Category Archives: Gene Medicine

July 21, 2017 Credit: CC0 Public Domain

A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation in the arid1b gene was created and then used to show that growth hormone treatments reverse some manifestations of the mutation.

The ARID1B gene is one of the most commonly mutated genes in patients with intellectual disability and autism spectrum disorders, but scientists have not yet discerned if and how defects in the ARID1B gene contribute to these clinical manifestations. To understand how reduced levels of the protein product of the gene might cause these disorders, a team of researchers led by Dr. Hao Zhu and including graduate student Cemre Celen genetically modified mice to carry a mutation in one of two copies of the ARID1B gene. This mutation replicates the genetics of Coffin-Siris syndrome, a disorder that some patients with defects in the ARID1B gene have that is characterized by speech and social development problems, intellectual disability, and delayed physical growth.

The hope is that by understanding the molecular basis of Coffin-Siris syndrome, scientists will gain a deeper understanding of more common diseases involving intellectual and social impairment.

Scientists found mice with the mutated ARID1B gene exhibited the same type of physical and social changes seen in children with Coffin-Siris syndrome, such as abnormal brain development, muscle weakness, and increased anxiety and fear. The mice also displayed features consistent with autism spectrum disorder, such as social interaction abnormalities, repetitive behaviors, and abnormal "squeaks" or vocalizations. Further testing found these mice had lower-than-expected growth hormone and insulin-like growth factor (IGF1) levels in the blood, potentially explaining the small stature and delayed development seen in human patients. Treating mutant mice with growth hormones restored body size and muscle function, but did not significantly change the behaviors associated with the syndrome.

"These results suggest that growth hormone treatment could be a useful therapy for ARID1B patients. This is an interesting finding because we know some pediatricians already treat Coffin-Siris patients with growth hormones, although they were unaware that this response might be common to many people with ARID1B mutations," said Dr. Zhu, an Assistant Professor at CRI with joint appointments in Internal Medicine and Pediatrics at UT Southwestern Medical Center and a CPRIT Scholar in Cancer Research.

Dr. Zhu said he believes the study provides the scientific community with an important animal model to further investigate ARID1B's role in human brain disorders and will be a useful tool for therapeutic testing of potential treatments for autism, intellectual disability, and Coffin-Siris syndrome.

Explore further: Mice provide insight into genetics of autism spectrum disorders

More information: Cemre Celen et al. Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment, eLife (2017). DOI: 10.7554/eLife.25730

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Scientists provide insight into genetic basis of neuropsychiatric disorders - Medical Xpress

WILMINGTON, Del.--(BUSINESS WIRE)--Personalized cancer therapies are on the horizon thanks to a new genomic cancer research partnership between the Gene Editing Institute of Christiana Care Health Systems Helen F. Graham Cancer Center & Research Institute and the biotechnology company NovellusDx.

The Gene Editing Institute has licensed its innovative gene editing technology to Jerusalem-based NovellusDx to improve the efficiency and speed of NovellusDxs cancer diagnostic screening tools. With the use of advanced gene editing technology, NovellusDx will be able to identify the genetic mechanism responsible for both the onset and progression of many types of cancer and determine the most effective cancer therapy. NovellusDx will pay royalties to Christiana Care for ten years for the use of its innovative gene editing technology.

This partnership promises to redefine and transform cancer treatment by speeding progress in breakthrough personalized medicine for many forms of cancer, said Nicholas J. Petrelli, M.D., the Bank of America endowed medical director of Christiana Cares Helen F. Graham Cancer Center & Research Institute.

This work has the potential to change the way cancer treatment is carried out, said Haim Gil-Ad, CEO of NovellusDx. Once the genetic makeup of a patient is known, we will be able to immediately test and monitor the effect of a patients mutations in live cells and determine the appropriate treatment for that patient.

Today, genomic sequencing plays an ever-increasing role in cancer treatment, but the functional significance of most mutations found in a patients DNA is unknown and so is the effect drugs have on them. NovellusDx will use the gene editing tools to help determine which drug is best for individual patients by recreating the mutations in a test system and then screening a series of known cancer drugs against those mutations to determine their efficacy.

NovellusDx has established a unique approach to identify unknown driver gene mutations that accelerate and facilitate cancer progression. NovellusDx receives DNA sequence information and synthesizes the individual patients mutated genes and tests them in live cells to define the impact of each mutation on the activity of signaling pathways of the tumor and suggest the most effective therapy to the patients physician.

A $900,000 grant from the U.S.-Israel Binational Industrial Research and Development (BIRD) Foundation in December 2016 facilitated the Gene Editing Institute-NovellusDx partnership. The BIRD Foundation promotes collaboration between U.S. and Israeli companies in a wide range of technological fields for the purpose of joint product development.

About the Gene Editing Institute

The Gene Editing Institute of Christiana Care Health Systems Helen Graham Cancer Center & Research Institute is a worldwide leader in personalized genetic medicine. Founded and led by Eric Kmiec, Ph.D., the Gene Editing Institute is unlocking the genetic mechanisms that drive cancer and that can lead to new therapies and pharmaceuticals to revolutionize cancer treatment, as well as providing instruction in the design and implementation of genetic tools. Gene editing in lung cancer research has already begun so that clinical trials can be initiated. The Gene Editing Institute is integrated into the Molecular Screening Facility at The Wistar Institute in Philadelphia, PA, where its innovative gene-editing technologies are available to research projects at Wistar and to external users. Working with Wistar scientists, the Gene Editing Institute has begun research to conduct a clinical trial in melanoma. With funding from the U.S. National Institutes of Health, the Gene Editing Institute is partnering with Nemours to develop a gene editing strategy for the treatment of sickle cell anemia and leukemia.

About NovellusDx

NovellusDxs mission is to provide functional information about mutations and their responses to drugs so that oncologists can treat patients with precision therapies and bio-pharmaceutical companies can develop drugs more effectively. The NovellusDx approach is to monitor the functional effects of mutations and observe the effects of drugs, drug combinations and drug candidates on the activity level caused by the mutations. NovellusDxs headquarters and research and development operations are based in Jerusalem, Israel.

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New partnership between Christiana Care's Gene Editing Institute and NovellusDx speeds progress toward ... - Business Wire (press release)

Developing a potent therapy for Alzheimers disease will be one of the biggest healthcare challenges over the next few decades.

Multiple pharmaceutical companies have taken a crack at creating a drug for this debilitating condition but a variety of factors revolving around the complexity of the disease and competing theories about how it forms has hindered the clinical development process.

However, a series of a new discoveries focusing on genes and proteins could potentially lay the groundwork for better diagnosis for early warnings signs as well as a new avenue for novel targeted treatments.

New Strategies for Enlisting the Immune System

An international research collaboration discovered three new gene variants that appear to indicate the brains immune cells in the onset of the disorder.=

The scientists found these variants after analyzing the DNA from 85,000 patients who have samples in the International Genomics of Alzheimers Project, according to the announcement from the University of Pennsylvania.

The three rare variants are PLCG2, ABI3, and TREM2. All three of them are protein-coding mutations highly expressed in microglia. The trio is also a part of an immune cell protein network where numerous components contribute to risk of Alzheimers disease.

Its been known for decades that microglia a first-line-of-defense cell we are born with surround amyloid plaque deposits associated with Alzheimers. These multiple gene hits all originating from microglia are the clearest demonstration that these cells are part of Alzheimers pathology and, more importantly, provide clear protein targets where we can start to intervene with drugs, said Gerard D. Schellenberg, Ph.D., a professor of Pathology and Laboratory Medicine, and director of the Alzheimer Disease Genetics Consortium (ADGC) at UPenns School of Medicine.

PLCG2 is an enzyme that is a potential drug target, but more work needs to be done in order to assess the right process for targeting microglia and whether that injury response should be inhibited or activated and at what stage of the disease.

Since prevention is a key goal of therapy, influencing microglial cells before onset of cognitive changes needs to be explored, continued Schellenberg.

Better Risk Assessment

Scientists from Cardiff University uncovered two genes that may play a role in influencing an individuals risk of developing the neurodegenerative disease.

Both of these genes, previously not considered candidates for Alzheimers, were identified during an analysis comparing the DNA of tens of thousands of individuals with Alzheimers against other age-matched people who had no signs of the disease.

"In addition to identifying two genes that affect the risk of developing Alzheimer's disease, our new research reveals a number of other genes and proteins that form a network likely to be important in its development. These particular genes, which suggest that immune cells in the brain play a causal role in the disease, are also very good targets for potential drug treatment," said Dr Rebecca Sims from Cardiff University's School of Medicine, in a statement.

The teams previous research identified 24 susceptibility genes, which could ultimately contribute to a better understanding of the mechanisms underlying the disease.

"The discovery of two new risk genes for Alzheimer's is an exciting advance that could help to deepen our understanding of what happens in the brains of people with the disease. These genes reinforce a critical role for special cells in the brain - called microglia - that are responsible for clearing up debris including damaged cells and proteins, said Dr. Doug Brown, the director of research and development at the Alzheimers Society.Insights like this are vital to help unravel the complexities of Alzheimer's disease and show researchers where to focus their efforts in the search for new, effective treatments.

Protein Capture

A team of scientists from the University of Bradford and University of Dundee implemented a new methodology for ensnaring proteins associated with the onset of neurodegenerative conditions like Alzheimers disease.

The technique traps proteins containing a specific modification that can provide potential markers for certain conditions. These alterations are based on sugar and when attached to a protein affects how it functions.

Essentially, the scientists grow a protein with an engineered tail that specifically grabs sugar-modified proteins. This tail then becomes a handle to pull out all the proteins with this sugar modification and then separates those proteins from their non-modified counterparts.

This methodology represents a major step forward. We are now in a position where we can easily trap the proteins we need to target. If we can do this we can then identify the proteins which we think may be involved in the disease process, said lead researcher Dr. Ritchie Williamson of the University of Bradford, in a statement.We also have the potential to find biomarkers, especially in younger people, and to probe different diseases.

An experiment like this can be easily replicated because it doesnt required highly specialized laboratory equipment and wide-ranging validation of these proteins.

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New Gene Discoveries Could Redefine Alzheimer's Treatment - Drug Discovery & Development

"Because of my family history, I expected to be diagnosed at some point," said the New York-based real estate attorney. She's now 34 and said she's cancer-free.

In 2013, an MRI screening at the Memorial Sloan Kettering Cancer Center in New York revealed signs of cancer in Golkin-Nigliazzo's right breast. She then had a spot mammogram and biopsy performed.

The next day, Golkin-Nigliazzo received a phone call from her doctor.

"She said, 'We found some malignant cells.' That's what she started off with, and everybody knows that's breast cancer," Golkin-Nigliazzo said.

Because of her family history, Golkin-Nigliazzo was tested after her diagnosis for mutations on the BRCA1 and BRCA2 genes, which increase the risk of breast and ovarian cancers in women.

The tests came back negative.

"I was more surprised to hear my genetic results rather than my own diagnosis, because I assumed I inherited some kind of genetic mutation that would make me susceptible to developing breast cancer," Golkin-Nigliazzo said. Additionally, behavioral and environmental risk factors had been determined to be unlikely.

"So right now, I am one big genetic question mark," she said. "We don't know all of the genes that have an effect on cancers, but I know that with the amazing research that is being done by geneticists, when my daughter is old enough to take advantage of genetic testing, there will be more genes to test, and we will be able to learn more about our genetic risk."

Golkin-Nigliazzo, the mother of an 18-month-old daughter, said she has enrolled as a participant in a number of studies at Memorial Sloan Kettering's research lab on unknown genetic mutations that may increase breast cancer risk.

One reason why the new mom has decided to participate in research is because of her daughter, she said.

"When I found out I was having a little girl, I knew I would be passing on my familial risk of breast cancer. Being able to participate in these studies is my own way of helping researchers identify the genes that affect breast cancer risk in many women, including my daughter," Golkin-Nigliazzo said.

"I hope that genetics (research) takes us to the next level so that she knows all of her risks and is able to really conquer cancer head-on if that's something in her future," she said. "There's something in my blood that's genetically predisposing myself and my family to the disease, and one day, I'm hopeful that science will uncover that."

But what's the likelihood of carrying such mutations?

Researchers are getting a step closer to answering that question, especially in Jewish women like Golkin-Nigliazzo.

A new study of 1,007 women of Ashkenazi Jewish ancestry who had been diagnosed with breast cancer found that a whopping 903 had none of the widely known mutations in the BRCA1 or BRCA2 genes.

Rather, among those 903 women, 31, or 3.4%, carried a damaging mutation in lesser-known genes that are related to breast cancer. And seven, or 0.8%, carried a different mutation on BRCA1 or BRCA2 than what's widely known.

"I am an Ashkenazi Jew, and I personally found this article to be particularly fascinating," Golkin-Nigliazzo said.

The DNA samples were sequenced, and the researchers targeted 23 established and candidate breast cancer genes, including BRCA1 and BRCA2.

The researchers found that overall, 142, or 14.1%, of the women carried a germline mutation responsible for their breast cancer, which broke down to 11% in the BRCA1 or BRCA2 genes and 3.1% in CHEK2 or another breast cancer gene.

However, the study had some limitations, including that only those genes known or suspected to harbor breast cancer-related mutations were sequenced and considered for the study.

Also, more research is needed to determine whether or how the findings could be applied to non-Jewish populations.

"This paper is part of an ongoing quest to identify women at high risk for breast cancer," said Dr. Matthew Ellis, professor and director of the Lester and Sue Smith Breast Center at Baylor College of Medicine, who was not involved in the new study.

"We are inexorably moving towards a world where there will be widespread, even universal, genetic screening to risk-stratify patients for early diagnostic techniques, such as mammography and MRI and for surgical intervention," he said. "This paper is a further step in that direction by looking beyond BRCA1 and 2, as there are dozens of other genes that, when abnormal, also increase breast cancer risk."

The researchers wrote in the study that Ashkenazi Jewish patients with breast cancer can benefit from testing for all breast cancer genes.

"Approximately half of the patients with a damaging mutation in any breast cancer gene did not have a family history suggesting inherited predisposition," the authors wrote. "Therefore, to limit genetic testing to patients with a suggestive family history is to miss about 50% of patients with actionable mutations."

"The most recent national screening guidelines recommend genetic testing for all Ashkenazi Jewish patients with breast cancer," the authors wrote. "This recommendation is fine, but testing women only after they develop cancer severely limits the power of precision medicine."

Though more inherited genetic mutations associated with breast cancer have been identified in recent years, the scientific understanding of those mutations and how they impact patients needs to be more fleshed out, Ellis said.

"The biology behind each one of these genes and the epidemiology is becoming increasingly well-understood," he said. "Although for now, I would say we're still struggling with this in clinic."

For instance, when one of the rarer genetic mutation diagnoses is made, there are still many questions about what type of guidance should be provided to a patient, he said.

"Should you take (the hormone-blocking drug) tamoxifen? Should you have your mastectomies? Or should you just have more frequent screening?" Ellis said. "Each one of these gene abnormalities is a separate diagnosis. It's a different gene, a different biology, and it might take a different approach. So there's an awful lot of work ahead of us."

Golkin-Nigliazzo hopes work in the field of breast cancer research might hold clues to the familial breast cancer that she and some of her relatives have been diagnosed with.

For treatment, Golkin-Nigliazzo decided to have a double mastectomy, a procedure in which both of her breasts were removed. Her father, Jeffrey Golkin, and now-husband, David Nigliazzo, stayed by her side during her appointments and surgery.

Since the cancer was detected early, Golkin-Nigliazzo said, "finding the breast cancer at 30 was empowering rather than scary, because I knew that I had done what I needed to do to make my chances of survival as high as possible."

"The fact is, researchers are just scratching the surface and making breakthroughs in genetics every day," Golkin-Nigliazzo said.

"To say that identifying a genetic mutation that increases breast cancer risk is like finding a needle in a haystack is an understatement. The human genome is incredibly complex," she said. "There are no known genetic mutations associated with my genetic background, but that doesn't mean that there aren't any out there."

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Study sheds light on the 'other' breast cancer genes - CNN International

Gene drive technology might limit the ability of Anopheles gambiae mosquito to transmit malaria to humans.

CDC/James Gathany

By Kelly ServickJul. 19, 2017 , 4:00 PM

We dont yet know whether the gene-spreading approach known as gene drive, intended to wipe out invasive pests or reduce the spread of insect-borne disease, will work in the wild. But groups of genetic experts are already talking about how to make it stop working if needed.

And at a symposium today in Washington, D.C., organized by the International Life Sciences Instituteand the National Academies of Sciences, Engineering, and Medicine, researchers and policy experts discussed how to measure and limit a gene drive strategys environmental risks. And the U.S. militarys research arm announced it will fund efforts by several high-profile genetics labs to develop ways to reverse or limit the spread of an introduced gene if it should have unintended consequences on animals or an ecosystem.

Were in the business of preventing technological surprise, but also being prepared for the surprises that come from the use of these technologies, said Renee Wegrzyn, a program manager at the Defense Advanced Research Projects Agency (DARPA) in Arlington, Virginia, which today announced seven research teams that will share a $65 million pot of funding under the agencys Safe Genes program over the next 4 years.

Gene drive works by tinkering with the rules of inheritance, increasing the likelihood a gene will be passed to the next generation. The phenomenon occurs in nature by a variety of mechanisms, but all increase a genes ability to permeate a population quickly and thoroughly, even if it doesnt carry any survival advantage. Inspired by natural gene drives, researchers have spent decades trying to perfect a system that might endow a population of mosquitoes with a malaria resistance gene, for example, or spread a lethal gene that cuts down a local population of invasive insects or rodents.

Progress surged with the discovery of CRISPR/Cas9 gene editing. By inserting the gene for a new trait alongside genes for a DNA-cutting enzyme and an RNA guide, scientists can prompt a cell to slice out copies of the original, wild-type gene from its chromosomes and use the inserted gene as a template for repair. Its sperm and egg cells will thus bear two copies of the new gene, which radically increases the odds that its offspring will inherit it.

But the notion of wiping out an entire species or unleashing a gene that could spread like wildfire through a population has also bred controversy. Evidence that CRISPR gene drives could be extremely efficient in lab-reared insects led prominent researchers to urge caution.

Todays meeting included some practical discussion of how gene drive might be contained. Molecular biologist Bruce Hay of the California Institute of Technology in Pasadena presented his labs research into high-threshold gene drives, designed to spread effectively only if individuals with the new gene make up a large fraction of the total population. Wayward migrants thus wouldnt manage to spread the gene widely outside the intended area. And if an introduced gene had unexpected consequences, researchers might reverse a gene drive by introducing more wild, unmodified individuals to outnumber the new ones. I think we really can do safe, local, and reversible gene drive, Hay told the audience. This is not just a fantasy.

But CRISPR brings a whole new set of unknowns. It might have unpredictable, off-target effects on the genome, and scientists dont know how to shut it down. Among the seven teams selected for the Safe Genes program are some CRISPR pioneers. Harvard University geneticist George Church will lead efforts to develop more precise gene-editing systems that distinguish between similar sequences. Molecular biologist Jennifer Doudna of the University of California (UC), Berkeley, will, according to DARPAs news release, look for anti-CRISPR proteins that could prevent unwanted editing.

Several more projects explicitly focus on gene drive applications: A group at UC Riverside led by molecular biologist Omar Akbari will try to document the genetic diversity of the Aedes aegypti mosquito and test ways to limit or reverse gene drives in contained test environments. Biologist John Godwins team at North Carolina State University in Raleighwill test ways to cut down rodent populations by targeting gene variants present only in invasive communities.

Experts still predict that testing of gene drive in the field is still years away. This is such early days in the field, Wegrzyn told the audience today. Why dont we build those [control] tools in now, rather than trying to retrofit them into these systems?

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How will we keep controversial gene drive technology in check? - Science Magazine

Researchers in the Department of Physiology and Biophysics are studying genetic and epigenetic factors in Alzheimers disease to develop novel ways of restoring function to patients in the later stages of the neurodegenerative disorder.

While most research on Alzheimers has focused on early diagnosis and treatment, the new study is focusing on finding novel ways to restore cognitive function and will utilize studies in mouse models carrying gene mutations for familial Alzheimers (where more than one family member has the disease) and in human stem cell-derived neurons from Alzheimers patients.

The work involving preclinical research to unravel genetic and epigenetic factors that cause Alzheimers is funded by a five-year, $2 million grant from the National Institutes of Healths National Institute on Aging. Zhen Yan, PhD, professor of physiology and biophysics, is principal investigator.

Epigenetic factors can change gene expression without altering the underlying DNA sequence which in turn affects how cells read the genes. Such changes may profoundly impact human health.

We hypothesize that Alzheimers is produced by a combination of genetic risk factors and environmental factors, such as aging, that induce the dysregulation of specific epigenetic processes that lead to impaired cognition, Yan says.

The research will explore how epigenetic changes that accompany Alzheimers disease also might help identify a much sought-after biomarker for the disease, which could allow for novel treatment.

Numerous clinical trials in recent years have focused on reducing amyloid beta plaque in the brain. So far, such efforts havent yet translated into improving cognitive function, Yan says.

Our research, by contrast, will target synaptic function, which is at the root of cognitive function, she explains. Our hypothesis is that this approach will have a more fundamental effect.

Yan and her colleagues will investigate aberrant histone methylation, an epigenetic process that affects the expression of genes encoding key proteins that allow for signals to be transmitted between neurons.

When this process is dysregulated in Alzheimers disease, neuronal signaling doesnt function properly, leading to cognitive impairment.

Even though Alzheimers patients can often easily remember something that happened 20 years ago, the later stages of the disease are characterized by a growing inability to recall recently learned information.

That kind of short-term working memory, Yan explains, is dependent on excitatory transmission in the frontal cortex, mediated by glutamate receptors.

At the later stages of the disease, we know that there is a loss of glutamate receptors that are crucial for learning and memory, she says. When these receptors lose the ability to communicate, there is a loss of cognition.

Our research will try to restore gene expression in these glutamate receptors using epigenetic tools, with the ultimate goal of restoring cognitive function.

Jian Feng, PhD, professor of physiology and biophysics, is a co-investigator on the grant titled A Novel Epigenetic Mechanism for Alzheimers Disease.

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Restoring Cognitive Function for Alzheimer's Disease - UB School of Medicine and Biomedical Sciences News

The discovery that the brain can generate new cells about 700 new neurons each day has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital have developed a novel mouse model that for the first time selectively identifies neural stem cells, the progenitors of new adult brain cells. In these mice, researchers have found a novel mechanism by which descendants of neural stem cells can send feedback signals to alter the division and the fate of the mother cell. These findings appear in eLife.

Our initial goal for this study was to find a gene that is selectively expressed in primary neural stem cells. Based on the information obtained from publicly available expression databases, we started with roughly 750 potential candidate genes. It took an enormous amount of hard work and meticulousness to systematically narrow it down to a single gene it was like looking for a needle in a haystack, said Dr. Mirjana Maleti-Savati, assistant professor of pediatrics and neurology at Baylor and Texas Childrens Hospital, who led this study. After extensive analysis, we were convinced that the gene lunatic fringe, a member of the well-studied Notch signaling pathway, was the selective marker of neural stem cells.

Previous studies in a number of animal models have shown that members of the Notch signaling pathway participate in the regulation of stem cell fate.The finding that lunatic fringe is a selective marker for neural stem cells and a member of the Notch family was a clue of its possible role as regulator of neural stem cell fate. This represented a potentially significant step forward in the field of neurogenesis because the precise mechanism and the fine-tuning of Notch signaling in the hippocampus of the adult brain, where new neurons are born, had remained elusive until now.

Lunatic fringe helps keep the brain renewable

Maleti-Savati and her colleagues show that lunatic fringe mediates a mechanism that helps preserve neural stem cells, so that they can form new neurons throughout life while also ensuring optimal number of neurons.

Interestingly, neural stem cells and their progeny physically cluster closely around one another, which makes it an ideal environment for direct cell-cell communication between neural stem cells and adjacent cells. The scientists found that lunatic fringe allows neural stem cells to distinguish between and respond differently to surrounding cells expressing other markers, namely those expressing the Delta marker and those expressing the Jagged1 marker.

When surrounded by Delta-neurons, most neural stem cells remain in a stand-by mode, protected from random activation and unnecessary division. On the other hand, when neural stem cells interact with Jagged1-neurons, they begin to divide. Combined, these processes allow division of every neural stem cell to be finely regulated to prevent excessive division and premature exhaustion of its potential.

This study and the mouse model we have generated is a huge step forward in the field of neural stem cell biology because now we not only have a benchmark to specifically label primary neural stem cells, but have identified a key quality control step that determines their fate, said Fatih Semerci, postdoctoral student in Maleti-Savati lab and the lead author of this study. Lunatic fringe allows neural stem cells to decide whether to stay dormant or not, and, once they start to divide, whether to continue or to stop.

This study has far-reaching implications on the field of neurogenesis because age-related mental decline and psychiatric disorders such as anxiety and depression have been associated with a reduced ability to generate new neurons in the hippocampus, the center of learning and memory. The formation of new neurons is affected by many factors, both internal and external. For example, physical activity and enriched environment enhance it, while loneliness and depression dampen it. Adult hippocampal neurogenesis has garnered significant interest because targeting it could result in new therapies for many disorders.

Others who contributed to this study include William Tin-Shing Choi, Aleksander Bajic, Aarohi Thakkar, Juan Manuel Encinas, Andrew Groves of Baylor College of Medicine; Frederic Depreux of the Rosalind Franklin University of Medicine and Science in Chicago and Neil Segil of University of Southern California.

Funding for this study comes from the Nancy Chang Award and the CPRIT grant (RP130573CPRIT), and in part by the Microscopy, RNA In Situ Hybridization and Neuropathology Core facility at Baylor College of Medicine, supported by the NIH Shared Instrumentation grant (1S10OD016167) and the NIHIDDRC grant U54HD083092. Further support was provided by the Cytometry and Cell Sorting Core (NCRR grant S10RR024574, NIAID AI036211 and NCI P30CA125123).

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Lunatic Fringe gene plays key role in renewable brain | Baylor ... - Baylor College of Medicine News (press release)

Recent research from Intermountain Healthcare's clinicians shows the successful application of genomic-based approaches to studying individual cancer cases.

Oncologists Lincoln Nadauld, MD, and Derrick Haslem, MD, work at the Southwest Cancer Center in St. George, Utah. In addition to treating patients, they conduct research aimed at improving cancer care and precision medicine.

Their recent research has been published in two national peer-reviewed journals in collaboration with Intermountain Healthcare doctors and researchers from Stanford School of Medicine.

[Also:Precision medicine: Hype today but the promise is even bigger than we think]

One study outlines what the doctors call an "impressive" clinical course and positive outcome of a patient with metastatic colon cancer treated with a precision oncology approach. It was published in the Journal of Clinical Oncology-Precision Oncology, a research publication outlet from the American Society of Clinical Oncologists.

The second publication, co-authored by Nadauld and published in Genome Medicine, shows that linked read sequencing is useful in characterizing oncogenic rearrangements in cancer metastasis.

Both studies were done in collaboration with Hanlee P. Ji, MD, senior associate director of the Stanford Genome Technology Center and Associate Professor at Stanford's School of Medicine.

Linked read sequencing, the researchers note, is a process that allows scientists and doctors to look at the molecular structure of tumor DNA in longer reads of 50,000 base pairs, as opposed to the typical 200-300, and thus "revealing the genomic complexity of patient tumors."

In reference to the Genome Medicine study, Nadauld points out: "In this patient, we were able to identify an amplification of a gene called FGFR2, which is critical because there are drugs that target that mutation.

"This case indicates there are broader applications for linked read technology, including diagnostic purposes and defining additional treatment options for patients along with new genes to target," he added. "With further study, pharmaceutical and biotech technologies can start to develop new drugs that target different molecular phenomena."

Twitter: @Bernie_HITN Email the writer: bernie.monegain@himssmedia.com

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Intermountain, Stanford University see promise for precision medicine in cancer cases - Healthcare IT News

Physicians have practiced precision medicine, defined as the tailoring of medical treatment by taking into account individual differences in peoples genes, environments and lifestyles, for decades. The main difference today is that technological advances have given us greater power to combine comprehensive data collected over time about an individual to help provide appropriate care.

The precision medicine initiative, now known as the All of Us Research Program, launched by the National Institutes of Health, is an ambitious effort to gather data for over a million people living in the U.S. It will likely accelerate precision medicine research with the goal of eventually benefiting everyone by providing information that healthcare providers can use in the clinic. However, there are aspects of precision medicine that have emerged, or are beginning to emerge, in different clinics across the country and are being used to benefit patients today.

Pharmacogenomics (PGx), the study of genetic variations that cause individuals to respond differently to medications, is the most widely used form of precision medicine today. Virtually all of us harbor at least one genetic change that predisposes us to metabolize a common medication differently than the average person. A PGx panel with multiple genes can provide gene-drug guidelines for dozens of medications, including common ones like Warfarin, Clopidogrel or various antidepressants.

In addition to government initiatives, PGx and precision medicine is being fueled by the decreasing cost of genomic testing and growing consumer interest in it. More than 50% of adults are interested in genetic testing, and 6% indicate that they have already undergone it, according to patient surveys[1].

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Where is precision medicine headed? - ModernMedicine

July 18, 2017

Researchers at University of Massachusetts Medical School and Auburn University College of Veterinary Medicine are nearing human clinical trials on a genetic therapy for two rare neurological diseases that are fatal to children.

The scientists are seeking approval from the U.S. Food and Drug Administration (FDA), to test a gene therapy treatment for Tay-Sachs and Sandhoff diseases, genetic disorders in a category known as lysosomal storage diseases.

Tay-Sachs and Sandhoff are inherited neurologic diseases that occur when genetic mutations prevent cells from producing enzymes needed to break down and recycle materials. Without these enzymes, the materials accumulate to toxic levels, slowly destroying the nervous system. The researchers are working on a gene therapy to correct the enzyme deficiency using adeno-associated virus, or AAV, vectors.

The average life expectancy for children with infantile Tay-Sachs or Sandhoff disease is only 3 to 5 years. There is currently no treatment. The gene therapy in development has shown promise in animal models of these diseases by extending lifespans by up to four times those of untreated animals.

"The proof-of-concept studies in affected animals are compelling, and the FDA provided a clear path of remaining experiments needed to seek approval for human clinical trials," said Douglas R. Martin, a professor at Auburn University's College of Veterinary Medicine. "We now need the funding to complete the studies."

The animal phase of toxicity studies necessary to demonstrate the safety of the gene therapy for Tay-Sachs and Sandhoff diseases has been completed with the support of the National Tay-Sachs & Allied Disease Association and the Cure Tay-Sachs Foundation.

"Too many children with Tay-Sachs and Sandhoff have died since we started this project. The time has finally arrived to push back on these diseases," says Miguel Sena-Esteves, PhD, associate professor of neurology at UMass Medical School. "Our single-minded goal is to get a safe and potentially effective therapy to patients and their families as quickly as possible."

"Hopefully, once the news gets out that we are this close to human clinical trials, fundraising efforts will be sufficient so we can complete the IND-enabling studies and proceed to human clinical trials," said veterinarian Heather Gray-Edwards, an assistant professor at Auburn University College of Veterinary Medicine.

Additional funding of $1.2 million is being sought to complete the safety studies, fund the production of clinical grade AAV, and complete regulatory filings.

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Promising therapy for fatal genetic diseases in children nears human trials - Medical Xpress