitulated patients predilection to DIC. The study also indicated that genetic and molecular analyses could provide a powerful tool to predict clinical toxicity to therapeutic agents.

The findings in the research setting are very intriguing, comments Dr. Altman. There is a lot of engineering to make them more reliable and reproducible.

Even though stem cell studies have shown a lot of promise, reproducibility has been particularly challenging, and results from different labs may vary depending on multiple factors, including small differences in experimental protocols and the versions of the stem cells used by various labs, for which it is very difficult to show equivalency.

The work is only half complete when the research is published, Dr. Altman concludes. Lots of details need to be addressed before this can be put into routine clinical use.

Here is the original post:
Gene Expression's Big Rethink - Genetic Engineering & Biotechnology News

Viable Editing

One of the most fascinating and promising developments in genetics is the CRISPR genome editing technique. Basically, CRISPR is a mechanism by which geneticists can treat disease by either disrupting genetic code by splicing in a mutation or repairing genes by splicing out mutations and replacing them with healthy code.

Researchers in China at the Third Affiliated Hospital of Guangzhou Medical University have successfully edited genetic mutations in viable human embryos for the first time. Typically, to avoid ethical concerns, researchers opt to use non-viable embryos that could not possibly develop into a child.

Previous research using these non-viable embryos has not produced promising results. The very first attempt to repair genes in any human embryos used these abnormal embryos. The study ended with abysmal results, with fewer than ten percent of cells being repaired. Another study published last year also had a low rate of success, showing that the technique still has a long way to gobefore becoming a reliablemedical tool.

However, after experiencing similar results with using the abnormal embryos again, the scientists decided to see if they would fare better with viable embryos. The team collected immature eggs from donors undergoing IVF treatment. Under normal circumstances, these cells would be discarded, as they are less likely to successfully develop. The eggs were matured and fertilized with sperm from men carrying hereditary diseases.

While the results of this round of study were not perfect, they were much more promising than the previous studies done with the non-viable embryos. The team used six embryos, three of which had the mutation that causes favism (a disease leading to red blood cell breakdown in response to certain stimuli), and the other three had the mutation that results in a blood disease called beta-thalassemia.

The researchers were able to correct two of the favism embryos. In the other, the mutation was turned off, as not all of the cells were corrected. This means that the mutation was effectively shut down, but not eliminated. It created what is called a mosaic. In the other set, the mutation was fully corrected in one of the embryos and only some cells were corrected in the other two.

These results are not perfect, but experts still do find potential in them. It does look more promising than previous papers, says Fredrik Lanner of the Karolinska Institute. However, they do understand that results from a test of only six embryos are far from definitive.

Gene editing with CRISPR truly has the possibility to revolutionize medicine. Just looking at the development in terms of disease treatment, and not the other more ethically murky possible applications, it is an extremely exciting achievement.

Not only could CRISPR help eradicate hereditarydisease, but it is also a tool that could help fight against diseases like malaria. There is a long road ahead for both the scientific and ethical aspects of the tech. Still, the possible benefits are too great to give up now.

Excerpt from:
The First Results of Gene Editing in Normal Embryos Have Been Released - Futurism

Modern America is obsessed with data. Big data, everyday data, any and all kinds of data.

Some of this obsession can be seen locally in the growing quantum of data under the general rubric of Genetics. Consider: We each have about 19,000 protein-coding genes...our area universities feature centers for genetic medicine that engage more than 300 faculty members in more than 30 different departments...our medical directory already lists scores of genetic specialists...the annual birthrate here averages 44,000 infants with all those billions of genes instantly joining our metropolitan human gene pool.

Mix and match these data and what do we find? One answer would be the many cancer patients & survivors who until recently had no way of knowing that we were born with a genetic time bomb.

At first glance -- by the healthy -- the topic may be of passing interest. But to those whose genetic codes actually translated into diseases, it takes on more immediacy. Could we have been forewarned and thus forearmed? If so, how so? Questions no one asked when medical science did not yet know they existed.

Here in the Chicago area geneticists and ethicists are engaging such questions with increasing intensity. Assuming they can identify and isolate a disease-bearing gene, should the patient be told? Not told? Only the family told? After billions of evolutionary years, humanity has at long indomitable last been gifted with such questions; but like all gifts, neither bearer nor recipient can be quite sure of their consequences.

To stay with this image of a gift, we are reminded of ancient tales about the mixed blessings of other gifts. The Apple in the Bible...Pandora's Box in Greek mythology...Aladdin's Lamp in Arabic mythology...Seth's Chest for the Egyptian God Osiris.

In each tale there is the Before & the After.

Before ~ as in the case of an expectant woman, genetic testing can now help identify chances for cystic fibrosis, muscular dystrophy, hemophilia, sickle cell anemia, and kidney disease. What it cannot identify are the consequences of her choice about her pregnancy. For instance, do I take it upon myself to give birth to a new human being whose destiny might be something magnificent from out of a deformed body?

After ~ as in the case cancer patients, genetic testing can help identify survival rates. What it cannot identify are the consequences of our choice about what do we do with our lives now. For instance with brain, breast or prostate cancer growing, do I tell the one to whom I am betrothed I cannot fulfill my promise to marry you?

Power is a seductive gift most everyone seeks in their lives. Power in the form of strength, of status, or of knowledge. In our century we have succeeded in harnessing vast stores of such power, long foreshadowed by stories from the wise. Theirs, however, was the luxury of envisioning without the burden of choosing.

Many of us now have that remarkable burden. We are only now discovering how to use it.

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Taking A Second Look - ChicagoNow (blog)

A number of recent headlines imply a case study just published in the New England Journal of Medicine proves that gene therapy has cured sickle cell diseasea genetic disorder that incurs tremendous pain, suffering and diminished life expectancy. Here, we will unpack the significance of the researchers findings.

First, lets address why this news could be so groundbreaking to those afflicted and their loved ones.

Sickle Cell Disease is an inherited condition that causes a mutated hemoglobinthe protein within red blood cells (RBCs) that carries oxygen for delivery to vital tissues. Oxygen feeds our organs so they can stay healthy and perform their respective jobs. This Hemoglobin S (aka Sickle Hemoglobin) polymerizes on deoxygenation and rids the RBCs of their malleability. As a result, these malformed sickled cells are stiff and clump together thereby occluding vessels which in turn prompts organ damage.

Roughly 90,000 Americans have Sickle Cell Disease. (1) The natural course of the illness involves a complex cascade of events intermingled with crises often triggered by infections. Anemia is commonplace (and often profound) given these faulty cells get readily destroyed, over consumed and dont last as long as healthy RBCs. Vasoocclusive Crises result from infarction and ischemiain infants the hands and feet swell, in particular. Basically, adequate blood flow is halted wherever the obstruction takes place. Aggressive pain management and rehydration is essential.

Prophylactic antibiotics are a mainstay in an effort to stave off infection which can routinely catapult patients into a life-threatening crisis. By early childhood, they develop a functional asplenia or ineffective spleen. So, they become especially susceptible to overwhelming infection by encapsulatedbacteriahence, why vaccination for pneumococcus and the like is so important. Sepsis can result. Parvovirus can cause an aplastic crisis.

Strokes. Pulmonary infarcts with subsequent hypoxia. Acute Chest Syndrome. Gallstones. Blood transfusions are frequent. Though the blood supply is well-tested for safety, recurrent transfusion can lead to issues like iron overload, for instance. This too must be treated. The list goes on of the challenges, battles and treatment complexities these patients endure. Because fetal hemoglobin has a higher oxygen carrying capacity, a disease-modifying drug like Hydroxyurea that increases its presence is used.

Allogeneic hematopoietic stem-cell transplantation represents the only cure, but less than 18% of those with severe disease have sibling donors who are a match. (2) This is also not without great risk, though those need to be weighed against how advanced the disease. Due to such limited progress in management of this condition, this team of researchers sought to examine whether therapeutic ex vivo gene transfer into autologous hematopoietic stem cells referred to as gene therapy, may provide a long-term and potentially curative treatment for sickle cell disease. (3)

What does this mean? They took samples from the bone marrow of a patient with severe disease. The cells here provide the origins of our blood components which includes our red blood cells. This is where the problem begins in generating the sickling. A cancer drug, busulfan, was used to condition the body expected adverse effects from this occurred which resolved with standard care (e.g. anemia, low platelets, neutropenia and so on). Using a lentiviral vector, they transferred an anti-sickling gene into the patients stem cells (retrieved from the bone marrow) which get put back into the patient in the hope they will multiply and replace the cells made with the defective gene.

In a study funded in part by Bluebird Bio whose product is LentiGlobin BB305 (the antisickling gene therapy subject of this publication), the team concludes their patient had complete clinical remission with correction of hemolysis and biologic hallmarks of the disease. Furthermore, after fifteen months the antisickling protein remained high at approximately 50% and the patient had no crises or hospitalizations. Before, the patient required regular transfusions. After, all medications were stopped, no pain ones were needed, and the patient returned to full activities at school. (4)

Ongoing research is underway in a U.S. multi center, phase 1/2 clinical study. The intention is to use this gene therapy to treat those with severe sickle cell disease and another condition called beta-thalessemia. So far, in the few patients who have participated, their results seemingly support this work. Clearly, longer term follow-up and larger populations are crucial to understanding the significance of this report. Additionally, stem cell transplantation is no minor feat.

That said, for a disease that disables at such a young age, this option could be quite an extraordinary one if the success persists. ACSHs Senior Fellow in Molecular Biology, Dr. Julianna LeMieux, puts the promise of gene therapy into even greater context for this and other disease entities:"This is an incredibly promising result, even with the obvious caveat that it is only one person. Sickle Cell is a disease that is ripe for genetic advances for a few reasons. First,the gene that is affected is known andcan be replaced by the healthy variant. Also, the cells that are needed to be alteredare easily accessible inthe bone marrow. In many diseases, this is not the case. But, this one success story is incredibly encouraging for the sickle cell community and for moving the field of curing diseases using genetic editing forward."

The team proved their concept. To know if "cure" is in this gene therapy's future, much more data needs to be acquired and study be implemented. Promising with cautious optimism might be the most apt description.

Source(s):

(1) (2) (3) (4) Jean-Antoine Ribeil, M.D., Ph.D. et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 376;848-855. March 2, 2017.

Note(s):

To learn more about "Orphan Diseases" or rare ones that afflict less than 200,000 (but in total impact 25 million Americans) and drug discovery challenges, review: Did Pompe Disease Geta New Champion in President Trump? and Pompe Disease, Newborn Screening and Inborn Errors of Metabolism.

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Did Gene Therapy Cure Sickle Cell Disease? - American Council on Science and Health

NEW YORK (GenomeWeb) Before the National Institutes of Health can begin to genetically test participants within its precision medicine initiative, it will have to figure out what results to return, how to minimize reporting false positives, and how to provide counseling to help them navigate the often uncertain and evolving evidence on genetic information.

And the project will have to figure out how to do all this on an unprecedented scale, for a million participants that the All of Us Research Program hopes to enroll over the next four years.

A trial upgrade to GenomeWeb Premium gives you full site access, interest-based email alerts, access to archives, and more. Never miss another important industry story.

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Precision Medicine Project Mulls How to Return Genetic Test Results to 1M Participants - GenomeWeb

February 23, 2017 A laboratory at UW Medicine in Seattle where DNA research is underway to better understand genetic risks of disease. Credit: Clare McLean

Gene discovery research is uncovering new information about similarities and differences underlying various neurodevelopmental disorders.

These are a wide-ranging collection of conditions that affect the brain. They include autism, intellectual impairments, developmental delays, attention deficits, tic disorders and language difficulties.

To better understand how gene-disrupting mutations contribute to the biology of neurodevelopmental disorders, researchers recently conducted a large, international, multi-institutional study.

More than 11,700 affected individuals and nearly 2,800 control subjects underwent targeted DNA sequencing of 208 suspected disease-risk genes. The candidate genes were chosen based on previously published studies.

By looking at greater numbers of cases and using a reliable yet inexpensive molecular inversion probe, the project team wanted to measure the statistical significance of individual, implicated genes.

Their results are reported in Nature Genetics. The study leaders were Holly A. F. Stessman, Bo Xiong and Bradley P. Coe, of the genome sciences laboratory of Evan Eichler at the University of Washington School of Medicine and the Howard Hughes Medical Institute. Stessman is now at Creighton University.

Their samples were collected through the Autism Spectrum/Intellectual Disability 15-center network spanning seven countries and four continents. An advantage of this collection, the researchers said, is the ability to check back on a large fraction of cases to try to relate genetic results to clinical findings.

In their study population, the researchers associated 91 genes with the risk of a neurodevelopmental disorder. These included 38 genes not previously suspected of playing a role. Based on some of the family studies, however, mutations even in two or more of the risk genes may not be necessary or sufficient to cause disease.

Of the 91 genes, 25 were linked with forms of autism without intellectual disability. The scientists also described a gene network that appeared to be related to high-functioning autism. Individuals with this form of autism have average to above average intelligence, but may struggle in learning to talk, interact socially, or manage anxiety and sensory overload.

While observing that some genes were more closely associated with autism and others with intellectual or developmental impairments, the researchers found that most of the genes implicated were mutated in both conditions. This result reinforces the substantial overlap among these conditions in their underlying genetics and observable characteristics.

"Most of these genes are clearly risk factors for neurodevelopmental disorders in a broad sense," the researchers explained. "But analysis of both the genetic and subsequent patient follow-up data did single out some genes with a statistical bias towards autism spectrum disorder, rather than an intellectual disability or developmental delay."

Additional findings suggest that less severe mutations may be behind autism that is not accompanied by intellectual disability.

By following up with patients, the researchers could start to assess the newly discovered mutations. Such clinical information is important in determining how the genes might function, and how their disruption might lead to specific traits or symptoms.

In addition to looking at the overall severity of each neurodevelopmental disorder present, the scientists also summarized other features such as seizures, head size, and congenital abnormalities.

The researchers did in fact observe patterns from combining clinical and genetic data. They partitioned those genes most strongly associated with autism, and those more related to developmental disabilities.

Although the overall numbers were low, several autism risk genes appeared predominantly in males, including some detected exclusively in males who had autism without intellectual impairment.

To obtain additional evidence for how risk genes might affect behavior and nervous system function, the researchers investigated 21 genes in fruit fly models. They wanted to see if any of the mutations disrupted a fundamental form of learninggrowing accustomed to harmless stimuli.

Problems with the neuronal mechanisms behind habituation are thought to account for some autism features, such as inability to filter sensory input. The fruit fly studies showed habituation deficits from several of the gene mutations under review, thereby providing additional evidence that they may have a role in cognitive function.

Numerous grants and other funding from government agencies and private foundations in several countries supported this research.

"The scientists are continuing this project and are eager to work with interested families," said Raphael Bernier, associate professor of psychiatry and behavioral sciences and clinical director of the Seattle Children's Autism Center and associate director of the UW Center on Human Development and Disability.

Explore further: Genetic cause identified for previously unrecognized developmental disorder

More information: Holly A F Stessman et al, Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases, Nature Genetics (2017). DOI: 10.1038/ng.3792

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Gene discovery research is uncovering new information about similarities and differences underlying various neurodevelopmental disorders.

A University of Toronto (U of T) study on fruit flies has uncovered a gene that could play a key role in obesity in humans.

Our genes play a significant role in how anxious we feel when faced with spatial and mathematical tasks, such as reading a map or solving a geometry problem, according to a new study by researchers from King's College London.

Gene editing techniques developed in the last five years could help in the battle against cancer and inherited diseases, a University of Exeter scientist says.

(Medical Xpress)A team of researchers with New England Biolabs Inc. (NEB) has found that sequenced DNA samples held in public databases had higher than expected low-frequency mutation error rates. In their paper published ...

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Sorting out risk genes for brain development disorders - Medical Xpress

Researchers may be one step closer to determining the cause of schizophrenia, after uncovering an abnormal genetic process associated with the disease that begins in the womb.

By transforming skin cells from patients with schizophrenia into neuronal progenitor cells - cells that form neurons in early development - researchers identified an abnormal gene pathway called nuclear FGFR1 (nFGFR1) that impairs early brain development.

Senior study author Michal K. Stachowiak, Ph.D., of the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo in New York, and colleagues say that their findings may bring us closer to treatments that could prevent schizophrenia in utero.

The researchers recently reported their results in the journal Schizophrenia Research.

According to the National Institute of Mental Health, around 1.1 percent of adults in the United States have schizophrenia - a mental health disorder characterized by hallucinations, delusions, and abnormal thoughts.

While the exact causes of schizophrenia remain unclear, researchers have long known that the condition can run in families, suggesting a genetic origin. Furthermore, an increasing number of studies have uncovered genetic mutations associated with an increased risk of schizophrenia.

For their study, Stachowiak and colleagues sought to learn more about the genomic processes that occur in utero that might influence the risk of schizophrenia development.

To reach their findings, the researchers collected skin cells from four adults with schizophrenia and four adults without the disorder.

The skin cells were reprogrammed into induced pluripotent stem cells, and these differentiated into neuronal progenitor cells. This enabled the team to assess the processes that occur during early brain development in people with schizophrenia.

The researchers pinpointed a dysregulated nFGFR1 pathway that targets and mutates numerous genes associated with schizophrenia. The team explains that just one of these gene mutations can impact brain development.

According to the authors, these findings provide proof of concept that schizophrenia may be caused by a dysregulated genomic pathway that influences the brain before birth.

"In the last 10 years, genetic investigations into schizophrenia have been plagued by an ever-increasing number of mutations found in patients with the disease. We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here."

Michal K. Stachowiak, Ph.D.

Furthermore, the team says that these findings open the door to new schizophrenia treatments. For example, a drug could be administered to expectant mothers, whose offspring has a high risk of developing schizophrenia, that prevents processes related to the disease occurring in the developing fetus.

In future studies, the researchers plan to grow "mini brains" using the same processes used in the current study, with the aim of gaining a deeper understanding of how dysregulation of the nFGFR1 pathway influences early brain development, as well as to provide a model to test possible treatments.

Learn how B vitamins might improve symptoms of schizophrenia.

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Schizophrenia begins in the womb, study suggests - Medical News Today

In the case of patients with low risk of lung cancer, the current diagnostic procedure can sometimes be invasive and unnecessary. However, new research may have uncovered a less invasive, less costly way to screen these patients.

A team of researchers from Boston University School of Medicine (BUSM) in Massachusetts may have found a more convenient way to determine whether lung lesions are malignant. The findings were published in the Journal of the National Cancer Institute.

Lung lesions - or solitary pulmonary nodules - are small growths in the lungs that are usually detected incidentally when a patient has an X-ray for other reasons. Although physicians are typically worried about cancer upon discovering the lesions, these are benign in the majority of cases.

For instance, of all the patients screened using computed tomography (CT) as part of the National Lung Cancer Screening Trial, 25 percent had a lung lesion, but approximately 95 percent of these cases were, in the end, found to be benign.

As the authors of the new study point out, many of the patients who ultimately receive a benign diagnosis undergo invasive medical procedures such as surgical lung biopsy. The new research, however, uncovers a genomic tool that could enable physicians to tell whether a patient has a malignant lesion by simply taking a swab of their nose.

BUSM researchers collected nasal epithelial brushings from patients who were in the process of having their lung lesions evaluated. These participants were people who currently and formerly smoked, and who were enrolled in the two Airway Epithelium Gene Expression in the Diagnosis of Lung Cancer clinical trials.

The epithelium is a membrane of cellular tissue that, in this case, encloses and protects the nasal cavity. Scientists examined these nasal epithelial brushings and profiled the participants' gene expression by using microarrays - a genetic tool commonly used to detect gene mutations, such as in BRCA1 or BRCA2, in a person's DNA.

The researchers found cancer-associated gene expressions to be altered in a similar way across the two airway sites. This led them to believe that the nasal airway epithelial field in people who smoke extends all the way to the nose, and that the brushings could be a biomarker for lung cancer.

Marc Lenburg, Ph.D., a professor of medicine at BUSM and co-senior author of the study, explains the significance of the findings:

"Our findings clearly demonstrate the existence of a cancer-associated airway field of injury that also can be measured in nasal epithelium. We find that nasal gene expression contains information about the presence of cancer that is independent of standard clinical risk factors, suggesting that nasal epithelial gene expression might aid in lung cancer detection. Moreover, the nasal samples can be collected non-invasively with little instrumentation or advanced training."

Corresponding author Dr. Avrum Spira, a professor of medicine, pathology, and bioinformatics at BUSM, also weighs in:

"There is a clear and growing need to develop additional diagnostic approaches for evaluating pulmonary lesions to determine which patients should undergo CT surveillance or invasive biopsy," Dr. Spira says. The ability to test for molecular changes in this 'field of injury' allows us to rule out the disease earlier without invasive procedures."

This research builds on previous work by the same team, who located another biomarker for lung cancer, found in the epithelium of the bronchus.

"Our group previously derived and validated a bronchial epithelial gene-expression biomarker to detect lung cancer in current and former smokers," Dr. Spira explains. "This innovation [...] is measurably improving lung cancer diagnosis. Given that bronchial and nasal epithelial gene expressions are similarly altered by cigarette smoke exposure, we sought to determine in this study if cancer-associated gene expression might also be detectable in the more readily accessible nasal epithelium."

Learn how a colorful compound in fruits and vegetables could lower smokers' lung cancer risk.

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Nasal swab could help diagnose lung cancer - Medical News Today

Research by Professor of Chemical and Biomolecular Engineering Huimin Zhao and graduate student Behnam Enghiad at the University of Illinois is pioneering a new method of genetic engineering for basic and applied biological research and medicine. Their work, reported in ACS Synthetic Biology on February 6 [DOI:10.1021/acssynbio.6b00324], has the potential to open new doors in genomic research by improving the precision and adherence of sliced DNA.

"Using our technology, we can create highly active artificial restriction enzymes with virtually any sequence specificity and defined sticky ends of varying length," said Zhao, who leads a synthetic biology research group at the Carl R. Woese Institute for Genomic Biology at Illinois. "This is a rare example in biotechnology where a desired biological function or reagent can be readily and precisely designed in a rational manner."

Restriction enzymes are an important tool in genomic research: by cutting DNA at a specific site, they create a space wherein foreign DNA can be introduced for gene-editing purposes. This process is not only achieved by naturally-occurring restriction enzymes; other artificial restriction enzymes, or AREs, have risen to prominence in recent years. CRISPR-Cas9, a bacterial immune system used for "cut-and-paste" gene editing, and TALENs, modified restriction enzymes, are two popular examples of such techniques.

Though useful in genetic engineering, no AREs generate defined "sticky ends" -- an uneven break in the DNA ladder-structure that leaves complementary overhangs, improving adhesion when introducing new DNA. "If you can cleave two different DNA samples with the same restriction enzyme, the sticky ends that are generated are complementary," explained Enghiad. "They will hybridize with each other, and if you use a ligase, you can stick them together."

However, restriction enzymes themselves have a critical drawback: the recognition sequence which prompts them to cut is very short -- usually only four to eight base pairs. Because the enzymes will cut anywhere that sequence appears, researchers rely on finding a restriction enzyme whose cut site appears only once in the genome of their organism or plasmid -- an often difficult proposition when the DNA at hand might be thousands of base pairs long.

This problem has been partially solved simply by the sheer number of restriction enzymes discovered: more than 3600 have been characterized, and over 250 are commercially available. "Just in our freezer, for our other research, we have probably over 100 different restriction enzymes," said Enghiad. "We look through them all whenever we want to assemble something ... the chance of finding the unique restriction site is so low.

"Our new technology unifies all of those restriction enzymes into a single system consisting of one protein and two DNA guides. Not only have you replaced them, but you can now target sites that no available restriction enzymes can."

Enghiad and Zhao's new technique creates AREs through the use of an Argonaute protein (PfAgo) taken from Pyrococcus furiosus, an archeal species. Led by a DNA guide, PfAgo is able to recognize much longer sequences when finding its cut site, increasing specificity and removing much of the obstacles posed by restriction enzymes. Further, PfAgo can create longer sticky ends than even restriction enzymes, a substantial benefit as compared to other AREs.

"When we started, I was inspired by a paper about a related protein -- TtAgo. It could use a DNA guide to cleave DNA, but only up to 70 degrees," explained Enghiad. "DNA strands start to separate over 75 degrees, which could allow a protein to create sticky ends. If there were a protein that was active at higher temperatures, I reasoned, that protein could be used as an artificial restriction enzyme.

"So I started looking for that, and what I found was PfAgo."

In addition to replacing restriction enzymes in genetic engineering processes, Enghiad and Zhao believe their technology will have broad applications in the biological research. By creating arbitrary sticky ends, PfAgo could make assembly of large DNA molecules easier, and enables cloning of large DNA molecules such as biochemical pathways and large genes.

The application of these techniques is broad-reaching: ranging from discovery of new small molecule drugs to engineering of microbial cell factories for synthesis of fuels and chemicals to molecular diagnostics of genetic diseases and pathogens, which are the areas Zhao and Enghiad are currently exploring.

"Due to its unprecedented simplicity and programmability (a single protein plus DNA guides for targeting), as well as accessibility ... we expect PfAgo-based AREs will become a powerful and indispensable tool in all restriction enzyme or nuclease-enabled biotechnological applications and fundamental biological research," said Zhao. "It is to molecular biology as the CRISPR technology is to cell biology."

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New method of genetic engineering indispensable tool in ... - Science Daily

February 10, 2017

An article published in Experimental Biology and Medicine (Volume 242, Issue 3, February, 2017) identifies microRNAs (miRNAs) as key factors in some hemoglobinopathies, genetic disorders characterized by alterations in the level or structure of the globin proteins that are responsible for oxygen transport in the blood. The study, led by Dr. Thais Fornari, from the Department of Internal Medicine at the University of Campinas in Brazil demonstrated that differential expression of miRNAs may be responsible for the variations in globin gene expression observed in patients with two hemoglobinopathies: hereditary persistence of fetal hemoglobin deletion type 2 (HPFH-2) and Sicilian-thalassemia.

HPFH-2 and Sicilian-thalassemia are conditions described as large deletions of the human -like globin cluster, with no -globin expression and compensatory increases in -globin expression. MicroRNAs (miRNAs) are small non-coding RNAs that participate in a wide range of biological processes including erythropoiesis. miRNAs silence the expression of other genes by binding to their mRNAs, and blocking protein synthesis and/or initiating mRNA degradation. Transcription factors such as BCL11A and SOX6, which regulate -globin gene expression, are potential targets for several microRNAs based on in silico analysis. Thus, novel miRNA-mediated pathways may explain the differences in the expressions of -globin in Sicilian thalassemia and HPFH-2.

In the current study, Dr. Fornari and colleagues compared the miRNA profiles of erythroid cells derived from individuals heterozygous for HPFH-2 and Sicilian-thalassemia. Forty-nine differentially expressed miRNAs that may participate in -globin gene regulation and red blood cell function were identified. Twelve of these miRNAs potentially targeted the BCL11A gene, and down-regulation of BCL11A gene expression in HPFH-2 was verified by qPCR. This research suggests an important action of miRNAs in the regulation of globin expression in patients. Fornari said that these findings "may partially explain the phenotypic differences between HPFH-2 and Sicilian -thalassemia and the variable increases in -globin gene expression in these conditions. Moreover, these data support erythroid BCL11A as a therapeutic target for sickle cell disease and -thalassemia major patients."

Dr. Steven R. Goodman, editor-in-chief of Experimental Biology and Medicine, said, "Fornari and colleagues provide further evidence for the role of miRNA networks in the regulation of fetal hemoglobin expression, via altered expression of BCL11A and SOX6. These studies are important when considering these transcription factors as potential therapeutic targets".

Explore further: Mechanisms, therapeutic targets of microRNA-associated chemoresistance in epithelial ovarian cancer

Journal reference: Experimental Biology and Medicine

Provided by: Experimental Biology and Medicine

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Researchers find potential treatments for hemoglobinopathies - Medical Xpress

Using stem cells and gene therapy to treat orcure disease may still sound like science fiction, but a scientific meeting here last week emphasizedall the fronts onwhich it is moving closer and closer to fact.

Were entering a new era in medicine, said Lloyd Minor, MD, dean of the School of Medicine, in his opening remarks at the first annual symposium of the schools new Center for Definitive and Curative Medicine. Stanford researchersare poised to use stem cells and gene therapy to amelioratea wide swath of diseases, from common diagnoses such as diabetes and cancerto rare diseases ofthe brain, blood, skin, immune system and other organs. Ultimately, the goal is to create one-time treatments that can provide lifetime cures; hence the definitive and curative part of the centers name. Stanford is a leader in this branch of medical research, Minor said, addingThis is a vital component of our vision for precision health.

Stanford has a long history of leading basic-science discoveries in stem cell biology, andis now engaged in studyingmany different ways those discoveries couldbenefit patients, saidMaria Grazia Roncarolo, MD, who leads the new center.Our job is to produce clinical data so compelling that industry will pick up the product and take it to the next stage, Roncaraolo told the audience.

Among otherevent highlights:

More coverage of the days events is available in a story from the San Jose Mercury News that describeshowAnthonyOro, MD, PhD, and his colleagues are fighting epidermolysis bullosa, a devastating genetic disease of the skin. Oro closed his talk with a slightly goofy photo of a man getting a spray tan. It got a laugh, but his point was serious: Our goal for the cell therapy of the future is spray-on skin to correct a horrible genetic disease.

Ambitious? Yes. Science fiction? In the future, maybe not.

Previously: One of the most promising minds of his generation: Joseph Wu takes stem cells to heart,Life with epidermolysis bullosa: Pain is my reality, pain is my normaland Rat-grown mouse pancreases reverse diabetes in mice, say researchers Photo of Matthew Porteus courtesy of Stanford Childrens

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Stanford scientists describe stem-cell and gene-therapy advances in scientific symposium - Scope (blog)

San Francisco, California (UroToday.com)Approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC) cannot be assessed for a response using RECIST 1.1 criteria and there is a need to develop a dynamic endpoint that provides an early indication of clinical benefit. Circulating tumor cells (CTCs) are easily accessible, reflect tumor biology, and could be a marker of anti-tumor activity beyond PSA and conventional imaging. CTC0 and CTC conversion to <5 CTCs/7.5 mL blood may occur very early on treatment and were highly correlated with OS across 5 large phase III trials of mCRPC therapies in a recent landmark paper by Heller et al.1 Niraparib, a highly potent and selective poly (ADP-ribose) polymerase (PARP) inhibitor received breakthrough designation by US FDA for treatment of patients withBRCA1,2mutant mCRPC who progressed on taxane and androgen receptor-targeted therapy. CTC detection associates with poor outcomes, with declining counts consistent with improved survival. At todays prostate cancer session at GU ASCO 2020, Matthew Smith presented results of their CTC correlative data assessing CTC0 as an endpoint in mCRPC.

The GALAHAD study assessed niraparib (300 mg daily) in patients with mCRPC plus DRD. Patients with non-measurable soft tissue disease by RECIST 1.1 were required to have a baseline CTC count 1 cell/7.5 mL blood. CTC response was defined as CTC conversion to <5 for patients with baseline CTC5 and CTC drop to 0 post-baseline for patients with 1 baseline CTC.

There were 204 patients included in this study. For the primary efficacy population of patients withBRCA1/2mutations, the objective response rate (ORR) by RECIST 1.1 criteria was 41.4%. CTC response rates for this population were as high as ORR regardless of measurability:

CTC0 and CTC conversion were early indicators of response and are associated with longer time on therapy in patients with measurable and non-measurable disease. Furthermore, CTC0 and CTC conversion are associated with longer OS:

Additionally, CTC0 was associated with improved rPFS in the overall population, and CTC0 and CTC conversion were also associated with PSA reduction among these BRCA patients.

Dr. Smith concluded with several take home messages:

Clinical trial information:NCT02854436

Presented by: Matthew R. Smith, MD, Ph.D., Professor of Medicine, Harvard Medical School, Assistant in Medicine, Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Written by: Zachary Klaassen, MD, MSc Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_mdat the 2020 Genitourinary Cancers Symposium, ASCO GU#GU20, February 13-15, 2020, San Francisco, California

References:

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ASCO GU 2020: Niraparib in Patients with mCRPC and Biallelic DNA-Repair Gene Defects: Correlative Measures of Tumor Response in Phase II GALAHAD Study...

Say precision medicine and people think of personalized cancer treatment. But this innovation has already begun to revolutionize primary care tooeven though the jury is still out, in many cases, on whether it makes a clear difference in outcomes.

Just what precision (alias personalized) medicine is isnt always spelled out precisely. But usually it is discussed as prevention or treatment that takes into account individual differences among patients, most often genetic differences. Some people expand the concept to consider individual differences in environment and lifestyle.

In adult primary care, two subsets of precision medicine have attracted the most attention recently: predictive genetic testing and pharmacogenomics.

Predictive genetic testing is what it sounds like: A genetic test that forecasts a persons chance of getting a disease. The term is also applied to germline genetic tests that provide some indication of the predisposition being passed down to offspring. Proponents see predictive genetic testing for certain inherited conditions as a way to unearth risks in people who can then get early treatment or take preventive steps to head off serious and possibly costly conditions. Actor Angelina Jolie put BRCA testing as a predictive genetic test into the public consciousness with her announcement in 2013 that she underwent a double mastectomy after testing positive for a BRCA mutation.

Pharmacogenomics studies show how a persons genes can affect his or her response to medications. Ideally, pharmacogenomic (sometimes called pharmacogenetic) results could end some of the trial and error with drugs and help providers and patients choose the most effective drug right off the bat.

Where federal dollars are concerned, precision medicine has already stepped out of the cancer box. In 2015, President Barack Obama committed $215 million to precision medicine research, including a genomic study of more than a million Americans to extend precision medicine from cancer to other diseases. A year later, the 21st Century Cures Act expanded this funding to $1.5 billion over the next 10 years.

Aided by a multibillion-dollar genomic testing industry, some providers have started testing precision medicine beyond oncology. In 2018, Geisinger Health System in central Pennsylvania made a splash by announcing that it would add DNA sequencing to routine primary care. A small number of other hospitals are starting to monetize these tests. In August 2019, STAT reported that a handful of academic medical centers, including Brigham and Womens Hospital and the Mayo Clinic, have started elective genome sequencing clinics for generally healthy patients willing to pay hundreds, sometimes thousands of dollars in cash for a genetic workup.

Skeptics see carts preceding horses; solid evidence that routine genetic testing results in better outcomes is lacking. As one genome-sequencing clinic leader conceded in the STAT article, such testing can lead to expensive follow-up testing. Not surprisingly, payers have been reluctant to cover sequencing tests of various kinds.

Regulators have breathed life into some kinds of testing and poured cold water on others. Last year, 23andMe was the first testing company to get FDA approval to market a direct-to-consumer genetic test for three (of the more than 1,000 known) BRCA gene mutations linked to increased risk of breast, ovarian, and prostate cancer. But in April 2019, the agency issued a warning letter to Inova Health System in Northern Virginia to stop marketing pharmacogenomics tests it claimed could predict patients responses to antidepressants, opioids, and other drugs. The FDA said it was unaware of data to support these claims.

A survey published two years ago in Clinical Pharmacology and Therapeutics found that clopidogrel, a blood thinner, was the medication most commonly tested for a druggene interaction, followed by simvastatin and warfarin. Nearly 40 academic medical centers and community health systems testing ways to implement pharmacogenomics in clinical practice were surveyed.

Some evidence suggests that traditional screening methods may not identify everyone at risk for certain inherited conditions. In a study published in Science three years ago, researchers at Geisinger and Regeneron (which manufactures Praluent, a drug used to treat familial hypercholesterolemia) found that only about one in four people carrying the familial hypercholesterolemia gene variant met the Dutch Lipid Clinic Network criteria (widely used diagnostic criteria) for genetic testing. Still, evidence for the clinical utility of many pharmacogenomic or predictive genetic tests is pretty scanty at this point.

Right now, for the average primary care provider, there are a relatively limited number of situations where pharmacogenomic testing is clearly beneficial to outcomes in a way thats dramatic, says Greg Feero, MD, a faculty member at Maine Dartmouth Family Medicine Residency and a former senior advisor to the director of the NIHs genomics research division.

For predictive genetic testing, there are a few notable exceptionshereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemiaif certain criteria such as family history of the condition are met. The CDC has designated genomics applications for these conditions as Tier 1, the highest tier on its evidence-based ranking system of genomic applications by their potential for a positive public health impact.

In a 2017 editorial published in American Family Physician, Vinay Prasad, MD, and Adam Obley, MD, of Oregon Health and Science University said that rigorous meta-analyses havent yet shown that genotype-guided dosing for warfarin, clopidogrel, or antidepressant selection is better than usual care. Prasad is a well-known critic of what he sees as the proliferation of medical treatments and therapies without good evidence behind them. We need to know on a broad scale that [these tests] improve outcomes for patients, and dont just reassure physicians theyre choosing a better drug, Obley tells Managed Care.

Prasad and Obley also argued in their editorial that without further proof of improved outcomes, routine genetic testing could just fuel more inappropriate care. Guidelines carve out clear boundaries for who should get tested because there are scenarios in which the risks and benefits of preventive measures arent known, they said, noting that the U.S. Preventive Services Task Force advises against genetic testing for BRCA mutations in women without a family history of BRCA-related cancers.

A small pilot study suggests that genetic testing in primary care may not lead to improved outcomes. In 2017, The Annals of Internal Medicine published the first randomized trial of whole-genome sequencing in primary care. Gene variants were found in 20% of the participants whose genomes were sequenced. But six months later none of them had improved outcomes.

The test produces lots of information, says Obley, who wasnt involved in the study. But its not clear that any patient was managed differently in a way that improved their health.

Without evidence supporting the clinical utility of routine pharmacogenomics or genetic testing, most payers are unwilling to cover them. Some exceptions exist, such as employers that offer routine genetic testing as an employee benefit. In a blog post published in 2018, Color Genomics touted Visa and the German software company SAP as customers. Medicare covers pharmacogenomic testing of two gene variants that predict warfarin responsiveness for beneficiaries enrolled in a randomized, controlled clinical study that meets certain standards.

The high cost of genetic testing has been cited as another reason insurance coverage is limited, but payers may not budge even as testing gets cheaper. The cost of doing the test itself has been declining quite rapidly, says Kathryn Phillips, a health economics professor at University of CaliforniaSan Francisco who researches personalized medicine access, quality, and reimbursement. She has disclosed in recent studies that she is a paid consultant for Illumina, a DNA sequencing company. But she says its hardand its going to take longerto figure out where to use genetics in primary care in healthy populations, and [for insurers] to pay for it.

The current state of evidence and bleak reimbursement prospects havent deterred early adopters from embracing precision medicine in primary care. For Megan Mahoney, MD, chief of general primary care at Stanford Medicine, precision medicine begins with going after data on key determinants of healthnot just genes, but also environmental factors, social determinants, and health behaviors.

In a yearlong pilot of 50 patientsmore than half of whom were at risk for cardiovascular conditionsStanford Medicine care teams created personalized care plans to prevent and manage chronic illness. The plans leveraged data from several sources, including genetic-risk assessments and genetic testing for the three CDC Tier 1 conditions and remote monitoring devices.

Before the pilot, which ended in 2018, Stanford did not offer routine genetic testing in primary care. So far, that hasnt changed. But Stanford is making the genetic-risk assessment tested in the pilot available to its primary care providers, hoping it can increase screening rates for the Tier 1 conditions, says Mahoney. Studies show that many primary care providers are uncomfortable evaluating and addressing genetic risk. Five patients in the pilot discovered through the genetic risk screening that theyre at high risk for breast cancer, demonstrating that this type of tool can help to identify previously unknown risks.

Post-pilot, Stanford is also offering patients with poorly controlled blood pressure connection to a Bluetooth-enabled blood pressure cuff and health coaching as part of a larger study. Genetic testing has dominated the discussion of precision medicine in primary care, but Stanfords experience shows that it isnt the only way to tailor preventive care to individual patients needs.

Even if clinical utility is ultimately shown, folding precision medicine into primary care will likely follow the path of many new developments in medicine: There will be some early adopters, but most practices will have a wait-and-see and depends-on-the-reimbursement attitude.

Educating doctors on how to interpret, use, and communicate genetic testing results to patients will be one of the biggest hurdles. Theyll be learning on the job, says Susanne Haga, associate professor of internal medicine at Duke Universitys medical school, who leads educational activities in genetics and genomics for the Duke Center for Applied Genomics. An obstacle course of other possible barriers awaits: the limited number of certified genetic counselors, concerns about privacy and genetic discrimination, and the potential for the lack of diversity in genomic data sets to exacerbate disparities in care.

Still, Haga sees the convergence of three factors that will force the health care systems hand and usher in precision medicine in primary care: patients increasing ability to influence decisions about their care, the declining cost of testing, and a critical mass of people, numbering in the millions, who will have had their DNA sequenced in genome programs such as Geisingers or several national genomics research initiatives.

Its coming, she says, one way or another.

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Precision Medicine in Primary Care: Bespoke. Genetic and Genomic. And Maybe Not Ready. - Managed Care magazine

Manipulating cellular metabolism may provide a promising therapeutic intervention in autoimmune diseases.

Laurie Harrington, Ph.D.Patients with autoimmune diseases like multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis have an imbalance between two types of immune system T cells. Destructive Th17 cells that mediate chronic inflammation are elevated, and regulatory T cells, or Treg cells, which suppress inflammatory responses and play a protective role in autoimmune disorders, are diminished.

Both cells differentiate from the same precursors nave CD4 T cells and the beginning of their change to either Th17 or Treg cells starts with the same signal. Subsequently, a fate decision occurs, like a fork in the road, steering the changing CD4 cells to become either inflammatory T cells or regulatory T cells.

New, preclinical research, led by Laurie Harrington, Ph.D., associate professor in the UAB Department of Cell, Developmental and Integrative Biology at the University of Alabama at Birmingham, shows a pivotal role for cellular metabolism to regulate that fate decision, a decision that occurs very early in the activation of CD4 T cells. This opens a possibility that manipulating the cellular metabolism of T cells may provide a new, promising therapeutic intervention to modulate the balance between pathogenic Th17 and Treg cells in chronic autoimmune disorders. The research is published in the journal Cell Reports.

Upon activation, T cells were known to rapidly increase metabolism, including glycolysis and mitochondrial oxidative phosphorylation, or OXPHOS, to meet the energetic demands of differentiation. But the precise contribution of OXPHOS to that Th17 differentiation was not defined.

The UAB researchers, and one colleague at New York University, found that ATP-linked mitochondrial respiration during Th17 differentiation was essential to upregulate glycolysis and the TCA cycle metabolism. Strikingly, it also was essential to promote inflammation of the central nervous system by Th17, as shown in a mouse model for multiple sclerosis.

In the mouse model, experimental autoimmune encephalitis, Th17 cells cause the disease progression. For the experiment, harvested CD4 T cells were differentiated using a combination of Th17-polarizing cytokines. One group was the polarized control, and one group was polarized in the presence of oligomycin, an inhibitor of mitochondrial OXPHOS. Then the T cells were transferred into experimental mice. Mice receiving the T cells treated with oligomycin during polarizing conditions showed a significantly delayed onset of disease and reduced disease severity. Both groups of T cells proliferated robustly after transfer.

In mechanistic experiments, the researchers detailed the early molecular events that differ between cells polarized in the presence or absence of oligomycin. These included gene sets that are upregulated or downregulated, presence or absence of Th17 or Treg cell markers, expression of signature transcription factors needed for Th17 differentiation, and expression of gene products that play a role in T cell receptor signaling.

A surprise was found in the timing of the fate decision. In an experiment, CD4 T cells were exposed to Th17-polarizing conditions with oligomycin present only during the first 24 hours. They were then washed and allowed to continue differentiation in the polarizing conditions. The effects of this brief exposure to oligomycin were T cells that lacked Th17 markers and instead showed hallmarks of Treg cells, including expression of Foxp3. Thus, the brief early exposure to oligomycin imprinted the Foxp3 fate decision.

Overall, Harrington said, inhibition of mitochondrial OXPHOS ablates Th17 pathogenicity in a mouse model of multiple sclerosis and results in generation of functionally suppressive Treg cells under Th17 conditions.

Co-authors with Harrington of the study, Mitochondrial oxidative phosphorylation regulates the fate decision between pathogenic Th17 and regulatory T cells, are Boyoung Shin, UAB Department of Cell, Developmental and Integrative Biology; Gloria A. Benavides and Victor M. Darley-Usmar, UAB Department of Pathology; Jianlin Geng and Hui Hu, UAB Department of Microbiology; and Sergei B. Koralov, New York University Grossman School of Medicine.

Support came from National Institutes of Health grants AI113007 and DK079337, American

Heart Association grant 16PRE29650004, an AMC21 Award from the UAB School of Medicine, and a Blue Sky Award from the UAB School of Medicine.

At UAB, Darley-Usmar holds the Endowed Professorship in Mitochondrial Medicine and Pathology.

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Cellular metabolism regulates the fate decision between pathogenic and regulatory T cells - UAB News

Many mammals gain weight and become insulin resistant during fall. However, these changes are easily reversible, and the mammals will not develop any further unhealthful symptoms. Researchers believe that the explanation for this lies in mechanisms associated with hibernation.

Researchers have recognized the fact that a wide array of animals have "superpowers."

Specifically, the same conditions that affect humans some of which can be life threatening may not affect animals at all.

Two such examples are elephants and whales, whose cancer risk is practically zero. Other animals are unlikely to develop metabolic conditions such as obesity. Why is this?

Researchers Elliott Ferris and Christopher Gregg, from the University of Utah in Salt Lake City, believe that hibernation may have something to do with it.

Many mammals around the world hibernate in the cold season. Hibernation is characterized by entering a sleep-like state in which body temperature drops, breathing slows down, the heart beats more slowly, and all other metabolic (automated, self-regulating physiological processes) slow down.

This allows hibernating animals to survive during the winter months, when food becomes scarce and living conditions less friendly.

As Ferris and Gregg note in their new study paper in the journal Cell Reports, many hibernating animals actually put on a lot of weight in the buildup to hibernation. They also become insulin resistant.

These are two aspects characteristic of obesity. However, in hibernating animals, they mean only that the animals are able to access a timely reserve of fat during the winter months.

Unlike when humans develop obesity, hibernators can later easily shed the extra weight, and their bodies automatically reverse insulin resistance. Also, unlike humans with obesity, hibernating mammals do not develop hypertension or low-grade inflammation, both of which could lead to further health concerns.

For these reasons, Ferris and Gregg believe that some genetic mechanisms involved in regulating hibernation may also play a role in obesity control.

"Hibernators have evolved an incredible ability to control their metabolism," explains Gregg, an associate professor in the Department of Neurology & Anatomy at the University of Utah.

"Metabolism shapes risks for a lot of different diseases, including obesity, type 2 diabetes, cancer, and Alzheimer's disease," he adds. "We believe that understanding the parts of the genome that are linked to hibernation will help us learn to control risks for some these major diseases."

"A big surprise from our new study is that these important parts of the genome were hidden from us in 98% of the genome that does not contain genes we used to call it 'junk DNA,'" says Gregg.

For their new study, Gregg and Ferris analyzed the genomes of four hibernating mammalian species: the thirteen-lined ground squirrel, the little brown bat, the gray mouse lemur, and the lesser hedgehog tenrec.

When comparing the genomes of these species, the researchers found that they had all evolved on an independent basis a series of short DNA sections called "parallel accelerated regions."

Accelerated regions also exist in humans, though scientists understand very little about them. What researchers know so far is that accelerated regions feature noncoding DNA, and that they did not change much as mammals evolved through the ages.

Except in humans, that is, in whom they suddenly started changing and shifting around the time that we split from our primate "cousins."

After further analyzing the data, the researchers noticed that parallel accelerated regions appear close to genes linked with obesity in humans.

To confirm the link between accelerated regions and genes that play a role in obesity control, Gregg and Ferris then analyzed a very specific set of genes: those that drive Prader-Willi syndrome, a rare genetic condition in humans.

Among other symptoms, this condition is characterized by an excessive appetite, which can lead to unhealthful weight gain and obesity.

In looking at the genes linked to Prader-Willi syndrome, the researchers did find that these genes are associated with more hibernator accelerated regions when compared with genes that did not play a role in this genetic condition.

Following these results, Gregg and Ferris now suggest that hibernating animals may have evolved mechanisms that allow them to automatically "switch off" the activity of certain genes associated with obesity. This is not the case for nonhibernating mammals.

The investigators also identified as many as 364 genetic elements that may help both regulate hibernation and control obesity.

"Our results show that hibernator accelerated regions are enriched near genes linked to obesity in studies of hundreds of thousands of people, as well as near genes linked to a syndromic form of obesity," says Ferris.

"Therefore, by bringing together data from humans and hibernating animals, we were able to uncover candidate master regulatory switches in the genome for controlling mammalian obesity," he adds.

Using specialized gene editing technology, the researchers are currently testing the role of these 364 genetic elements in mouse models. They hope that their findings will eventually help them find a way of controlling not just obesity, but also other conditions related to metabolic mechanisms.

"Since obesity and metabolism shape risks for so many different diseases, the discovery of these parts of the genome is a really exciting insight that lays foundations for many important new research directions. We have new projects emerging for aging, dementia, and metabolic syndrome."

Christopher Gregg

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Why scientists are studying hibernation to tackle obesity - Medical News Today

A consultant studies a mammogram. The drug olaparib could slow cancer growth by three months, researchers have found. Photograph: Rui Vieira/PA

A type of inherited and incurable breast cancer that tends to affect younger women could be targeted by a new therapy, researchers have found.

A small study presented at the worlds largest cancer conference found treating patients with the drug olaparib could slow cancer growth by three months and be less toxic for patients with inherited BRCA-related breast cancer.

Researchers said there was not enough data to say whether patients survived longer as a result of the treatment.

We are in our infancy, said Dr Daniel Hayes, president of the American Society of Clinical Oncology and professor of breast cancer research at the University of Michigan. This is clearly an advance; this is clearly proof of concept these can work with breast cancer.

Does it look like its going to extend life? We dont know yet, he said.

The drug is part of the developing field of precision medicine, which targets patients genes to tailor treatment.

It is a perfect example of how understanding a patients genetics and the biology of their tumor can be used to target its weaknesses and personalize treatment, said Andrew Tutt, director of the Breast Cancer Now Research Centre at The Institute of Cancer Research.

Olaparib is already available for women with BRCA-mutant advanced ovarian cancer, and is the first drug to be approved that is directed against an inherited genetic mutation. The study was the first to show olaparib can slow growth of inherited BRCA-related breast cancer. The drug is not yet approved for that use.

People with inherited mutations in the BRCA gene make up about 3% of all breast cancer patients, and tend to be younger. The median age of women in the olaparib trial was 44 years old.

BRCA genes are part of a pathway to keep cells reproducing normally. An inherited defect can fail to stop abnormal growth, thus increasing the risk of cancer. The study examined the effectiveness of olaparib against a class of BRCA-related cancers called triple negative. Olaparib is part of a class of four drugs called PARP-inhibitors that work by shutting down a pathway cancer cells use to reproduce.

The study from Memorial Sloan Kettering Cancer Center in New York randomly treated 300 women with advanced, BRCA-mutated cancer with olaparib or chemotherapy. All the participants had already received two rounds of chemotherapy.

About 60% of patients who received olaparib saw tumors shrink, compared with 29% of patients who received chemotherapy. That meant patients who received olaparib saw cancer advance in seven months, versus four months for only chemotherapy.

Researchers cautioned it is unclear whether olaparib extended life for these patients, and that more research was needed to find out which subset of patients benefit most from olaparib.

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New therapy offers hope against incurable form of breast cancer - The Guardian

SUNDAY, June 4, 2017 (HealthDay News) -- A twice-daily pill could help some advanced breast cancer patients avoid or delay follow-up sessions of chemotherapy, a new clinical trial reports.

The drug olaparib (Lynparza) reduced the chances of cancer progression by about 42 percent in women with breast cancer linked to BRCA1 and BRCA2 gene mutations, according to the study.

Olaparib delayed cancer progression by about three months. The drug also caused tumors to shrink in three out of five patients who received the medication, the researchers reported.

"Clearly the drug was more effective than traditional chemotherapy," said Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society.

"This is a group where a response is more difficult to obtain -- a young group with a more aggressive form of cancer -- and nonetheless we saw a close to 60 percent objective response rate," he said.

The study was funded by AstraZeneca, the maker of Lynparza.

Olaparib works by cutting off the avenues that malignant cancer cells use to stay alive, said lead researcher Dr. Mark Robson. He's a medical oncologist and clinic director of Clinical Genetics Service at Memorial Sloan Kettering Cancer Center in New York City.

The drug inhibits PARP, an enzyme that helps cells repair damaged DNA, Robson said.

Normal cells denied access to PARP will turn to the BRCA genes for help, since they also support the repair of damaged DNA, Robson said.

But that "backup capability" is not available to breast cancer cells in women with BRCA gene mutations, Robson said.

"When you inhibit PARP, the cell can't rescue itself," Robson said. "In theory, you should have a very targeted approach, one specifically directed at the cancers in people who have this particular inherited predisposition."

Olaparib already has been approved by the U.S. Food and Drug Administration for use in women with BRCA-related ovarian cancer. Robson and his colleagues figured that it also should be helpful in treating women with breast cancer linked to this genetic mutation.

The study included 302 patients who had breast cancer that had spread to other areas of their body (metastatic breast cancer). All of the women had an inherited BRCA mutation.

They were randomly assigned to either take olaparib twice a day or receive standard chemotherapy. All of the patients had received as many as two prior rounds of chemotherapy for their breast cancer. Women who had hormone receptor-positive cancer also had been given hormone therapy.

After 14 months of treatment, on average, people taking olaparib had a 42 percent lower risk of having their cancer progress compared with those who received another round of chemotherapy, Robson said.

The average time of cancer progression was about seven months with olaparib compared with 4.2 months with chemotherapy.

Tumors also shrank in about 60 percent of patients given olaparib. That compared with a 29 percent reduction for those on chemotherapy, the researchers said.

Severe side effects also were less common with olaparib. The drug's side effects bothered 37 percent of patients compared with half of those on chemo. The drug's most common side effects were nausea and anemia.

"There were fewer patients who discontinued treatment because of toxicity compared to those who received chemotherapy," Robson said. "Generally it was pretty well tolerated."

Only about 3 percent of breast cancers occur in people with BRCA1 and BRCA2 mutations, the researchers said in background notes.

Despite this, the results are "quite exciting," said Dr. Julie Fasano, an assistant professor of hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City.

Olaparib could wind up being used early in the treatment of metastatic breast cancer as an alternative to chemotherapy, and future studies might find that the drug is effective against other forms of breast cancer, Fasano said.

"It may be a practice-changing study, in terms of being able to postpone IV chemotherapy and its associated side effects" like hair loss and low white blood cell counts, Fasano said.

Lichtenfeld noted that olaparib also places less burden on patients.

"It may be easier for women to take two pills a day rather than go in for regular chemotherapy," Lichtenfeld said. "Clearly, this is a treatment that will garner considerable interest.

The findings were scheduled to be presented Sunday at the American Society of Clinical Oncology's annual meeting, in Chicago. The study was also published June 4 in the New England Journal of Medicine.

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Drug Helps Fight Breast Tumors Tied to 'Cancer Genes' - The Tand D.com

A newly discovered type of genetic mutation that occurs frequently in cancer cells may provide clues about the diseases origins and offer new therapeutic targets, according to new research from Weill Cornell Medicine and the New York Genome Center.

Using next-generation sequencing technology, scientists have previously traced cancers roots to mutations that disrupt the sequence of proteins. As a result, the cell either creates hyperactive or dysfunctional versions of proteins, or fails to produce them at all, leading to cancer. Now, a study published Jan. 12 in Cell illuminates a possible new type of driver of the disease: small (one-50 letter) insertions or deletions of DNA sequence, also called indels, in regions of the genome that do not code for protein.

Dr. Marcin Imielinski Photo credit: John Abbott

Those non-coding regions are still important because they contain sequences that affect how genes are regulated, which is critical for normal cell development, said lead author Dr. Marcin Imielinski, an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine and a core member at the New York Genome Center. We already know they are biologically important. The question is whether they can impact cancer development.

In the study,Dr.Imielinski and his colleagues analyzed sequencing data from several publically available databases of tumor samples, focusing on the 98 percent of the genome that does not code for protein. They initially looked at lung adenocarcinoma, the most common type of lung cancer, and found that the most frequent indel-mutated regions in their genomes landed in genes encoding surfactant proteins. Though these genes are essential for healthy lung function, they had not previously been associated with lung cancer. However, they are highly and specifically expressed by the cell type that gives rise to lung adenocarcinoma.

The researchers then looked at the genomes of 12 other cancer types and found similar patterns in liver, stomach and thyroid tumors. In each cancer, noncoding indels clustered in genes that are critical to organ function, but had not been associated with the cancer, said Dr. Imielinski, who is also an assistant professor of computational genomics in theHRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicineand a member of theSandra and Edward Meyer Cancer Centerat Weill Cornell Medicine.

This image shows genetic mutations (blue) in the context of their surrounding DNA sequence, highlighting a sequence motif (red) that Dr. Imielinski discovered.

Most strikingly, these non-coding indels are very common, occurring in 20-50 percent of the associated cancers. They occur as frequently as the most famous cancer-causing mutations, said Dr. Imielinski, who is a paid consultant for the company 10X Genomics, which sells devices and technology to analyze genetic information. Any gene or any sequence that mutated at this frequency has been shown to play a causal role in cancer. That would be an exciting outcome, if we can prove it.

Even if these mutations are not shown to cause cancer, they can be used in the future to improve cancer diagnosis and treatment. These mutations can be biomarkers that help us to diagnose a cancer early, or they could be used to pinpoint a primary cancer when there are metastases and we cant find the original cancer, Dr. Imielinski said. There are a lot of potential clinical implications from these findings.

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New Type of Genetic Mutation Identified in Cancer - Cornell Chronicle