Monthly Archives: November 2014

PUBLIC RELEASE DATE:

11-Nov-2014

Contact: Scott LaFee slafee@ucsd.edu 619-543-6163 University of California - San Diego @UCSanDiego

With the help of mouse models, induced pluripotent stem cells (iPSCs) and the "tooth fairy," researchers at the University of California, San Diego School of Medicine have implicated a new gene in idiopathic or non-syndromic autism. The gene is associated with Rett syndrome, a syndromic form of autism, suggesting that different types of autism spectrum disorder (ASD) may share similar molecular pathways.

The findings are published in the Nov. 11, 2014 online issue of Molecular Psychiatry.

"I see this research as an example of what can be done for cases of non-syndromic autism, which lack a definitive group of identifying symptoms or characteristics," said principal investigator Alysson Muotri, PhD, associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine. "One can take advantage of genomics to map all mutant genes in the patient and then use their own iPSCs to measure the impact of these mutations in relevant cell types. Moreover, the study of brain cells derived from these iPSCs can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental/neurological disorders."

But to effectively exploit iPSCs as a diagnostic tool, Muotri said researchers "need to compare neurons derived from hundreds or thousands of other autistic individuals." Enter the "Tooth Fairy Project," in which parents are encouraged TO register for a "Fairy Tooth Kit," which involves sending researchers like Muotri a discarded baby tooth from their autistic child. Scientists extract dental pulp cells from the tooth and differentiate them into iPSC-derived neurons for study.

"There is an interesting story behind every single tooth that arrives in the lab," said Muotri.

The latest findings, in fact, are the result of Muotri's first tooth fairy donor. He and colleagues identified a de novo or new disruption in one of the two copies of the TRPC6 gene in iPSC-derived neurons of a non-syndromic autistic child. They confirmed with mouse models that mutations in TRPC6 resulted in altered neuronal development, morphology and function. They also noted that the damaging effects of reduced TRPC6 could be rectified with a treatment of hyperforin, a TRPC6-specific agonist that acts by stimulating the functional TRPC6 in neurons, suggesting a potential drug therapy for some ASD patients.

The researchers also found that MeCP2 levels affect TRPC6 expression. Mutations in the gene MeCP2, which encodes for a protein vital to the normal function of nerve cells, cause Rett syndrome, revealing common pathways among ASD.

Original post:
Multiple models reveal new genetic links in autism

New York, Nov 11 (IANS): Effecting changes to a single gene called FosB could help control both addiction and depression, says a new research.

Researchers have also developed a DNA regulatory technique that modifies the environment around this gene to control gene expression and behavioural consequences.

Using mouse models, the researchers introduced synthetic-transcription factors into a brain region called the nucleus accumbens near the gene FosB.

They found that changes to this single gene brought on by the transcription factors made the study mice more resilient to stress and less likely to become addicted to cocaine.

Transcription factors act by epigenetic mechanisms: chemically modifying either the DNA itself, or the histone proteins packaged around DNA.

"Because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease," said lead researcher Eric Nestler from Icahn School of Medicine at Mount Sinai.

To directly address this issue, the researchers developed an innovative method to control epigenetic regulation of FosB.

Heller introduced synthetic transcription factors called Zinc Finger Proteins (ZFPs), designed to target only a single gene out of 20,000, by incorporating them into a virus and injecting that virus into the reward-related brain region.

Upon binding to that one gene, the FosB-ZFPs modified histones in the vicinity of the FosB gene, in order to either activate (turn on) or repress (turn off) expression.

The study appeared online in the journal Nature Neuroscience.

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Tinkering with a gene could control addiction, depression

PUBLIC RELEASE DATE:

11-Nov-2014

Contact: Kathryn Ryan kryan@liebertpub.com 914-740-2100 Mary Ann Liebert, Inc./Genetic Engineering News @LiebertOnline

New Rochelle, NY, November 11, 2014--Zelig Eshhar, PhD, The Weizmann Institute of Science and Sourasky Medical Center, and Carl H. June, MD, PhD, Perelman School of Medicine, University of Pennsylvania, are co-recipients of the Pioneer Award, recognized for lentiviral gene therapy clinical trials and for their leadership and contributions in engineering T-cells capable of targeting tumors with antibody-like specificity through the development of chimeric antigen receptors (CARs). Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers, is commemorating its 25th anniversary by bestowing this honor on the leading Pioneers in the field of cell and gene therapy selected by a blue ribbon panel* and publishing a Pioneer Perspective by the award recipients. The Perspectives by Dr. Eshhar and Dr. June are available free on the Human Gene Therapy website at http://www.liebertpub.com/hgt until December 11, 2014.

In his Pioneer Perspective entitled "From the Mouse Cage to Human Therapy: A Personal Perspective of the Emergence of T-bodies/Chimeric Antigen Receptor T Cells" Professor Eshhar chronicles his team's groundbreaking contributions to the development of the CAR T-cell immunotherapeutic approach to treating cancer. He describes the method's conceptual development including initial proof-of-concept, and the years of experimentation in mouse models of cancer. They first tested the CAR T-cells on tumors transplanted into mice then progressed to spontaneously developing cancers in immune-competent mice, which Dr. Eshhar describes as "a more suitable model that faithfully mimics cancer patients." He recounts successful antitumor effects in mice with CAR modified T-cells injected directly into tumors, with effects seen at the injection site and at sites of metastasis, and even the potential of the CAR T-cells to prevent tumor development.

Dr. Carl H. June has led one of the clinical groups that has taken the CAR therapeutic strategy from the laboratory to the patients' bedside, pioneering the use of CD19-specific CAR T-cells to treat patients with leukemia. In his Pioneer Perspective, "Toward Synthetic Biology with Engineered T Cells: A Long Journey Just Begun" Dr. June looks back on his long, multi-faceted career and describes how he combined his knowledge and research on immunology, cancer, and HIV to develop successful T-cell based immunotherapies. Among the lessons Dr. June has embraced throughout his career are to follow one's passions. He also says that "accidents can be good: embrace the unexpected results and follow up on these as they are often times more scientifically interesting than predictable responses from less imaginative experiments."

"These two extraordinary scientists made seminal contributions at key steps of the journey from bench to bedside for CAR T-cells," says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

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*The blue ribbon panel of leaders in cell and gene therapy, led by Chair Mary Collins, PhD, MRC Centre for Medical Molecular Virology, University College London selected the Pioneer Award recipients. The Award Selection Committee selected scientists that had devoted much of their careers to cell and gene therapy research and had made a seminal contribution to the field--defined as a basic science or clinical advance that greatly influenced progress in translational research.

About the Journal

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Zelig Eshhar and Carl H. June honored for research on T cell engineering for cancer immunotherapy

Playing a computer game or letting your mind go to its happy place might one day ease a migraine, administer drugs or prevent epileptic seizures, according to Swiss bioengineers who pulled off a strange mind-over-gene trick.

The researchers took advantage of a technique that engineers genes to switch into action in response to light input. But instead of just flipping on a light, they got brain waves to trip the switch.

Neither element by itself is all that novel these days. Synthetic biology and cybernetics have brought us the ability to insert DNA that responds to light into the regulatory programming of a gene. Electroencephalogram (EEG) receivers, which detect voltage changes from brain cells, have been linked to computers to control movement of prosthetic limbs or to play computer games. Hooking that up in tandem was the trick.

A brain is essentially nothing else but electricity the nerve cells firing electricity around as our brain thinks, said bioengineer Martin Fussenegger of the Swiss Federal Institute of Technology, lead investigator of the study published online Tuesday in Nature Communications. So we have electricity, which can then be linked to the light, and the light can then be linked to gene expression. If we daisy-chain these features, it allows us to control transgenes by the power of our thoughts.

The gene they used isnt as important as the concept itself at least not yet. They chose one that triggered production of a protein thats easy to see and measure, to figure out if their synthetic signalingpathway would work. Still, these were human brain waves controlling the inner workings of cells derived from human kidney stem cells -- albeit injected in a mouse.

The human volunteers needed little training beyond learning to play Minecraft, or taking relaxing breaths and thinking pleasant thoughts, Fussenegger said. Once they learned to associate such mental states with the light rigged to the mouse, they readily tinkered with the rodents genetic biochemistry.

Scientists aren't really after this kind of purposeful mind control of genetic activity - after all, it's a lot easier to just push a button to turn on implanted light-sensitive DNA.

What we intend to do is to capture pathological brain wave patterns, Fussenegger said.

That way, Fussenegger said, the brain waves could automatically trigger genes involved in pain mitigation, or perhaps genes engineered to administer medicine for those who are "locked in" by degenerative brain diseases.

A proof of concept is always a crucial step in science, but its also a baby step. Even if this strange bit of sci-fi wi-fi leads in the right direction, there are some foreseeable chasms to bridge en route to a world in which we think our way to health.

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Sci-fi meets wi-fi in a mind over gene experiment