Category Archives: Gene Medicine

Contact Information

Available for logged-in reporters only

Newswise NEW YORK (January 30, 2014) Steven Libutti, M.D., F.A.C.S., professor and vice chairman in the Department of Surgery at Montefiore Medical Center and Albert Einstein College of Medicine at Yeshiva University, director at the Montefiore Einstein Center for Cancer Care and professor in the Department of Genetics and associate director of clinical services at Albert Einstein College of Medicine has been named Editor-in-Chief of Cancer Gene Therapy, a journal for cancer researchers and clinicians.

Cancer Gene Therapy serves as a respected resource for scientists and clinicians on the latest gene and cellular therapies for cancer. Topics will range from DNA synthesis and repair to the latest original laboratory research and case reports on translational research and tumor immunotherapies.

The progression of personalized cancer treatments and evolution of new technologies for monitoring genetic changes holds new promise for those impacted by cancer, said Dr. Libutti. Cancer Gene Therapy will cover innovative scientific developments and prompt clinical questions that I hope spark new perspectives and industry dialogue about whats next.

As a pioneer in tumor-targeted gene therapy, Dr. Libutti is developing novel cancer therapies through his study of the complex interactions that occur within a tumors microenvironment. Since 2009, he has spearheaded multidisciplinary efforts in research and treatment of cancer at the Montefiore Einstein Center for Cancer Care.

We feel honored to be working in conjunction with an expert of Dr. Libuttis caliber, said Andrea Macaluso, publishing manager, Nature Publishing Group. His vast experience discovering new and effective ways to treat cancer combined with his record of excellent basic research and clinical care made him a natural choice to lead our journal and further strengthen Nature Publishing Groups library of scientific and medical publications.

Dr. Libutti is an internationally recognized expert in surgical oncology and endocrine surgery and has published more than 250 peer-reviewed journal articles and 16 oncology book chapters. He has received the NIH Directors Award and the National Cancer Institutes Directors Gold Star and Intramural Innovation Awards. Dr. Libutti also has appeared on Castle Connollys list of Top Doctors in America and on New York Magazines list of Top Doctors in New York. In 2009, he was named the Marvin L. Gliedman, M.D., Distinguished Surgeon at Montefiore Medical Center. Prior to being appointed director of the Montefiore Einstein Center for Cancer Care, Dr. Libutti was a researcher, surgeon and Section Head at the National Cancer Institute.

About Montefiore Medical Center As the University Hospital for Albert Einstein College of Medicine, Montefiore is a premier academic medical center nationally renowned for its clinical excellence, scientific discovery and commitment to its community. Recognized among the top hospitals nationally and regionally by U.S. News & World Report, Montefiore provides compassionate, patient- and family-centered care and educates the healthcare professionals of tomorrow. The Children's Hospital at Montefiore is consistently named in U.S. News' "America's Best Children's Hospitals." With four hospitals, 1,491 beds and 90,000 annual admissions, Montefiore is an integrated health system seamlessly linked by advanced technology. State-of-the-art primary and specialty care is provided through a network of more than 130 locations across the region, including the largest school health program in the nation and a home health program. Montefiore's partnership with Einstein advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. The medical center derives its inspiration for excellence from its patients and community, and continues to be on the frontlines of developing innovative approaches to care. For more information please visit http://www.montefiore.org and http://www.montekids.org. Follow us on Twitter; like us on Facebook; view us on YouTube.

About Albert Einstein College of Medicine of Yeshiva University Albert Einstein College of Medicine of Yeshiva University is one of the nations premier centers for research, medical education and clinical investigation. During the 2013-2014 academic year, Einstein is home to 734 M.D. students, 236 Ph.D. students, 106 students in the combined M.D./Ph.D. program, and 353 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2013, Einstein received more than $155 million in awards from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center Einsteins founding hospital, and five other hospital systems in the Bronx, Manhattan, Long Island and Brooklyn, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit http://www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.

Original post:
Montefiore Einstein Center for Cancer Care Director Named Editor-in-Chief of Cancer Gene Therapy

A group of researchers from Mexico's General Hospital, Health Secretariat, Medicine Faculty and the Institute of Cellular Physiology of the National Autonomous University of Mexico (UNAM) identified a therapeutic target for cervix cancer: gene CDKN3.

The researched performed at the lab indicates that when this gene is blocked in culture cancerous cells, the neoplastic proliferation greatly diminishes.

Jaime Berumen Campos, who coordinates the research said that this gene is blocked by a "siRNA" (small interference RNA), molecular technique applied to several strands of cervix cancer cells making them incapable of proliferating, and confirmed that tumors in mice stopped growing.

To achieve this, researchers first analyzed eight thousand and 638 genes in 43 samples of cervix cancer cells, identifies six suspect of making cervical cancer grow.

One of these genes is CDKN3, which apparently is the most important, given that its activity was highly elevated in most of explored cancers.

Later, clinical evolution of 42 patients was studied during five years, and was found that when CDKN3 is very active, patients have little survival, Berumen Campos explained, who because of this research won the Award of Medical Research "Dr. Jorge Rosenkranz" 2013, in the clinical area.

"70 per cent of the patients with a high activity of this gene, died less than two years of developing the illness, meanwhile only 15 per cent of patients with a low activity of this indicator died while the study was being performed."

Experimentation in culture cells and observation in women with cancer, indicate that this gene is linked to the aggressiveness and malignant growth of the tumor. Besides, the findings indicate that this gene could be a good therapeutic target, meaning, that overriding its primary function (promoting cellular growth), it would be possible to diminish the proliferation of tumors in women.

Cervical cancer is treated by surgery, chemo and radiotherapy or a combination of all the above, according to the clinical stage. The success and survival diminish as the disease advances.

The percentage of women who survive five years is reduced by 93 percent in the first stage, and to 15 percent in the fourth stage. Contrary to other types of cancer, for which drugs against specific molecular targets exist, this have not been developed for cervical cancer.

The rest is here:
New technique developed to control cervical cancer

Contact Information

Available for logged-in reporters only

Rutgers Cancer Institute of New Jersey Researchers Awarded $240K to Explore Breast Cancer Treatment Implications in Gene Fusion Study

Newswise New Brunswick, N.J., January 28, 2014 The Breast Cancer Research Foundation has awarded a pair of investigators at Rutgers Cancer Institute of New Jersey a one-year, $240,000 grant to examine treatment implications for a genetic variation found in a quarter of Caucasians and in a small percentage of Caucasian breast cancer patients.

Arnold J. Levine, PhD, a resident member at the Cancer Institute of New Jersey and professor of pediatrics and biochemistry at Rutgers Robert Wood Johnson Medical School; and Kim M. Hirshfield, MD, PhD, a medical oncologist at the Cancer Institute and assistant professor of medicine at Robert Wood Johnson Medical School, are building on previous research that led to the identification of a new gene product as a result of two cancer-causing genes being fused together.

Drs. Levine and Hirshfield are examining the pairing of the KANSL1 and ARL17A genes. KANSL1 is part of a protein complex that regulates tumor suppression function and DNA repair proteins involved in cancer formation and cancer cell behavior. ARL17A is involved in movement of proteins within a cell and in turn, affects cell function.

When the two genes are combined, the resulting fusion gene presents itself as a genetic variation in the human genome in one quarter of Caucasian populations. In particular, the gene product was detected in 12 percent of breast cancers in this group. The new fusion genes impact on protein activity further sheds light on why some cancers including breast have difficulty maintaining the integrity of their DNA. As a result, two sets of drugs were identified that could be useful in the treatment of cancers with the fusion variation. The grant will support laboratory study of these agents and their impact on targeted therapy.

The award period runs through October 1.

About Rutgers Cancer Institute of New Jersey Rutgers Cancer Institute of New Jersey (www.cinj.org) is the states first and only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, the Cancer Institute of New Jersey is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention. Physician-scientists at the Cancer Institute engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support the Cancer Institute of New Jersey, call 732-235-8614 or visit http://www.cinj.org/giving. Follow us on Facebook at http://www.facebook.com/TheCINJ.

The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research

See the original post here:
Rutgers Cancer Researchers Examine Gene Fusion and Treatment Implications for Breast Cancer

Anne Roberts of Moorhead

Anne Roberts of Moorhead talks about her decision to have her breasts removed after being diagnosed with the gene that made her a high risk for developing breast cancer. David Samson / The Forum

Sanford medical lab scientist Tylise Graff looks at tumor tissue from a breast cancer sample which helps determine the course of treatment. David Samson / The Forum

Would you consider genetic testing?

FARGO Anne Roberts considers herself a breast cancer previvor.

After learning that she inherited a gene that placed her at very high risk and knowing her family history was riddled with cancer she opted for preventive surgery, a double mastectomy.

My surgeon explained to me it wasnt a matter of if, she said. I was going to get cancer. It was a question of when.

Roberts was 55 when she had the surgery four years ago the same age her older sister first developed breast cancer, and the age of her paternal grandmother when she died of cancer.

Genetic testing revealed the Moorhead woman had an 87 percent chance of developing breast cancer. Preemptive surgery reduced her risk by 90 percent.

Now, the kind of genetic screening and counseling that has long been common in treating cancer and assessing prenatal or childhood risk of inheriting disease is spreading to primary care at Sanford Health clinics under a new $125 million initiative in genetic medicine.

View post:
Genetic screening spreads to primary care at Sanford clinics

Contact Information

Available for logged-in reporters only

Newswise NEW YORK, NY (January 22, 2014) Columbia University Medical Center (CUMC) researchers have identified a gene, called matrix metalloproteinase-9 (MMP-9), that appears to play a major role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease. The findings, made in mice, explain why most but not all motor neurons are affected by the disease and identify a potential therapeutic target for this still-incurable neurodegenerative disease. The study was published today in the online edition of the journal Neuron.

One of the most striking aspects of ALS is that some motor neuronsspecifically, those that control eye movement and eliminative and sexual functionsremain relatively unimpaired in the disease, said study leader Christopher E. Henderson, PhD, the Gurewitsch and Vidda Foundation Professor of Rehabilitation and Regenerative Medicine, professor of pathology & cell biology and neuroscience (in neurology), and co-director of Columbias Motor Neuron Center. We thought that if we could find out why these neurons have a natural resistance to ALS, we might be able to exploit this property and develop new therapeutic options.

To understand why only some motor neurons are vulnerable to ALS, the researchers used DNA microarray profiling to compare the activity of tens of thousands of genes in neurons that resist ALS (oculomotor neurons/eye movement and Onufs nuclei/continence) with neurons affected by ALS (lumbar 5 spinal neurons/leg movement). The neurons were taken from normal mice.

We found a number of candidate susceptibility genesgenes that were expressed only in vulnerable motor neurons. One of those genes, MMP-9, was strongly expressed into adulthood. That was significant, as ALS is an adult-onset disease, said co-lead author Krista J. Spiller, a former graduate student in Dr. Hendersons laboratory who is now a postdoctoral fellow at the University of Pennsylvania. The other co-lead author is Artem Kaplan, a former MD-PhD student in the lab who is now a neurology resident at NewYork-Presbyterian Hospital/Columbia University Medical Center.

In a follow-up experiment, the researchers confirmed that the product of MMP-9, MMP-9 protein, is present in ALS-vulnerable motor neurons, but not in ALS-resistant ones. Further, the researchers found that MMP-9 can be detected not just in lumbar 5 neurons, but also in other types of motor neurons affected by ALS. It was a perfect correlation. said Dr. Henderson. In other words, having MMP-9 is an absolute predictor that a motor neuron will die if the disease strikes, at least in mice.

Taking a closer look at the groups of vulnerable motor neurons, the researchers found differences in MMP-9 expression at the single-cell level. Fast-fatigable neurons (which are involved in movements like jumping and sprinting and are the first to die in ALS) were found to have the most MMP-9 protein, whereas slow neurons (which control posture and are only partially affected in ALS) had none. So, MMP-9 is not only labeling the most vulnerable groups of motor neurons, it is labeling the most vulnerable subtypes within those groups, as well, said Dr. Spiller.

In another experiment, the researchers tested whether MMP-9 has a functional role in ALS by crossing MMP-9 knockout mice with SOD1 mutant mice (a standard mouse model of ALS). Progeny from this cross with no MMP-9 exhibited an 80-day delay in loss of fast-fatigable motor neuron function and a 25 percent longer lifespan, compared with littermates with two copies of the MMP-9 gene. This effect on nerve-muscle synapses is the largest ever seen in a mouse model of ALS, said Dr. Spiller.

The same effect on motor neuron function was seen when MMP-9 was inactivated in SOD1 mutant mice using chemical injections or virally mediated gene therapy.

Read more from the original source:
Study Identifies Gene Tied to Motor Neuron Loss in ALS

PUBLIC RELEASE DATE:

21-Jan-2014

Contact: Garth Sundem garth.sundem@ucdenver.edu University of Colorado Denver

Ewing's Sarcoma is an aggressive pediatric cancer, most commonly caused by the improper fusion of the gene EWS with the gene FLI1. Though the cause has long been known, therapeutic targeting of this fusion has to date proven very difficult. A University of Colorado Cancer Center study, recently published in the journal Oncogene, looked downstream from this fusion to discover other links in the chain of events that leads to cancer this fusion puts in motion microRNA-22, which regulates another gene, KDM3A, and this signaling chain helps ensure that the outcome of the EWS/FLI1 fusion is cancer. Researchers suggest that these new targets may provide more easily druggable alternatives to the EWS/FLI1 fusion itself.

"We started with all the microRNAs downstream from the EWS/FLI1 fusion and narrowed in on microRNA-22. But then we looked even further downstream from there and found that microRNA-22 works through another gene, KDM3A, to cause this cancer. When we turned down this gene (KDM3A) in lab studies, we observed a profound inhibition of the tumorigenic properties of Ewing Sarcoma cells," says Paul Jedlicka, MD, PhD, CU Cancer Center investigator and assistant professor of pathology at the University of Colorado School of Medicine.

This study highlights the complex cascade of events that cause cancer. Even in seemingly "simple" cancers like Ewing Sarcoma with known oncogenic drivers, cancer-causing action tends to depend on a cascade of events the oncogenes initiate. In other words, oncogenes may sit at the head of long, complex strings of cellular events, all of which are needed to cause cancer.

Likewise, genes aren't the only level at which this string of events can be interrupted between a gene and its expression as a (potentially dangerous) protein lies all the mechanics of transcription, including the involvement of chemicals that transport a gene's information to the machinery that makes proteins (RNA), and chemicals that decide how often a gene should be manufactured into a protein (e.g. microRNA). Understanding of the mechanics of this complex cascade, in turn, can yield new therapeutic targets.

In this study, Jedlicka and colleagues used another form of RNA called shRNA to mute the expression of the tumor-promoting gene KDM3A. But Jedlicka points out that, in general, while shRNA is an extremely useful tool in the laboratory, its use as a therapeutic agent is thus far limited.

"We can design shRNA to silence nearly any chosen gene, but then in cell studies we use a virus to carry this shRNA inside cells. There are a number of challenges to this approach in humans," Jedlicka says.

However, since KDM3A has an enzymatic activity it modifies the cell's genetic material to affect how other genes are expressed it could potentially be targeted with small-molecule inhibitors, similar in structure to many drugs currently in use. Such inhibitors could theoretically be taken in pill form and would be able to cross into cancer cells where they could inhibit tumor growth. Importantly, genetic studies in model organisms suggest that KDM3A is not needed in most normal cells, so it's possible that its targeting could be well tolerated as a therapy.

Continue reading here:
Study: Possible new druggable target in Ewing's Sarcoma

Contact Information

Available for logged-in reporters only

Newswise Ewings Sarcoma is an aggressive pediatric cancer, most commonly caused by the improper fusion of the gene EWS with the gene FLI1. Though the cause has long been known, therapeutic targeting of this fusion has to date proven very difficult. A University of Colorado Cancer Center study, recently published in the journal Oncogene, looked downstream from this fusion to discover other links in the chain of events that leads to cancer this fusion puts in motion microRNA-22, which regulates another gene, KDM3A, and this signaling chain helps ensure that the outcome of the EWS/FLI1 fusion is cancer. Researchers suggest that these new targets may provide more easily druggable alternatives to the EWS/FLI1 fusion itself.

We started with all the microRNAs downstream from the EWS/FLI1 fusion and narrowed in on microRNA-22. But then we looked even further downstream from there and found that microRNA-22 works through another gene, KDM3A, to cause this cancer. When we turned down this gene (KDM3A) in lab studies, we observed a profound inhibition of the tumorigenic properties of Ewing Sarcoma cells, says Paul Jedlicka, MD, PhD, CU Cancer Center investigator and assistant professor of pathology at the University of Colorado School of Medicine.

This study highlights the complex cascade of events that cause cancer. Even in seemingly simple cancers like Ewing Sarcoma with known oncogenic drivers, cancer-causing action tends to depend on a cascade of events the oncogenes initiate. In other words, oncogenes may sit at the head of long, complex strings of cellular events, all of which are needed to cause cancer.

Likewise, genes arent the only level at which this string of events can be interrupted between a gene and its expression as a (potentially dangerous) protein lies all the mechanics of transcription, including the involvement of chemicals that transport a genes information to the machinery that makes proteins (RNA), and chemicals that decide how often a gene should be manufactured into a protein (e.g. microRNA). Understanding of the mechanics of this complex cascade, in turn, can yield new therapeutic targets.

In this study, Jedlicka and colleagues used another form of RNA called shRNA to mute the expression of the tumor-promoting gene KDM3A. But Jedlicka points out that, in general, while shRNA is an extremely useful tool in the laboratory, its use as a therapeutic agent is thus far limited.

We can design shRNA to silence nearly any chosen gene, but then in cell studies we use a virus to carry this shRNA inside cells. There are a number of challenges to this approach in humans, Jedlicka says.

However, since KDM3A has an enzymatic activity it modifies the cells genetic material to affect how other genes are expressed it could potentially be targeted with small-molecule inhibitors, similar in structure to many drugs currently in use. Such inhibitors could theoretically be taken in pill form and would be able to cross into cancer cells where they could inhibit tumor growth. Importantly, genetic studies in model organisms suggest that KDM3A is not needed in most normal cells, so its possible that its targeting could be well tolerated as a therapy.

In the meantime, Jedlicka and colleagues demonstrate a strong case for KDM3A as a new target in Ewings Sarcoma: they demonstrate that the gene is overexpressed in human samples of the cancer, that depletion of the gene inhibits the growth of tumors in patient-derived cell lines, and that depletion of the gene in mouse studies results in the inability of mice to grow tumors.

Read the original:
Possible New Druggable Target in Ewing's Sarcoma

PUBLIC RELEASE DATE:

20-Jan-2014

Contact: Laura Newman laura.newman@mountsinai.org 212-241-9200 The Mount Sinai Hospital / Mount Sinai School of Medicine

New York, NYResearchers from the Icahn School of Medicine at Mount Sinai have identified a new molecular mechanism by which cocaine alters the brain's reward circuits and causes addiction. Published online in the journal Proceedings of the National Academy of Sciences by Dr. Eric J. Nestler, MD, PhD, and colleagues, the preclinical research reveals how an abundant enzyme and synaptic gene affect a key reward circuit in the brain, changing the ways genes are expressed in the nucleus accumbens. The DNA itself does not change, but its "mark" activates or represses certain genes encoding synaptic proteins within the DNA. The marks indicate epigenetic changeschanges made by enzymesthat alter the activity of the nucleus accumbens.

In a mouse model, the research team found that chronic cocaine administration increased levels of an enzyme called PARP-1 or poly(ADP-ribosyl)ation polymerase-1. This increase in PARP-1 leads to an increase in its PAR marks at genes in the nucleus accumbens, contributing to long-term cocaine addiction. Although this is the first time PARP-1 has been linked to cocaine addiction, PARP-1 has been under investigation for cancer treatment.

"This discovery provides new leads for the development of anti-addiction medications," said the study's senior author, Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of the Friedman Brain Institute, at the Icahn School of Medicine at Mount Sinai. Dr. Nestler said that the research team is using PARP to identify other proteins regulated by cocaine. PARP inhibitors may also prove valuable in changing cocaine's addictive power.

Kimberly Scobie, PhD, the lead investigator and postdoctoral fellow in Dr. Nestler's laboratory, underscored the value of implicating PARP-1 in mediating the brain's reward center. "It is striking that changing the level of PARP-1 alone is sufficient to influence the rewarding effects of cocaine," she said.

Next, the investigators used chromatin immunoprecipitation sequencing to identify which genes are altered through the epigenetic changes induced by PARP-1. One target gene whose expression changed after chronic cocaine use was sidekick-1, a cell adhesion molecule concentrated at synapses that directs synaptic connections. Sidekick-1 has not been studied to date in the brain, nor has it been studied in relation to cocaine exposure. Using viral mediated gene transfer to overexpress sidekick-1 in the nucleus accumbens, investigators saw that this overexpression alone not only increased the rewarding effects of cocaine, but it also induced changes in the morphology and synaptic connections of neurons in this brain reward region.

The research opens the door to a brand new direction for therapeutics to treat cocaine addiction. Effective drug therapies are urgently needed. National data from the US National Institute of Drug Abuse reveal that nearly 1.4 million Americans meet criteria for dependence or abuse of cocaine.

###

More:
Mount Sinai researchers find promising new drug targets for cocaine addiction

A new supercomputer can sequence 20,000 genomes in a year for $1,000 a piece.

On Tuesday, Illumina, a global company that specializes in genomic analysis, announced the sale of a new genetic sequencing machine, that is faster and more affordable than existing technology.

"The new sequencer packs high-throughput performance into an affordable desktop form factor, enabling researchers to perform the most popular sequencing applications in less than a day,"said Jay Flatley, CEO of Illumina in a press release.

[READ: Researchers Link Aging Gene to Blood Cancer]

The new technology can sequence a whole human genome in a single run. And the sequencing data can be fed through open source or commercial programs or transferred, analyzed and stored in a secure space, the release noted.

The new machine can sequence 20,000 genomes in a year for $1,000 a piece, says HPC Wire. It can process 16 complete human genomes in three days. The "$1000 genome" is a long-sought marker of advancement that industry has seen as "a tipping point in the pace of genetic discovery" says Aaron Kroll at BioITWorld.

Dr. Gianrico Farrugia, director for the Center for Individualized Medicine at the Mayo Clinic, says that the new machinery's reduced cost and its ability to do large-scale processing will affect the reliability of doctor's results. When testing a person's genome having a larger data set to compare anomalies with will allow doctors to rule-out false positives that can sometimes occur when the pool of comparison data is too small. Doctors need to be certain that "what we call as abnormal is in fact abnormal," he says.

"So, being able to do this significantly larger scale sequencing at a lower cost allows you to collect information that you can apply to your individual patient, because you have more information," he adds.

Farrugia says he knew that the technology was being tested, but didn't know when it would be available. He's excited to try out the new machines and apply them to patient care. The first full human genome sequence was published in April 2003 for $3 billion, according to HPC Wire.

[STUDY: Same Genes May Cause Alcohol Abuse, Eating Disorders]

Go here to see the original:
New Gene Machine Could Mean More Accurate Diagnosis

Jan. 16, 2014 Gene therapies developed by University of Pennsylvania School of Veterinary Medicine researchers have worked to correct different forms of blindness. While effective, the downside to these approaches to vision rescue is that each disease requires its own form of gene therapy to correct the particular genetic mutation involved, a time consuming and complex process.

Hoping to develop a treatment that works more broadly across diseases, a Penn Vet team used canine disease models to closely examine how retinal gene activity varied during the progression of three different forms of inherited vision disease. Their results turned up an unexpected commonality: Early on in each of the diseases, genes involved in the same specific pathway of cell death appeared to be activated. These findings point to possible interventions that could curb vision loss across a variety of inherited retinal diseases.

The work, published in PLOS ONE, was conducted by Sem Genini, a senior research investigator; William A. Beltran, assistant professor of ophthalmology; and Gustavo D. Aguirre, professor of medical genetics and ophthalmology, all of Penn Vet's Department of Clinical Studies, Philadelphia.

The team examined three forms of retinal degenerative diseases, rod cone dysplasia 1 being the most severe, or earliest onset, followed by X-linked progressive retinal atrophy 2 and then early retinal degeneration. All of these diseases involve the death of photoreceptor cells and each is caused by a distinct genetic mutation. But what scientists did not know is how the mutations trigger a molecular signaling pathway that leads to the death of photoreceptor cells.

"What we have in mind is to be able to address multiple forms of disease with one treatment," Beltran said. "We wanted to get a better understanding of whether there are any common cell death or cell survival pathways that could be targeted in some of these diseases."

The researchers looked at the activity of 112 genes in diseased retinas and compared it to gene activity in normal retinas. They assessed gene activity at time points known to correspond with key phases of disease: the "induction phase," the time before the peak level of photoreceptor cell death; the "execution phase," when the highest rates of photoreceptor cell death occur; and the "chronic phase," during which photoreceptor cell death continues at somewhat reduced levels.

During the execution and chronic phases of disease, the researchers identified a number of genes involved in programmed cell death, or apoptosis, that had noticeably different patterns of expression between the diseased and normal dogs.

Of note, several proteins involved in the tumor necrosis factor, or TNF, pathway increased in activity during the induction and execution phases. This pathway is implicated in many diseases, from diabetes to cancer to rheumatoid arthritis.

"This is quite a new result," Genini said. "It was not expected to have the TNF pathway upregulated."

"We assumed," Aguirre said, "the diseases would be different from one another and that cells would commit suicide by their own specific pathway and that perhaps quite late they would have a common final pathway. But what this shows is that there is an early trigger that is quite similar among all three diseases."

Read more from the original source:
Same cell death pathway involved in three forms of blindness, study finds