Category Archives: Gene Medicine

Image Caption: This shows regenerated auditory nerves after gene therapy (top) compared with no treatment (below). Credit: UNSW Translational Neuroscience Facility

[ Watch The Video: Bionic Ear Delivers DNA To Regrow Auditory Nerve Cells ]

University of New South Wales

Researchers at UNSW Australia have for the first time used electrical pulses delivered from a cochlear implant to deliver gene therapy, thereby successfully regrowing auditory nerves.

The research also heralds a possible new way of treating a range of neurological disorders, including Parkinsons disease, and psychiatric conditions such as depression through this novel way of delivering gene therapy.

The research is published today (Thursday 24 April) in the prestigious journal Science Translational Medicine.

People with cochlear implants do well with understanding speech, but their perception of pitch can be poor, so they often miss out on the joy of music, says UNSW Professor Gary Housley, who is the senior author of the research paper.

Ultimately, we hope that after further research, people who depend on cochlear implant devices will be able to enjoy a broader dynamic and tonal range of sound, which is particularly important for our sense of the auditory world around us and for music appreciation, says Professor Housley, who is also the Director of the Translational Neuroscience Facility at UNSW Medicine.

The research, which has the support of Cochlear Limited through an Australian Research Council Linkage Project grant, has been five years in development.

[ Watch The Video: Regenerated Auditory Nerves ]

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Existing Cochlear Technology Used To Re-grow Auditory Nerves

Australian researchers are trying a novel way to boost the power of cochlear implants: They used the technology to beam gene therapy into the ears of deaf animals and found the combination improved hearing.

The approach reported Wednesday isn't ready for human testing, but it's part of growing research into ways to let users of cochlear implants experience richer, more normal sound.

Normally, microscopic hair cells in a part of the inner ear called the cochlea detect vibrations and convert them to electrical impulses that the brain recognizes as sound. Hearing loss typically occurs as those hair cells are lost, whether from aging, exposure to loud noises or other factors.

Cochlear implants substitute for the missing hair cells, sending electrical impulses to directly activate auditory nerves in the brain. They've been implanted in more than 300,000 people. While highly successful, they don't restore hearing to normal, missing out on musical tone, for instance.

The idea behind the project: Perhaps a closer connection between the implant and the auditory nerves would improve hearing. Those nerves' bush-like endings can regrow if exposed to nerve-nourishing proteins called neurotrophins. Usually, the hair cells would provide those.

Researchers at Australia's University of New South Wales figured out a new way to deliver one of those growth factors.

They injected a growth factor-producing gene into the ears of deafened guinea pigs, animals commonly used as a model for human hearing. Then they adapted an electrode from a cochlear implant to beam in a few stronger-than-normal electrical pulses.

That made the membranes of nearby cells temporarily permeable, so the gene could slip inside. Those cells began producing the growth factor, which in turn stimulated regrowth of the nerve fibers - closing some of the space between the nerves and the cochlear implant, the team reported in the journal Science Translational Medicine.

The animals still needed a cochlear implant to detect sound - but those given the gene therapy had twice the improvement, they concluded.

Senior author Gary Housley estimated small studies in people could begin in two or three years.

Excerpt from:
Gene therapy may boost power of cochlear implants, study says

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PHILADELPHIA - Over the last few decades researchers have characterized a set of clock genes that drive daily rhythms of physiology and behavior in all types of species, from flies to humans. Over 15 mammalian clock proteins have been identified, but researchers surmise there are more. A team from the Perelman School of Medicine at the University of Pennsylvania wondered if big-data approaches could find them.

To accelerate clock-gene discovery, the investigators, led by John Hogenesch, PhD, professor of Pharmacology and first author Ron Anafi, MD, PhD, an instructor in the department of Medicine, used a computer-assisted approach to identify and rank candidate clock components. This approach found a new core clock gene, which the team named CHRONO. Their findings appear this week in PLOS Biology.

Hogenesch likens their approach to online profiling of movie suggestions for customers: Think of Netflix. Based on your personalized movie profile, it predicts what movies you may want to watch in the future based on what you watched in the past. He thought the team could use this approach to identify new clock genes, given criteria already established from the behavior of known clock genes identified in the past two decades:

Clock genes cause oscillations at the messenger RNA and protein level. Clock proteins physically interact with other clock proteins to form complexes that control daily rhythm inside cells. Disruption of clock genes in cell models cause changes in observable behavioral and metabolic traits on a 24-hour cycle. Clock genes are conserved across 600 million years of evolution from fruitflies to humans.

We used a simple form of machine learning to integrate biologically relevant, genome-scale data and ranked genes based on their similarity to known clock proteins, explains Hogenesch. Using biological big data such as that found in the Circadian Expression Profile Data Base (CircaDB) to search for new clock genes, the Penn team evaluated the features of 20,000 human genes to isolate other genes that have the same clock-gene characteristics. The hypothesis is that other genes that functionally resemble known clock genes are more likely to be clock genes themselves, just like movies that resemble your old favorites are more likely to become new favorites, says Anafi.

They found that several of the genes they identified physically interact with known clock proteins and modulate the daily rhythm of cells. One candidate, dubbed Gene Model 129, interacted with BMAL1, a well-known core clock component, and repressed the key driver of molecular rhythms, the BMAL1/CLOCK protein complex that guides the daily transcription of other proteins in a complicated system of genes that switch on and off over the course of the 24-hour day.

Given these results, the team renamed Gene Model 129, CHRONO, for computationally highlighted repressor of the network oscillator. The litmus test for identifying clock genes, however, is whether they regulate behavior: In mice in which CHRONO had been knocked out, Hogenesch found that the mice had a prolonged circadian period.

A companion study by colleagues at RIKEN in Japan and the University of Michigan, using a genome-wide analysis instead of a machine-learning approach, produced similar findings. Both studies link CHRONO to BMAL1. In the future, Anafi and Hogenesch will be investigating whether CHRONO regulates sleep, as most clock genes influence this behavior.

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Bioinformatics Profiling Identifies a New Mammalian Clock Gene

PHILADELPHIA Over the last few decades researchers have characterized a set of clock genes that drive daily rhythms of physiology and behavior in all types of species, from flies to humans. Over 15 mammalian clock proteins have been identified, but researchers surmise there are more. A team from the Perelman School of Medicine at the University of Pennsylvania wondered if big-data approaches could find them.

To accelerate clock-gene discovery, the investigators, led by John Hogenesch, PhD, professor of Pharmacology and first author Ron Anafi, MD, PhD, an instructor in the department of Medicine, used a computer-assisted approach to identify and rank candidate clock components. This approach found a new core clock gene, which the team named CHRONO. Their findings appear this week in PLOS Biology.

Hogenesch likens their approach to online profiling of movie suggestions for customers: Think of Netflix. Based on your personalized movie profile, it predicts what movies you may want to watch in the future based on what you watched in the past. He thought the team could use this approach to identify new clock genes, given criteria already established from the behavior of known clock genes identified in the past two decades:

We used a simple form of machine learning to integrate biologically relevant, genome-scale data and ranked genes based on their similarity to known clock proteins, explains Hogenesch. Using biological big data such as that found in the Circadian Expression Profile Data Base (CircaDB) to search for new clock genes, the Penn team evaluated the features of 20,000 human genes to isolate other genes that have the same clock-gene characteristics. The hypothesis is that other genes that functionally resemble known clock genes are more likely to be clock genes themselves, just like movies that resemble your old favorites are more likely to become new favorites, says Anafi.

They found that several of the genes they identified physically interact with known clock proteins and modulate the daily rhythm of cells. One candidate, dubbed Gene Model 129, interacted with BMAL1, a well-known core clock component, and repressed the key driver of molecular rhythms, the BMAL1/CLOCK protein complex that guides the daily transcription of other proteins in a complicated system of genes that switch on and off over the course of the 24-hour day.

Given these results, the team renamed Gene Model 129, CHRONO, for computationally highlighted repressor of the network oscillator. The litmus test for identifying clock genes, however, is whether they regulate behavior: In mice in which CHRONO had been knocked out, Hogenesch found that the mice had a prolonged circadian period.

A companion study by colleagues at RIKEN in Japan and the University of Michigan, using a genome-wide analysis instead of a machine-learning approach, produced similar findings. Both studies link CHRONO to BMAL1. In the future, Anafi and Hogenesch will be investigating whether CHRONO regulates sleep, as most clock genes influence this behavior.

This work is supported by the National Institute of Neurological Disorders and Stroke (1R01NS054794-06), the Defense Advanced Research Projects Agency (DARPA-D12AP00025), the American Sleep Medicine Foundation Grant to RCA, the National Institute on Aging (2P01AG017628-11), and the National Heart, Lung, and Blood Institute (5K12HL090021-05). This project is also funded, in part, by the Penn Genome Frontiers Institute under a HRFF grant with the Pennsylvania Department of Health, which disclaims responsibility for any analyses, interpretations or conclusions.

Co-authors are Yool Lee, Trey K. Sato, Anand Venkataraman, Jacqueline P. Growe, Andrew C. Liu, and Junhyong Kim, all from Penn, as well as Chidambaram Ramanathan, University of Memphis; Ibrahim H. Kavakli, Koc University, Istanbul, Turkey; Michael E. Hughes, University of Missouri-St. Louis, and Julie E. Baggs, Morehouse School of Medicine, Atlanta, GA

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Penn Bioinformatics Profiling Identifies a New Mammalian Clock Gene

Love your regular ham sandwich or grilled sausages? Experts say those who consume too much processed meat risk a higher chance of colorectal cancer if they possess a common gene variant identified as GATA3.

According to Dr. Jane Figueiredo, of the Keck School of Medicine at the University of Southern California, the new study published in PLOS Genetics is the first to understand whether some individuals are at higher or lower risk based on their genomic profile.

"This information can help us better understand the biology and maybe in the future lead to targeted prevention strategies" said Dr Figueiredo.

Pointing out that"diet is a modifiable risk factor for colorectal cancer",Dr Figueiredo andthe research team expanded on earlier studies ondiet, especially one that's high in red or processed meat and colorectal cancer risk.

The team looked at more than 9,000 colorectal cancer cases and a similar number of controls and the interaction between red meat, processed meat, fiber, fruit and vegetables, and colorectal cancer risk.

They founda significant interaction between the genetic variant "rs4143094"linked to a gene called GATA3and processed meat.

"The possibility that genetic variants may modify an individual's risk for disease based on diet has not been thoroughly investigated but represents an important new insight into disease development," concludes Dr. Li Hsu, the lead statistician on the study.

Continued here:
Gene link found in colorectal cancer risk from processed meats

PUBLIC RELEASE DATE:

21-Apr-2014

Contact: Darrell E. Ward Darrell.Ward@osumc.edu 614-293-3737 Ohio State University Wexner Medical Center

COLUMBUS, Ohio A small gene that is embedded in a larger, well-known gene is the true leukemia-promoting force usually attributed to the larger gene, according to a new study by researchers at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC James).

The findings are published in the journal Science Signaling.

The larger host gene is called BAALC (pronounced "Ball C"). The smaller embedded gene is called microRNA-3151 (miR-3151). The study investigated the degree to which each of the genes contributes to the development of acute myeloid leukemia (AML).

"We discovered that the smaller microRNA gene, and not the larger host gene, is the major oncogenic driver of the two molecules in AML," says principal investigator Albert de la Chapelle, MD, PhD, professor of Medicine and the Leonard J. Immke Jr. and Charlotte L. Immke Chair in Cancer Research.

"When both genes are highly expressed, it means a bad prognosis for patients, but our experiments indicate that it is high expression of miR-3151 that really matters. Overexpression of BAALC alone had only limited cancer-causing activity," he says.

The researchers discovered that miR-3151 promotes the development of leukemia by blocking a gene called TP53. Normally, TP53 is a central "tumor-suppressor" gene that protects against cancer by causing a cell with serious gene damage to self-destruct. "When miR-3151 blocks TP53 in the tumor cells, it enables the cells to survive, divide and grow faster," says co-senior author Clara D. Bloomfield, MD, Distinguished University Professor and Ohio State University Cancer Scholar.

"We also show that miR-3151 promotes growth in malignant melanoma cells in the same way, suggesting that the molecule might play a role in solid-tumor development," says Bloomfield, who is also senior adviser to the OSUCCC James and holds the William Greenville Pace III Endowed Chair in Cancer Research.

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A gene within a gene contributes to the aggressiveness of acute myeloid leukemia

PUBLIC RELEASE DATE:

20-Apr-2014

Contact: Byron Spice bspice@cs.cmu.edu 412-268-9068 Carnegie Mellon University

PITTSBURGHWith gene expression analysis growing in importance for both basic researchers and medical practitioners, researchers at Carnegie Mellon University and the University of Maryland have developed a new computational method that dramatically speeds up estimates of gene activity from RNA sequencing (RNA-seq) data.

With the new method, dubbed Sailfish after the famously speedy fish, estimates of gene expression that previously took many hours can be completed in a few minutes, with accuracy that equals or exceeds previous methods. The researchers' report on their new method is being published online April 20 by the journal Nature Biotechnology.

Gigantic repositories of RNA-seq data now exist, making it possible to re-analyze experiments in light of new discoveries. "But 15 hours a pop really starts to add up, particularly if you want to look at 100 experiments," said Carl Kingsford, an associate professor in CMU's Lane Center for Computational Biology. "With Sailfish, we can give researchers everything they got from previous methods, but faster."

Though an organism's genetic makeup is static, the activity of individual genes varies greatly over time, making gene expression an important factor in understanding how organisms work and what occurs during disease processes. Gene activity can't be measured directly, but can be inferred by monitoring RNA, the molecules that carry information from the genes for producing proteins and other cellular activities. RNA-seq is a leading method for producing these snapshots of gene expression; in genomic medicine, it has proven particularly useful in analyzing certain cancers.

The RNA-seq process results in short sequences of RNA, called "reads." In previous methods, the RNA molecules from which they originated could be identified and measured only by painstakingly mapping these reads to their original positions in the larger molecules.

But Kingsford, working with Rob Patro, a post-doctoral researcher in the Lane Center, and Stephen M. Mount, an associate professor in Maryland's Department of Cell Biology and Molecular Genetics and its Center for Bioinformatics and Computational Biology, found that the time-consuming mapping step could be eliminated. Instead, they found they could allocate parts of the reads to different types of RNA molecules, much as if each read acted as several votes for one molecule or another.

Without the mapping step, Sailfish can complete its RNA analysis 20-30 times faster than previous methods.

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Computational method dramatically speeds up estimates of gene expression

PUBLIC RELEASE DATE:

17-Apr-2014

Contact: Helen Dodson helen.dodson@yale.edu 203-436-3984 Yale University

New Haven, Conn. Researchers from Yale School of Medicine and Celera Diagnostics have confirmed the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture. The study appears online in PLOS ONE.

Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear dissection or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.

The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture.

"Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases," said senior author John Elefteriades, M.D., the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. "Such studies represent important steps along that path."

The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. "Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur," Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease.

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The Yale-New Haven Hospital Aortic Institute opens April 22. It will specialize in clinical care, basic science, and clinical research in aortic disease.

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Gene variant raises risk for aortic tear and rupture

The Harvard-MIT genomic science institute stays mute on how it will assert control over the tools expected to speed cures and change gene therapy.

One of the most important genetic technologies developed in recent years is now patented, and researchers are wondering what they will and wont be allowed to do with the powerful method for editing the genome.

On Tuesday, the Broad Institute of MIT and Harvard announced that it had been granted a patent covering the components and methodology for CRISPRa new way of making precise, targeted changes to the genome of a cell or an organism. CRISPR could revolutionize biomedical research by giving scientists a more efficient way of re-creating disease-related mutations in lab animals and cultured cells; it may also yield an unprecedented way of treating disease (see Genome Surgery).

The patent, issued just six months after its application was filed, covers a modified version of the CRISPR-Cas9 system found naturally in bacteria, which microbes use to defend themselves against viruses. The patent also covers methods for designing and using CRISPRs molecular components.

The inventor listed on the patent is Feng Zhang, an MIT researcher and core faculty member of the Broad. Zhang was an MIT Technology Review Innovator Under 35 in 2013.

The patent describes how the tools could be used to treat diseases, and lists many specific conditions from epilepsy, to Huntingtons, to autism, and macular degeneration. One of the most exciting possibilities for CRISPR is its potential to treat genetic disorders by directly correcting mutations on a patients chromosomes. That would enable doctors to treat diseases that cannot be addressed by more traditional methods, a goal already set by a startup cofounded by Zhang called Editas Medicine (see New Genome-Editing Method Could Make Gene Therapy More Precise and Effective).

Another founder of Editas, Jennifer Doudna, and her institute, the University of California, have a pending patent application for CRISPR technology. How that west coast application will be affected is not yet clear. Its also unclear what impact the Broads claims on the technology will have on its commercial use and on basic research.

Chelsea Loughran, an intellectual property litigation lawyer who has been following CRISPR over the last year, says that lots of people are already using CRISPR and its not clear if it will now become harder for them to do that. All of that is in the hands of MIT and the Broad, she says.

While MIT, Harvard, and the Broad all jointly own the CRISPR patents announced yesterday, the Broads technology licensing office is managing decisions about who will get licenses to use the technology, says Lita Nelsen, director of the MIT Technology Licensing Office. (Licenses areformal permissions to use a patented technology, often in exchange for money.)

A spokesperson for the Broad says that specific details around licensing arent available at this time, but the Broad does intend to make this technology broadly available to scientists.

The rest is here:
Broad Institute Gets Patent on Revolutionary Gene-Editing Method

MONDAY, April 14, 2014 (HealthDay News) -- A new study found that 10 percent of women with a personal or family history of breast or other cancers had at least one gene mutation that would lead their doctors to recommend changes in their routine care, including increased cancer screening.

These women did not have BRCA1 or BRCA2 mutations that are strongly associated with hereditary breast and ovarian cancer. However, they had mutations in other genes known to be linked with cancer, the Stanford University School of Medicine team said.

For the study, the researchers used what is called a multiple-gene panel -- rather than whole genome sequencing -- to sequence specific genes more quickly and cheaply. Whole genome sequencing is a laboratory process that involves "reading" all the characteristics of your DNA.

"Although whole-genome sequencing can clearly be useful under the right conditions, it may be premature to consider doing on everyone," study senior author Dr. James Ford, director of Stanford's clinical cancer genetics program, said in a university news release.

The researchers analyzed blood samples collected from 198 women who were part of the clinical cancer genetics program between 2002 and 2012. Of those women, 57 had BRCA1/BRCA2 mutations and 14 had mutations in 42 other genes associated with cancer.

Of those 14 women, 11 could be reached by telephone and 10 of them agreed to a follow-up appointment with a genetic counselor and a cancer specialist to discuss their test results. One woman had died since giving her blood sample, but her family members also accepted counseling.

Six of the women were advised to have annual breast MRIs and six were told to have regular screenings for gastrointestinal cancers. Some of the women were given more than one recommendation, according to the study published April 14 in the Journal of Clinical Oncology.

"Gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome," said Ford, an associate professor of medicine and of genetics. "It's a focused approach that should allow us to capture the most relevant information."

However, more research is needed before gene-panel screenings could become routine, the researchers said.

-- Robert Preidt

Link:
Cheaper 'Gene Panel' Screening May Reveal Cancer Risks