Category Archives: Gene Medicine

June 26, 2017 Credit: CC0 Public Domain

The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating development of new treatments and precision medicine.

The research, which generated over 20 million pieces of data, has found 360 new disease models and provides 28,406 new descriptions of the genes' effects on mouse biology and disease. The new disease models are being made available to the biomedical community to aid their research.

The International Mouse Phenotyping Consortium (IMPC) is aiming to produce a complete catalogue of mammalian gene function across all genes. Their initial results, now published in Nature Genetics, is based on an analysis of the first 3,328 genes (15 per cent of the mouse genome coding for proteins).

Lead author Dr Damian Smedley from Queen Mary University of London (QMUL) and a Monarch Initiative Principal Investigator, said: "Although next generation sequencing has revolutionised the identification of new disease genes, there is still a lack of understanding of how these genes actually cause disease.

"These 360 new disease models that we've identified in mice represent the first steps of a hugely important international project. We hope researchers will be able to use this knowledge to develop new therapies for patients, which is ultimately what we're all striving to achieve."

With its similarity to human biology and ease of genetic modification, the laboratory mouse is arguably the preferred model organism for studying human genetic disease. However, the vast majority of the mouse genome remains poorly understood, as scientists tend to focus their research on a few specific areas of the genome linked to the most common inherited diseases.

Development of therapies for rare disease lags far behind, with over half of diagnosed rare diseases still having no known causative gene. This is why the IMPC is aiming to build a complete database that systematically details the functions of all areas of the mouse genome, including neurological, metabolic, cardiovascular, respiratory and immunological systems.

Terry Meehan, IMPC Project Coordinator at European Bioinformatics Institute (EMBL-EBI) said: "Mouse models allow us to speed up patient diagnosis and develop new therapies. But before that can work, we need to understand exactly what each gene does, and what diseases it is associated with. This is a significant effort in data collection and curation that goes well beyond the capabilities of individual labs. IMPC is creating a data resource that will benefit the entire biomedical community."

The project involves going through the mouse genome systematically and knocking out a particular gene, one by one, in different mice. By looking at the mouse's resulting characteristics in a variety of standardised tests, the team then see if and how the gene knockout manifests itself as a disease, and link their findings to what is already known about the human version of the disease. The 'one by one' knockout approach lends itself to rare gene discovery, as often these diseases are caused by variants of a single gene.

More than half of the 3,328 genes characterised have never been investigated in a mouse before, and for 1,092 genes, no molecular function or biological process were previously known from direct experimental evidence. These include genes that have now been found to be involved in the formation of blood components (potentially involved in a type of anaemia), cell proliferation and stem cell maintenance.

For the first time, human disease traits were seen in mouse models for forms of Bernard-Soulier syndrome (a blood clotting disorder), Bardet-Biedl syndrome (causing vision loss, obesity and extra fingers or toes) and Gordon Holmes syndrome (a neurodegenerative disorder with delayed puberty and lack of secondary sex characteristics).

The team also identified new candidate genes for diseases with an unknown molecular mechanism, including an inherited heart disease called 'Arrhythmogenic Right Ventricular Dysplasia' that affects the heart muscle, and Charcot-Marie-Tooth disease, which is characterised by nerve damage leading to muscle weakness and an awkward way of walking.

Dr Smedley added: "In addition to a better understanding of the disease mechanism and new treatments for rare disease patients, many of the lessons we learn here will also be of value to precision medicine, where the goal is to improve treatment through the customisation of healthcare based on a patient's genomic information."

Explore further: Major mouse study reveals the role of genes in disease

More information: 'Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium' by Meehan et al., Nature Genetics. DOI: 10.1038/ng.3901

The functions of around 150 genes have been discovered by scientists across Europe in a major initiative to try to understand the part they play in disease and biology.

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The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating ...

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Characterizing the mouse genome reveals new gene functions and their role in human disease - Medical Xpress

June 26, 2017 New DNA-based LASSO molecule probe can bind target genome regions for functional cloning and analysis. Credit: Jennifer E. Fairman/Johns Hopkins University

Discovering the function of a gene requires cloning a DNA sequence and expressing it. Until now, this was performed on a one-gene-at-a-time basis, causing a bottleneck. Scientists at Rutgers University-New Brunswick in collaboration with Johns Hopkins University and Harvard Medical School have invented a technology to clone thousands of genes simultaneously and create massive libraries of proteins from DNA samples, potentially ushering in a new era of functional genomics.

"We think that the rapid, affordable, and high-throughput cloning of proteins and other genetic elements will greatly accelerate biological research to discover functions of molecules encoded by genomes and match the pace at which new genome sequencing data is coming out," said Biju Parekkadan, an associate professor in the Department of Biomedical Engineering at Rutgers University-New Brunswick.

In a study published online today in the journal Nature Biomedical Engineering, the researchers showed that their technologyLASSO (long-adapter single-strand oligonucleotide) probescan capture and clone thousands of long DNA fragments at once.

As a proof-of-concept, the researchers cloned more than 3,000 DNA fragments from E. coli bacteria, commonly used as a model organism with a catalogued genome sequence available.

"We captured about 95 percent of the gene targets we set out to capture, many of which were very large in DNA length, which has been challenging in the past," Parekkadan said. "I think there will certainly be more improvements over time."

They can now take a genome sequence (or many of them) and make a protein library for screening with unprecedented speed, cost-effectiveness and precision, allowing rapid discovery of potentially beneficial biomolecules from a genome.

In conducting their research, they coincidentally solved a longstanding problem in the genome sequencing field. When it comes to genetic sequencing of individual genomes, today's gold standard is to sequence small pieces of DNA one by one and overlay them to map out the full genome code. But short reads can be hard to interpret during the overlaying process and there hasn't been a way to sequence long fragments of DNA in a targeted and more efficient way. LASSO probes can do just this, capturing DNA targets of more than 1,000 base pairs in length where the current format captures about 100 base pairs.

The team also reported the capture and cloning of the first protein library, or suite of proteins, from a human microbiome sample. Shedding light on the human microbiome at a molecular level is a first step toward improving precision medicine efforts that affect the microbial communities that colonize our gut, skin and lungs, Parekkadan added. Precision medicine requires a deep and functional understanding, at a molecular level, of the drivers of healthy and disease-forming microbiota.

Today, the pharmaceutical industry screens synthetic chemical libraries of thousands of molecules to find one that may have a medicinal effect, said Parekkadan, who joined Rutgers' School of Engineering in January.

"Our vision is to apply the same approach but rapidly screen non-synthetic, biological or 'natural' molecules cloned from human or other genomes, including those of plants, animals and microbes," he said. "This could transform pharmaceutical drug discovery into biopharmaceutical drug discovery with much more effort."

The next phase, which is underway, is to improve the cloning process, build libraries and discover therapeutic proteins found in our genomes, Parekkadan said.

Explore further: Technical advances in reading long DNA sequences have ramifications in understanding primate evolution, human disease

More information: Long-adapter single-strand oligonucleotide probes for the massively multiplexed cloning of kilobase genome regions, Nature Biomedical Engineering (2017). DOI: 10.1038/s41551-017-0092

Technical advances in reading long DNA sequences have ramifications in understanding primate evolution and human disease.

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Cloning thousands of genes for massive protein libraries - Phys.Org

June 26, 2017 In this image of neurons in the cerebellum of the brain, the yellow cells are Purkinje cells in which the channelrhodopsin-2 gene is being produced. Credit: Horwitz Lab/UW Medicine Seattle

UW Medicine researchers have developed a technique for inserting a gene into specific cell types in the adult brain in an animal model.

Recent work shows that the approach can be used to alter the function of brain circuits and change behavior. The study appears in the journal Neuron in the NeuroResources section.

Gregory Horwitz, associate professor of physiology and biophysics at the University of Washington School of Medicine in Seattle, led the research team. He said that the approach will allow scientists to better understand what roles select cell types play in the brain's complex circuitry.

Researchers hope that the approach might someday lead to developing treatments for conditions, such as epilepsy, that might be curable by activating a small group of cells.

"The brain is made up of a mix of many cell types performing different functions. One of the big challenges for neuroscience is finding ways to study the function of specific cell types selectively without affecting the function of other cell types nearby," Horwitz said. "Our study shows it is possible to selectively target a specific cell type in an adult brain using this technique and affect behavior nearly instantly."

In their study, Horowitz and his colleagues at the Washington National Primate Research Center in Seattle inserted a gene into cells in the cerebellum, a small structure located at the back of the brain and tucked under the brain's larger cerebrum.

The cerebellum's primary function is controlling motor movements. Disorders of the cerebellum generally lead to often disabling loss of coordination. Recent research suggests the cerebellum may also be important in learning and may be involved in such conditions as autism and schizophrenia.

The cells the scientists selected to study are called Purkinje cells. These cells, named after their discoverer, Czech anatomist Jan Evangelista Purkinje, are some of the largest in the human brain. They typically make connections with hundreds of other brain cells.

"The Purkinje cell is a mysterious cell," said Horwitz. "It's one of the biggest and most elaborate neurons and it processes signals from hundreds of thousands of other brain cells. We know it plays a critical role in movement and coordination. We just don't know how."

The gene they inserted, called channelrhodopsin-2, encodes for a light-sensitive protein that inserts itself into the brain cell's membrane. When exposed to light, it allows ions - tiny charged particles - to pass through the membrane. This triggers the brain cell to fire.

The technique, called optogenetics, is commonly used to study brain function in mice. But in these studies, the gene must be introduced into the embryonic mouse cell.

"This 'transgenic' approach has proved invaluable in the study of the brain," Horwitz said. "But if we are someday going to use it to treat disease, we need to find a way to introduce the gene later in life, when most neurological disorders appear."

The challenge for his research team was how to introduce channelrhodopsin-2 into a specific cell type in an adult animal. To achieve this, they used a modified virus that carried the gene for channelrhodopsin-2 along with segment of DNA called a promoter. The promoter stimulates the cell to start expressing the gene and make the channelrhodopsin-2 membrane protein. To make sure the gene was expressed only by Purkinje cells, the researchers used a promoter that is strongly active in Purkinje cells, called L7/Pcp2."

In their paper, the researchers reported that by painlessly injecting the modified virus into a small area of the cerebellum of rhesus macaque monkeys, the channelrhodopsin-2 was taken up exclusively by the targeted Purkinje cells. The researchers then showed that when they exposed the treated cells to light through a fine optical fiber, they were able stimulate the cells to fire at different rates and affect the animals' motor control.

Horwitz said that it was the fact that Purkinje cells express L7/Pcp2 promoter at a higher rate than other cells that made them more likely to produce the channelrhodopsin-2 membrane protein.

"This experiment demonstrates that you can engineer a viral vector with this specific promoter sequence and target a specific cell type," he said. "The promoter is the magic. Next, we want to use other promoters to target other cell types involved in other types of behaviors."

Explore further: New insights into control of neuronal circuitry could lead to treatments for an inherited motor disorder

More information: Yasmine El-Shamayleh et al, Selective Optogenetic Control of Purkinje Cells in Monkey Cerebellum, Neuron (2017). DOI: 10.1016/j.neuron.2017.06.002

Journal reference: Neuron

Provided by: University of Washington

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Study shines light on brain cells that coordinate movement - Medical Xpress

Standard vaccines to prevent infectious diseases consist of killed or weakened pathogens or proteins from those microorganisms. Vaccines that treat cancer also rely on proteins. In contrast, a new kind of vaccine, which is poised to make major inroads in medicine, consists of genes. Genomic vaccines promise to offer many advantages, including fast manufacture when a virus, such as Zika or Ebola, suddenly becomes more virulent or widespread. They have been decades in the making, but dozens have now entered clinical trials.

Most vaccines work by teaching the immune system to recognize a foe. They accomplish this trick by delivering a dead or weakened pathogen; the immune system recognizes that certain bits of protein, called antigens, on the surface of the pathogen are foreign and prepares to pounce the next time it encounters them. (Many modern vaccines deliver only the antigens, leaving out the pathogens.) To treat cancer, doctors may deliver other proteins that enhance immune responses. These proteins can include the immune systems own guided missilesantibodies.

Genomic vaccines take the form of DNA or RNA that encodes desired proteins. On injection, the genes enter cells, which then churn out the selected proteins. Compared with manufacturing proteins in cell cultures or eggs, producing the genetic material should be simpler and less expensive. Further, a single vaccine can include the coding sequences for multiple proteins, and it can be changed readily if a pathogen mutates or properties need to be added. Public health experts, for instance, revise the flu vaccine annually, but sometimes the vaccine they choose does not match the viral strains that circulate when flu season comes. In the future, investigators could sequence the genomes of the circulating strains and produce a better-matched vaccine in weeks. Genomics also enables a new twist on a vaccination approach known as passive immune transfer, in which antibodies are delivered instead of antigens. Scientists can now identify people who are resistant to a pathogen, isolate the antibodies that provide that protection and design a gene sequence that will induce a persons cells to produce those antibodies.

With such goals in mind, the U.S. government, academic labs and companies large and small are pursuing the technology. A range of clinical trials to test safety and immunogenicity are under way, including for avian influenza, Ebola, hepatitis C, HIV, and breast, lung, prostate, pancreatic and other cancers. And at least one trial is looking at efficacy: the National Institutes of Health has begun a multisite clinical trial to see if a DNA vaccine can protect against Zika.

Meanwhile researchers are working to improve the technologyfor example, by finding more efficient ways to get the genes into cells and by improving the stability of the vaccines in heat. Oral delivery, which would be valuable where medical personnel are scarce, is not likely to be feasible anytime soon, but nasal administration is being studied as an alternative and is under study. Optimism is highthat any remaining obstacles can be solved.

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Genomic Vaccines - Scientific American

24 Jun 2017

Two new papers show how rare genetic mutations are helping scientists understand more about the processes that go wrong in the amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum. A hallmark of these diverse conditions is the abnormal clumping of the nuclear protein TDP-43 in the cytoplasm. In the June 6 Nature Communications, researchers led by David Kang, University of South Florida, Tampa, reported that mutations in the mitochondrial protein CHCHD10 induced TDP-43 translocation from the nucleus to the cytoplasm and poisoned mitochondria and synapses. In a second paper, Yongchao Ma and colleagues from Northwestern University Feinberg School of Medicine, Chicago, debut a new ALS gene, UBQLN4, identifying a variant in a woman with familial ALS. Their paper, published May 2 in eLIFE, shows that the D90A substitution in the ubiquilin impairs proteasome function and causes abnormal sprouting and branching of motor axons in model systems. The results further highlight the role of protein homeostasis in neuronal health and disease.

Kangs intriguing work suggests that wild-type CHCHD10 maintains TDP-43 nuclear localization and protects against TDP-43 toxicity, while disease-related mutations of CHCHD10 have opposite, damaging effects, said Ronald Klein, Louisiana State University Health in Shreveport. The work also adds significantly to the importance of mitochondrial function in neurodegenerative diseases, Klein wrote in an email toAlzforum.

The discovery, just over two years ago, of mutations in the mitochondrial protein CHCHD10 (short for coiled-coil-helix-coiled-coil-helix domain containing protein 10) in several families with amyotrophic lateral sclerosis/ frontotemporal dementia (ALS-FTD) suggested for the first time that dysfunction in the organelles, the cells power plants, could cause motor neuron disease (see Jun 2014 newsand Oct 2014 news).Scientists know little about the function of CHCHD10, which sits inside the mitochondria as part of a protein complex that stabilizes cristae, the organelles membrane folds. In patients with ALS-associated CHCHD10 mutations, mitochondria appear disorganized and dysfunctional (Genin et al., 2015).

Kang set out to understand how CHCHD10 mutations affect protein function, and whether they also impact TDP-43 accumulation and toxicity. To get at those issues, the researchers first turned to the roundworm Caenorhabditis elegans, whose single CHCHD10 homolog, har-1, includes both the arginine-15 (R15) and serine-59 (S59) residues that are mutated in ALS/FTD. Co-first author Courtney Trotter found that har-1 knockouts developed movement problems similar to those seen in worms overexpressing TDP-43. The animals crawled more slowly on an agar plate, and curled up when dropped in liquid, rather than thrashing about like wild-type worms. Their mitochondria appeared to be in poor health. They produced more superoxide than mitochondria from normal worms. Introducing a human CHCHD10 transgene into the har-1 knockouts completely normalized their behaviorthe transgenic worms crawled and swam normally, and their mitochondrial superoxide hovered at control levels. In contrast, human CHCHD10 bearing either the R15L or S59L mutation did not compensate at all, suggesting that the mutations caused a loss of CHCHD10function.

As the two other first authors, Jung-A. Woo and Tian Liu, worked their way through studies on mammalian cells, primary neurons, and finally mouse brains in vivo, they saw the same pattern. Loss of CHCHD10 function, either by knockdown or by overexpression of mutated protein, spelled trouble for mitochondria, disrupting their structure, increasing superoxide production, and causing expression of mitochondrial genes to decrease by half. In primary mouse hippocampal neurons, CHCHD10 mutant expression led to a 50 percent reduction in synaptic markers drebrin and synatophysin as visualized by confocal microscopy. All told, the results suggest the loss of CHCHD10 function in these models poisons mitochondria and zaps synapses.Does any of this affect TDP-43? In the primary neurons, TDP43 exclusively localized to the nucleus, but after knockdown of CHCHD10 or expression of the mutants, a fraction of the TDP-43 moved to the cytoplasm, reaching as far as neuritic processes. Expression of CHCHD10 mutants doubled the cytosol/nuclear ratio of TDP-43 over that seen in wild-type cells. Recent work suggests TDP-43s toxicity stems from its localization to mitochondria (Jul 2016 news). Indeed, under the influence of CHCHD10 mutants, nearly half of the cytosolic TDP-43 deposited inmitochondria.

TDP-43 (red) normally resides in the nucleus but in NIH3T3 mouse fibroblasts expressing R15L or S59L CHCHD10 mutations (second and third rows), it leaches into the cytoplasm, where it localizes with the mitochondrial outer membrane protein TOM20 (green). [Courtesy of DavidKang.]

The CHCHD10 variants also enhanced TDP43 toxicity. Adenovirus-mediated expression of TDP-43 in the brains of young mice caused synaptic markers to drop by 50 and 39 percent in the dentate gyrus and CA3 region of the hippocampus, respectively. Co-expression of CHCHD10 prevented the decline, and expression of either mutant exacerbated it. The results establish that CHCHD10 mutations influence toxicity of TDP43 in neurons, however, the researchers have yet to test this in motor neurons or cortical neurons, the cell types affected in ALS orFTD.

While the work connects CHCHD10 to TDP-43, many questions remain. How does CHCHD10 influence where TDP-43 localizes, and why do the mutations cause TDP-43 to appear in the cytoplasm? Co-immunoprecipitation hinted that CHCHD10 and TDP-43 physically associate, but that mutations do not disrupt this interaction. We have to work out the details, Kang said, noting that their next studies will focus on the mechanisms of CHCHD10 and TDP-43 translocations and theirregulation.

The second report details how a newly discovered ALS variant in UBQLN4 disrupts a different and equally fundamental homeostatic mechanismthe regulated recycling of proteins via the ubiquitin proteasome system. Ubiquilins deliver proteins to the proteasome. UBQLN1 and UBQLN2 are linked to Alzheimers disease and FTD/ALS, but this is the first time UBQLN4 variants have been linked to disease. Ma worked with coauthor Teepu Siddique, whose lab identified the variant through targeted gene sequencing in 267 familial and 411 sporadic ALS cases. One patient carried the single amino acid change, from aspartate to alanine at position 90. None of 332 in-house controls, or more than 60,000 people in a sequencing consortium database, had the change, suggesting it may be the pathogenicvariant.

To test this, first author Brittany Edens expressed wild-type or D90A UBQLN4 in cultured mouse spinal cord neurons, and found the mutant increased neurite number. In zebrafish embryos, the mutant induced abnormal motor neuron branching as well. These morphological effects accompanied inhibition of the proteasome and upregulation of -catenin, one of UBQLN4s target proteins and an important regulator of neuronal development. Treatment with the -catenin inhibitor quercetin reversed the mutant effects on morphology in neurons andzebrafish.

This is an interesting first report linking UBQLN4 to ALS, said Lihong Zhan of the University of California, San Francisco, who was not involved with the work. Zhan told Alzforum hed like to see how the mutation behaves in models more relevant to ALS, such as age-related neuron death. Ma agreed that the models are mainly developmental, but considers them still relevant for ALS, as early life events may render the neurons vulnerable later. The models used in the study were short-term expression systems; Ma told Alzforum they are now working on additional models that will enable a more thorough examination of the mutants impact across the lifespan. He hopes that -catenin, or other substrates of UBQNL4, could become useful therapeutic targets in ALS.Pat McCaffrey

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ALS/FTD Genes Reveal Pathways to Pathology - Alzforum

How might the shift towards personalized medicine and towards precision medicinetwo related but different conceptsimpact cancer care within the United States healthcare system? That question was explored in some depth during a presentation entitled, Using Precision Medicine and Personalized Medicine to Build a Patient-Centered Strategy, the first presentation given on June 15, during the Health IT Summit in Boston, held at Bostons Revere Hotel, and sponsored by Healthcare Informatics. The presentation was given by Kristin Darby, CIO at the Boca Raton, Fla.-based Cancer Treatment Centers of America, and John Halamka, M.D., CIO at Beth Israel Deaconess Medical Center in Boston.

After explaining in some detail the broad treatment philosophy and strategy at Cancer Treatment Centers of America, Darby noted that There are a lot of paradigm shifts going on as we start to change our industry, and some of the themes involved in oncology are similar to those emerging across U.S. healthcare as a whole. Among them, she said, are the move from predictive to reactive care, from sick care to wellness, and moving towards care thats specific to a patient. And when you look at precision medicine, there are specifics that can be determined about the classification of disease at the molecular level, rather than organ or body location.

What about the two terms? Personalized medicine and precision medicine are terms that are often used interchangeably, Darby said. But there is a difference, she pointed out. Precision medicine focuses on the specific needs of a patient and their known response to specific biomarkers. Patients typically go through genomic testing, and the results are tested based on known biomarkers, and their treatment is then adjusted. Meanwhile, personalized medicine can include precision medicine as one of its components, but also includes such things as lifestyle, patient preferences, and the patients lifestyle.

Darby went on to say that, As you start to look at the value of precision medicinehistorically, prior to this, the approach has been population-based, with the same approach for everyone, and only a certain percentage of those approaches working. And when it comes to oncology, those approaches kill healthy genes as well as diseased genes. But with personalized medicine, you take into account elements important to the patient. And it also includes looking at lifestyle and other factors that can really help the patient individually. She said that a famous quote from science fiction writer Isaac Asimov applies here: One of the saddest things in life, he said, is that science gains knowledge much faster than society gains wisdom, she said. And you can see that with precision medicine: advances are happening at such a rapid rate that individuals cannot absorb the new knowledge.

Kristin Darby and John Halamka, M.D. on June 15

Darby continued, Thats where technology comes in, to help individual patients. And typically, most healthcare providers are doing partial genome sequencing, which might include a 300-gene panel, followed by targeted therapies for specific abnormalities. What youll see sometime in the near future, she said, is an evolution of maturity where, when the test is done, the goal is to move that to time of diagnosis. And we believe at Cancer Treatment Centers of America that well continue to move closer to diagnosis in order to avert going through failed rounds of care. Often, she said, patients dont pursue genomic testing until after two or three rounds of treatment have already failed; meanwhile, overall health tends to decline with each round of chemotherapy. In contrast, she said, in the future, a personalized approach to treatment will be available. And it will mature from partial genome sequencing to full genome sequencing, which will look at healthy DNA. And instead of just looking at DNA, from a targeted therapy perspective, the abnormality causing the disease may only affect the patient as its expressed. And with proteomics, physicians will be able to offer more specific, targeted treatment.

Darby went on to share with the audience a case study that had been approved for public sharing, by the patient involved. The patient is Christine Bray, who was diagnosed at the age of 30 with metastatic ovarian cancer in 2010, when her youngest daughter was just three months old. Bray was given five months to live. Her goal was to survive at least a few years, so that her youngest daughter would have a memory of her. She went through a horrendous experience, with numerous treatments and surgeries, Darby said of Bray. Then she came to CTCA in Philadelphia, and received advanced genomic testing, which identified a therapy that would target the tumors genetic mutation (everolimus). It was when she got her third diagnosis of recurrence that she came to CTCA. And it was identified that she would benefit from genetic testing, and received targeted therapy. Within three months, she was cancer-free and has lived a normal life for five years now, with no evidence of disease. That shows the promise of precision medicine.

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At the Health IT Summit in Boston, a Fresh Look at the Emergence of Personalized Medicine - Healthcare Informatics

Xconomy Boston

One of the years most closely watched clinical studies could lead to a landmark approval of a gene therapy and throw wide open the debate over how to pay for expensive drugs. The first drips of data have emerged.

Bluebird Bio (NASDAQ: BLUE) says the first three patientsof 15 total expectedhave had good results from a revised version of its LentiGlobin gene therapy to treat certain genetic variants of the rare blood disease beta-thalassemia, which causes severe anemia and requires frequent transfusions.

Bluebird has changed the way it manufactures the product, which requires extracting a patients bone marrow cells, altering their DNA outside the body, then reintroducing the cells to the patient. This study, called NORTHSTAR-2, is the first test of the improved process, which regulators said last year would not require rewinding its clinical program back to the beginninga sigh of relief at the time for the company and its shareholders.

Caveats abound. The results are not only a small sample size, they are also early. Typically data from three patients in a study would not be worth singling out. But Bluebird, of Cambridge, MA, is trying to produce a type of medicine never approved before in the U.S. (Two have been approved in Europe, but one never took hold.)

And the FDA has already shown willingness to consider approval of medicines for rare diseases based on tiny sample sizeswith considerable controversy, in the case of a drug approved last year to treat Duchenne muscular dystrophy.

In one NORTHSTAR-2 patient, the healthy version of the blood protein hemoglobin has reached normal levels six months after a single dose of treatment. The second patients healthy hemoglobin levels are rising but lower than the first patient after three months. The third patient is only two months out from treatment.

For patients with good results, the treatments staying power will be crucial. Bluebird wants it to be a one-time cure, as of course will patients. Insurers will undoubtedly want the samebut what to do if something that costs hundreds of thousands or more than a million dollars, stops working after a few years?

Bluebird officials say they have already begun talking to payers about pay for performance arrangements. Our hope is to tie outcomes of the patient to the value generated, says chief financial and strategic officer Jeff Walsh. It can come in many different forms. (Xconomy reported on several creative drug-pricing ideas in this article.)

Bluebird hopes to make a case for approval for beta-thalassemia before U.S. and European regulators, perhaps in 2019, using data from the NORTHSTAR-2 trial and from previous trials that used the older LentiGlobin version. The main goal of NORTHSTAR-2 is for patients to produce enough of their own healthy hemoglobin to eliminate the need for regular blood transfusions. The first patient has reached that goal, says chief medical officer David Davidson.

The new version of LentiGlobin product, among other things, squeezes more copies of the correct gene into each targeted cellmore shots on goal to change each malfunctioning cell for the better, in other words.

The NORTHSTAR-2 patient with six months of results to report has fared better than similar beta-thalassemia patients six months after they received the previous version of LentiGlobin in a study called HGB-204. The NORTHSTAR-2 patient is producing 13.3 g/DL of hemoglobin, within the normal range for a woman; the median production among 10 HGB-204 patients after six months was 9.7 g/DL.

A doctor working on the study is presenting the data, along with updates from its LentiGlobin treatment for sickle cell disease, at the European Hematology Association meeting this weekend.

Alex Lash is Xconomy's National Biotech Editor. He is based in San Francisco.

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Bluebird Reports Early Results From Upgraded Gene Therapy - Xconomy

THURSDAY, June 22, 2017 (HealthDay News) -- Certain genes linked to heart disease may also improve your chances of having children, a new study suggests.

Australian researchers said the findings seem to offer a potential explanation for why evolution has allowed these genes to persist for centuries.

While lifestyle is clearly important in heart disease risk, scientists have found many genes also influence those odds.

"Genes play a very important role in coronary artery disease risk across an individual's lifetime," said study author Sean Byars, a research fellow at the University of Melbourne. In fact, it's estimated that genes account for about 50 percent of the risk.

The rest, he said, is due to other factors, including habits like smoking and eating a poor diet.

Heart disease is a major killer worldwide, and it has long plagued humanity. Scientists have found evidence of clogged arteries in Egyptian mummies, Byars and his colleagues pointed out.

The researchers said that raises a fundamental question: Why haven't the genes that promote heart disease been weeded out by natural selection?

Natural selection is the process by which organisms -- including humans -- evolve to have better survival odds.

The new study suggests one answer: Byars' team found that a few dozen genes tied to heart disease might also contribute to people's "reproductive success."

Since heart disease usually strikes later in life, after people have had their kids, it would be a reasonable trade-off for better fertility -- at least in terms of survival of the species.

The findings, published online recently in the journal PLOS Genetics, do not have any immediate implications for managing heart disease or fertility, Byars said.

"This study is more about potentially helping to provide a fundamental understanding of why [heart disease] is so prevalent in modern humans," he explained.

Byars did, however, point to a big-picture issue: The findings may sound a cautionary note about "gene-editing" -- a technology scientists are studying with the hope of correcting genetic flaws that cause disease.

"One potential concern a study like this raises," Byars said, "is that in an era of gene-editing, we need to be very careful about unintended consequences of modifying our genomes -- due to shared functions of these genes that are not always obvious."

For the study, the researchers used two large databases with a wealth of genetic information, along with data from a long-running health study of U.S. adults.

The investigators first focused on 76 genes that are linked to heart disease -- the kind caused by clogged arteries. From there, the researchers found that 40 genes were also tied to at least one aspect of reproductive "fitness."

Some were related to the number of children people had, while others were tied to a woman's age at her first and last menstrual period. There were 19 to 29 genes, the researchers said, that were tied to "traits" that can directly sway male or female fertility.

Heart disease is, of course, a complex condition that involves many different factors. Even if Mother Nature insists that humans carry heart-disease genes, there is still plenty that people can do about it, according to Dr. Robert Rosenson.

Rosenson, a cardiologist at Mount Sinai Health System in New York City, pointed to the example of familial hypercholesterolemia (FH).

FH is an inherited disorder caused by a single genetic defect, and it leads to very high "bad" cholesterol levels and a substantial risk of premature heart disease.

But even with those genetic cards stacked against them, Rosenson said, people with FH can prevent or delay heart complications -- by taking cholesterol medication, exercising regularly, not smoking and eating a healthy diet.

"Even if you have a disease-causing genetic trait, lifestyle absolutely makes a difference," Rosenson said.

Most genes tied to heart disease do not have such a dramatic effect -- a large number, he noted, have a "minor" impact on heart disease risk.

But studying the genetics of heart disease will hopefully lead to better treatments, Rosenson said.

Genes, he explained, may help explain why one person responds well to a cholesterol-lowering statin, while someone else "gains weight and develops diabetes," for example.

"Someone might develop a drug side effect simply because they've inherited a trait that interferes with a drug-elimination pathway," Rosenson said.

The hope for the future, he said, is to use genetic information to help predict which treatments will likely benefit an individual patient.

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Heart Disease: A Price Humans Pay for Fertility? - Twin Falls Times-News

This allows us to illuminate dark corners of the genome like never before, Ashley said. Technology is such a powerful force in medicine. Its mind-blowing that we are able to routinely sequence patients genomes when just a few years ago this was unthinkable.

The study was conducted in collaboration with Pacific Biosciences, a biotechnology company in Menlo Park, California, that has pioneered a type of long-read sequencing. Lead authorship of the paper is shared by Jason Merker, MD, PhD, assistant professor of pathology and co-director of the Stanford Clinical Genomics Service, and Aaron Wenger, PhD, of Pacific Biosciences.

The type of long-read sequencing developed by the research teams collaborators at the company can continuously spool long threads of DNA for letter-by-letter analysis, limiting the number of cuts needed.

This is exciting, said Ashley, because instead of having 100-base-pair words, you now have 7,000- to 8,000-letter words.

Thanks to technological advances and increased efficiency, the cost of long-read sequencing has been falling dramatically. Ashley estimated the current cost of the sequencing used for this study at between $5,000 and $6,000 per genome.

Though the cost of short-read sequencing is now below $1,000, according to Ashley, parts of the genome not accessible when cutting DNA into small fragments. Throughout the genome, series of repeated letters, such as GGCGGCGGC, can stretch for hundreds of base pairs. With only 100-letter words, it is impossible to know how long these stretches are, and the length can critically determine someones predisposition to disease.

Additionally, some portions of the human genome are redundant, meaning there are multiple places a 100-base pair segment could potentially fit in, said Ashley. This makes it impossible to know where to place those segments when reassembling the genome. With longer words, that happens much less often.

Given these issues, 5 percent of the genome cannot be uniquely mapped, the researchers wrote. And any deletions or insertions longer than about 50 letters are too long to detect.

For patients with undiagnosed conditions, short-read sequencing can help doctors provide a diagnosis in about one-third of cases, said Ashley. But Ramons case was not one of those.

The technique initially used to analyze Ramons genes failed to identify a mutation in the gene responsible for Carney complex, though Ashley said co-author Tam Sneddon, DPhil, a clinical data scientist at Stanford Health Care who browsed through the database of Ramons sequenced genome by hand, did notice something looked wrong. Ultimately, the long-read sequencing of Ramons genome identified a deletion of about 2,200 base-pairs and confirmed that a diagnosis of Carney complex was indeed correct.

This work is an example of Stanford Medicines focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Carney complex arises from mutations in the PRKAR1A gene, and is characterized by increased risk for several tumor types, particularly in the heart and hormone-producing glands, such as ovaries, testes, adrenal glands, pituitary gland and thyroid. According to the National Institutes of Health, fewer than 750 individuals with this condition have been identified.

The most common symptom is benign heart tumors, or myxomas. Open heart surgery is required to remove cardiac myxomas; by the time Ramon was 18 years old, hed had three such surgeries. He is under consideration for a heart transplant, and having the correct diagnosis for his condition was important for the transplant team. Beyond the typical screening for a transplant, Ashley said the team needed to ensure there werent other health issues that could be exacerbated by immune suppressants, which heart transplant patients must take to avoid rejection of the donated organ.

Though it helps his medical team to have a confirmed diagnosis of Carney complex, Ramon has found it disheartening to face the fact that he cannot escape his condition. I was pretty sad, he said. It took me a while to come to terms with the fact that Ill have this until the day I die.

He tries not to dwell on it, though. Live one day at a time, he said. The bad days are temporary storms, and theyll pass.

His story is quite incredible, said Ashley, who said it was a privilege to be working on Ramons team. To have such a burden on such young shoulders, and to decide whether or not he wants a transplant, requires incredible courage.

Because he couldnt wait any longer for a transplant, Ramon recently underwent his fourth surgery to remove three tumors in his heart. Joseph Woo, MD, professor and chair of cardiothoracic surgery, performed the operation at Stanford Hospital. It is exceedingly rare to have tumors in the heart, said Ashley. It was a particularly heroic operation. Though Ramon is still under consideration for a transplant, the need is less urgent now.

Im in good hands, Ramon said of the Stanford team. Im glad to be here.

Ashley said he and many other doctors believe that long-read technology is part of the future of genomics.

Now we get to see how to do it better, said Ashley. If we can get the cost of long-read sequencing down to where its accessible for everyone, I think it will be very useful.

Other Stanford co-authors of the study are genetic counselor Megan Grove; former graduate student Zach Zappala, PhD; postdoctoral scholar Laure Fresard, PhD; senior research engineer Daryl Waggott, MSc; Sowmi Utiramerur, MS, director of bioinformatics for Stanfords Clinical Genomics Service; research assistant Yanli Hou, PhD; research scientist Kevin Smith, PhD; Stephen Montgomery, PhD, assistant professor of pathology and of genetics; Matthew Wheeler, MD, PhD, clinical assistant professor of cardiovascular medicine; Jillian Buchan, PhD, clinical assistant professor of pathology; and James Ford, MD, professor of medicine and of genetics.

Ashley is a member of Stanford Bio-X, the Stanford Cardiovascular Institute and the Stanford Child Health Research Institute. He is also the founding director of the Stanford Center for Inherited Cardiovascular Disease, the co-director of the Stanford Clinical Genomics Service and the steering committee co-chair for the National Institutes of Health Undiagnosed Diseases Network.

Pacific Biosciences paid for the sequencing.

Stanfords Department of Pathology and the Stanford Cancer Institute also supported the work.

Originally posted here:
Researchers use long-read genome sequencing for first time in a ... - Stanford Medical Center Report

Meeting a young patient with Zellweger syndrome, a rare, life-threatening genetic disease, started a scientific investigation that culminated with an unexpected discovery. The condition, also known as peroxisomal biogenesis disorder, had been linked only to lipid or fat metabolism. Now, as a team of scientists from several institutions, including Baylor College of Medicine, reveals in PLoS Genetics, the condition also affects sugar metabolism. The discovery of this connection in animal models can potentially lead to treatments that might improve the condition.

Meeting this patient at Texas Childrens Hospital inspired me to begin a research investigation to learn more about this disorder, said first and corresponding author Dr. Michael Wangler, assistant professor of molecular and human genetics at Baylor College of Medicine. The family of the patient found out about this research and offered to help. They started Zellfest, a fundraising event in San Antonio, Texas, that has partially supported our investigation. This led us to study this disorder in the fruit fly model in collaboration with the research team led by Dr. Hugo Bellen, professor of molecular and human genetics and investigator at the Howard Hughes Medical Institute at Baylor College of Medicine.

Peroxisomal biogenesis disorder results from defects in the genes that form the peroxisomes, essential micro-machines inside the cell that are involved in breaking down and producing certain lipids. When peroxisomes do not form, people develop a wide range of conditions that may include poor muscle tone, seizures, hearing and vision loss, poor feeding, skeletal abnormalities, as well as life-threatening problems in organs such as the liver, heart and kidney. There is no cure or treatment, other than palliative care.

Its been well established that several lipid pathways are altered in this disease; these are known peroxisomal functions, but there has been very little focus on other parts of metabolism. Everybody was thinking this was mainly a lipid disorder, Wangler said.

The researchers genetically engineered the laboratory fly, Drosophila, to lack two of the genes that are needed to make peroxisomes, PEX2 and PEX16, and then analyzed the flies metabolism.

We began a collaboration with Dr. James McNew, professor in biosciences at Rice University, who had started looking at flies using a metabolomics approach, Wangler said. Metabolomics is like taking a snapshot of all the metabolism of an organism by measuring hundreds of small molecules all at once, rather than focusing on one molecule at a time. We analyzed lipids, small carbohydrates, amino acids, cholesterol and small lipids. This approach gave us a general view of the metabolism of the organism.

The scientists found that the flies lacking the peroxisome genes had many of the problems observed in patients. The scientists learned, for instance, that these flies had short lives and locomotor problems. Their thorough analysis suggests that flies without PEX genes represent an animal model in which to further investigate the human condition.

In addition, we were surprised to discover that these flies were very sensitive to low-sugar diet, Wangler said. They cannot tolerate a low-sugar diet as well as normal flies; without sugar, flies without peroxisomes appear to be starving.

The researchers also applied a metabolomics approach to mice genetically engineered to lack a mouse PEX gene. As they had found in the flies, mice without peroxisomes also had alterations in the metabolism of sugars.

Our understanding is that the enzymes that break down sugars are not directly connected to peroxisomes, Wangler said. We are continuing our investigations and hope they will lead us to better understand how sugar metabolism is linked to peroxisomal biogenesis disorders.

Peroxisomes also play a role in common diseases such as Alzheimers and cancer, Wangler said. Studying this rare disease can help us understand peroxisomes better, and, in turn, that knowledge will help clarify the role of peroxisomes in Alzheimers and other disorders. Rare diseases can help understand issues that also contribute to more common diseases.

Other authors that contributed to this work include Yu-Hsin Chao, Vafa Bayat, Nikolaos Giagtzoglou, Abhijit Babaji Shinde, Nagireddy Putluri, Cristian Coarfa, Taraka Donti, Brett H. Graham, Joseph E. Faust, Ann Moser, Marco Sardiello and Myriam Baes. The authors are affiliated with one of more of the following institutions: Baylor College of Medicine, Texas Childrens Hospital, KU Leuven, Rice University and the Howard Hughes Medical Institute.

This work was supported by the Clayton Murphy Peroxisomal Disorders Research Fund at Baylor College of Medicine, National Institutes of Health K08 (NS076547) award to Michael Wangler, a grant by the Simmons Family Foundation to foster collaborative efforts between Rice University and Texas Childrens Hospital, awarded to Michael Wangler, Hugo Bellen and James McNew, as well as the support of Hugo Bellen, a Howard Hughes Medical Investigator.

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Patient-inspired research uncovers new link to rare disorder - Baylor College of Medicine News (press release)