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Newswise Philadelphia, April 1, 2014 Beverly L. Davidson, Ph.D., a nationally prominent expert in gene therapy, is joining The Childrens Hospital of Philadelphia (CHOP) today.

Dr. Davidson, who investigates gene therapy for neurodegenerative diseases, arrives from the Center for Gene Therapy at the University of Iowa. She served as associate director at that Center, as well as director of the Gene Therapy Vector Core, and held the Roy J. Carver Biomedical Research Chair in Internal Medicine at the University. She also was Vice Chair of the Department of Internal Medicine and was a Professor in Internal Medicine, Neurology, and Physiology & Biophysics.

She has been named to the Arthur V. Meigs Chair in Pediatrics at CHOP and will join the hospitals Department of Pathology and Laboratory Medicine. We heartily welcome Dr. Davidson to our hospital, and are excited that she has chosen to continue her groundbreaking gene therapy research here, said Robert W. Doms, M.D., Ph.D., pathologist-in-chief at The Childrens Hospital of Philadelphia. She will greatly enhance our abilities to translate important biological discoveries into pioneering treatments for deadly diseases.

In addition, Dr. Davidson will serve as the new director of the Center for Cellular and Molecular Therapeutics at CHOP. The mission of the Center is to use pioneering research in cell and gene therapy to develop novel therapeutic approaches for hitherto untreatable illnesses. The inaugural director of the Center, Katherine A. High, M.D., said, I am thrilled that we have been able to recruit one of the premier translational investigators in the U.S. to serve as the next director of the Center. I have led the Center for the last ten years, and I eagerly look forward to the innovations of the next decade, under Dr. Davidsons leadership.

Dr. Davidson has concentrated on inherited genetic diseases that attack the central nervous system, with a particular focus on childhood-onset neurodegenerative diseases such as Batten disease and similar diseases called lysosomal storage disorders. In these disorders, the lack of an enzyme impairs lysosomes, proteins that perform crucial roles in removing unwanted by-products of cellular metabolism. Toxic waste products then accumulate in the brain and cause progressively severe brain damage.

Dr. Davidson has studied the cell biology and biochemistry of these disorders, and has developed novel methods to deliver therapeutic genes to the central nervous system. Her laboratory team has succeeded in reversing neurological deficits in small and large animal models of disease, and is working to advance this approach to treating human diseases.

In addition to lysosomal storage disorders, she has studied other inherited neurological diseases such as Huntingtons disease and spino-cerebellar ataxia. In these studies, she has delivered forms of RNA to the brains of animals to silence the activity of disease-causing genes. She also is collaborating with scientists at Massachusetts General Hospital in animal studies of Alzheimers disease.

Although much of Dr. Davidsons research has centered on delivering beneficial genes to the central nervous system, the viral vectors that she has developed are applicable to other organs and tissuesfor example, in gene therapy directed to the lungs or the liver.

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Gene Therapy Expert to Join The Children's Hospital of Philadelphia

PUBLIC RELEASE DATE:

1-Apr-2014

Contact: Sandy Van sandy@prpacific.com 808-526-1708 Cedars-Sinai Medical Center

LOS ANGELES (April 1, 2014) The Cedars-Sinai Regenerative Medicine Institute has received a $2.5 million grant from the Department of Defense to conduct animal studies that, if successful, could provide the basis for a clinical trial of a gene therapy product for patients with Lou Gehrig's disease, also called amyotrophic lateral sclerosis, or ALS.

The incurable disorder attacks muscle-controlling nerve cells motor neurons in the brain, brainstem and spinal cord. As the neurons die, the ability to initiate and control muscle movement is lost. Patients experience muscle weakness that steadily leads to paralysis; the disease usually is fatal within five years of diagnosis. Several genes have been identified in familial forms of ALS, but most cases are caused by a complex combination of unknown genetic and environmental factors, experts believe.

Because ALS affects a higher-than-expected percentage of military veterans, especially those returning from overseas duties, the Defense Department invests $7.5 million annually to search for causes and treatments. The Cedars-Sinai study, led by Clive Svendsen, PhD, professor and director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center, and Genevive Gowing, PhD, a senior scientist in his laboratory, also will involve a research team at the University of Wisconsin, Madison and a Netherlands-based biotechnology company, uniQure, that has extensive experience in human gene therapy research and development.

The research will be conducted in laboratory rats bred to model a genetic form of ALS. If successful, it could have implications for patients with other types of the disease and could translate into a gene therapy clinical trial for this devastating disease.

It centers on a protein, GDNF, that promotes the survival of neurons. In theory, transporting GDNF into the spinal cord could protect neurons and slow disease progression, but attempts so far have failed, largely because the protein does not readily penetrate into the spinal cord. Regenerative Medicine Institute scientists previously showed that spinal transplantation of stem cells that were engineered to produce GDNF increased motor neuron survival, but this had no functional benefit because it did not prevent nerve cell deterioration at a critical site, the "neuromuscular junction" the point where nerve fibers connect with muscle fibers to stimulate muscle action.

Masatoshi Suzuki, PhD, DVM, assistant professor of comparative biosciences at the University of Wisconsin, Madison, who previously worked in the Svendsen Laboratory and remains a close collaborator, recently found that stem cells derived from human bone marrow and engineered to produce GDNF protected nerve cells, improved motor function and increased lifespan when transplanted into muscle groups of a rat model of ALS.

"It seems clear that GDNF has potent neuroprotective effects on motor neuron function when the protein is delivered at the level of the muscle, regardless of the delivery method. We think GDNF will be able to help maintain these connections in patients and thereby keep the motor neuron network functional," Suzuki said.

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$2.5 million Defense Department grant funds gene therapy study for Lou Gehrig's disease

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Newswise Right now, options are limited for preventing heart attacks. However, the day may come when treatments target the heart attack gene, myeloid related protein-14 (MRP-14, also known as S100A9) and defang its ability to produce heart attack-inducing blood clots, a process referred to as thrombosis.

Scientists at Case Western Reserve School of Medicine and University Hospitals Case Medical Center have reached a groundbreaking milestone toward this goal. They have studied humans and mice and discovered how MRP-14 generates dangerous clots that could trigger heart attack or stroke, and what happens by manipulating MRP-14. This study describes a previously unrecognized platelet-dependent pathway of thrombosis. The results of this research will appear in the April edition of The Journal for Clinical Investigation (JCI).

This is exciting because we have now closed the loop of our original finding that MRP-14 is a heart attack gene, said Daniel I. Simon, MD, the Herman K. Hellerstein Professor of Cardiovascular Research and Medicine at the School of Medicine and director of the University Hospitals Harrington Heart & Vascular Institute. We now describe a whole new pathway that shows clotting platelets have MRP-14 inside them, that platelets secrete MRP-14 and that MRP-14 binds to a platelet receptor called CD36 to activate platelets.

This translational research has moved back and forth from the cardiac catheterization laboratory investigating patients presenting with heart attack to the basic research lab probing mechanisms of disease. The clinical portion of this research yielded a visually stunning elementblood clots extracted from an occluded heart artery loaded with MRP-14 containing platelets.

It is remarkable that this abundant platelet protein promoting thrombosis could have gone undetected until now, Simon said.

In detailed studies using MRP-14-deficient mice, the investigators discovered MRP-14 in action. One key finding is that, while MRP-14 is required for pathologic blood clotting, it does not appear to be involved in the natural, primary hemostasis response to prevent bleeding.

The practical significance of this research is that it may provide a new target to develop more effective and safer anti-thrombotic agents, Simon said. Current anti-clotting drugs are subject to significant bleeding risk, which is associated with increased mortality.

If we could develop an agent that affects pathologic clotting and not hemostasis, that would be a home run, Simon said. You would have a safer medication to treat pathologic clotting in heart attack and stroke.

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Heart Attack Gene, MRP-14, Triggers Blood Clot Formation

For a long time, people thought HIV was incurable. The main reason was that HIV is a retrovirus, meaning that it inserts its own viral DNA into the genome of its host perhaps we could treat the symptoms of HIV, but many doubted it was possible to actually correct the genes themselves.Our techniques for slicing up DNA are very advanced when that DNA sits suspended in a test solution, but nearly useless when we need to accurately edit millions of copies of a gene spread throughout a complex, living animal. Technologies aimed at addressing that problem have been the topic of intense study in recent years, and this week MIT announced that one of the most promising lines of research has achieved its first major goal: researchers have permanently cured a genetic disease in an adult animal.

This is a proof of concept for something medicine has been teasing for decades: useful, whole-body genome editing in fully developed adults. Until recently, most such manipulation was possible only during early development and many genetic diseases dont make themselves known until after birth, or even much later in life. While breakthroughs in whole-genome sequencing are bringing genetic early-warning to awhole new level for parents, there are still plenty of ways to acquire problem DNA later in life most notably, through viruses like HIV. Whether were talking about a hereditary genetic disease like Alzheimers or an acquired one like radiation damage, MITs newest breakthrough has the potential to help.

A simplified schematic of the CRISPR system. RNA guides Cas9 in cutting at the CRISPR sequences.

In this study[doi:10.1038/nbt.2884], researchers attacked a disease called hereditarytyrosinemia, which stops liver cells from being able to process the amino acid tyrosine. It is caused by a mutation in just a single base of a single gene on the mouse (and human) genome, and prior research has confirmed that fixing that mutation cures the disease. The problem is that, until now, such a correction was only possible during early development, or even before fertilization of the egg. An adult body was thought to be simply too complex a target.

The gene editing technology used here is called the CRISPR system, which refers to the Clustered Regularly Interspaced Short Palindromic Repeats that allow its action.As the name suggests, the system inserts short palindromic DNA sequences called CRISPRs that are a defining characteristic of viral DNA. Bacteria have an evolved defense that finds these CRISPRs, treating them (correctly, until now) as evidence of unwanted viral DNA. Scientists insert DNA sequences that code for this bacterial cutting enzyme, along with the healthy version of our gene of interest and some extra RNA for targeting. All scientists need do is design their sequences so CRISPRs are inserted into the genome around the diseased gene, tricking the cell into identifying it as viral from there, the cell handles the excision all on its own, replacing the newly viral gene with the studys healthy version. The whole process plays out using the cells own machinery.

This is how MIT chose to visualize the process.

The experimental material actually enters the body via injection, targeted to a specific cell type.In this study, researchers observed an initial infection rate of roughly 1 in every 250 target cells. Those healthy cells out-competed their unmodified brothers, and within a month the corrected cells made up more than a third of the target cell type. This effectively cured the disease; when the mice were taken off of previously life-saving medication, they survived with little ill effect.

There are other possible solutions to the problem of adult gene editing, but they can be much more difficult to use,less accurate and reliable, and are generally useful in a narrower array of circumstances. CRISPRs offer a very high level of fidelity in targeting, both to specific cells in the body and to very specific genetic loci within each cell.

Tyrosinemia affects only about 1 in every 100,000 people, but the science on display here is very generalizable. While many diseases will require a more nuanced approach than was used here, many will not; wholly replacing genes in adult animals is a powerful tool, capable of curing many, many diseases. Not every cell type will lend itself as well to the CRISPR system, nor every disease; particularly, this study relies on the fact that corrected cells will naturally replace disease cells, improving their initial infection rate. That wont always be possible, unfortunately.

Theres also very little standing between this technique and non-medical applications can you drug test an athlete or academic for the contents of their own genome? These questions and more will become relevant over the next few decades, though their effects should be minuscule when weighed against the positive impacts of the medical applications.

Link:
Gene therapy comes of age: We can now edit entire genomes to cure diseases