Inovio Pharmaceuticals’ HIV DNA Vaccine Achieves Strong T-Cell Immune Responses in Phase I Human Trial

BLUE BELL, Pa.–(BUSINESS WIRE)–Nov 17, 2010 – Inovio Pharmaceuticals, Inc. (NYSE Amex: INO), a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced today that it has achieved high vaccine-induced response rates and strong magnitude of immune responses in its Phase I clinical study of PENNVAX™-B, a DNA vaccine for the prevention of HIV infection. Similar to recently reported results from a Phase I clinical study of Inovio’s therapeutic DNA vaccine for cervical cancer, the response rates and magnitude of responses achieved in this study are significantly higher than those seen previously with other DNA vaccine trials. Dr. Spyros Kalams, principal investigator for the study and Immunology Director of the Vanderbilt Center for AIDS Research at Vanderbilt University Medical Center, presented the interim immune response and safety data at the Annual HIV Vaccine Trials Network (HVTN) Conference being held November 15-17 in Seattle, WA.

Inovio previously reported data from non-human primates demonstrating up to a 100-fold enhancement in immune responses resulting from the vaccine when delivered via in vivo electroporation compared to syringe injection without electroporation. This study, designated HVTN-080, involved vaccination of 48 healthy, HIV-negative volunteers to assess safety and levels of immune responses generated by Inovio’s PENNVAX-B vaccine delivered with its CELLECTRA® electroporation device. PENNVAX-B is a SynCon™ DNA vaccine that targets HIV gag, pol, and env proteins. This randomized, double-blind, multi-center study is being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), an agency of the National Institutes of Health, and conducted by the NIAID-funded HVTN, at several clinical sites.

Of the 48 total volunteers, eight subjects received a placebo, 10 subjects received a 1 mg dose of PENNVAX™-B vaccine, and 30 subjects received a 1 mg dose of PENNVAX-B along with IL-12 DNA. The IL-12 for this study (Genevax-IL-12), manufactured under a contract with DAIDS, was provided by Profectus Biosciences. All volunteers received vaccine or placebo administered with electroporation at months 0, 1, and 3. The T-cell immune responses were detected using a validated flow cytometry-based intracellular cytokine staining (ICS) assay at the HVTN core immunology laboratory at the Fred Hutchinson Cancer Research Center (Seattle, WA).

Preliminary data from the trial reported at the meeting included safety data from all trial participants (48) and immunogenicity data from 38 out of 40 samples from vaccine recipients post-second-dose and from 31 out of 40 samples from vaccine recipients post-third-dose. The data indicate that antigen-specific T-cell responses were generated by the vaccine in a majority of subjects. Either CD4+ or CD8+ or both T-cell responses were observed against at least one of the vaccine antigens in 61% (23 out of 38) of evaluated subjects after two vaccinations. After three vaccinations, 84% (26 out of 31) of evaluated subjects had positive T-cell responses.

Notably, after three vaccinations:

• 67% (6 out of 9) of evaluated subjects receiving PENNVAX-B and 91% (20 of 22) of evaluated subjects receiving PENNVAX-B + IL-12 were observed to have generated antigen-specific T-cell responses (either CD4+ or CD8+).
• Antigen-specific CD4+ T-cell responses were generated by the vaccine in 70% of evaluated vaccine recipients (21 out of 30).
• Significantly strong antigen-specific, CD8+ T-cell responses were also generated by the vaccine in 55% of evaluated vaccine recipients (17 out of 31).
• Samples from eight placebo recipients and pre-vaccine samples from vaccine recipients were also tested and were negative for both CD4+ T-cell responses and CD8+ T-cell responses.
• PENNVAX-B delivered using the CELLECTRA® intramuscular electroporation delivery device with or without IL-12 was generally safe and well tolerated. There were no vaccine-related serious adverse events. Reported adverse events and injection site reactions were mild to moderate and required no treatment.

Dr. Kalams stated, “The preliminary immune response data from this novel DNA-based vaccine are indeed very encouraging. We look forward to our continuing work with Inovio to develop the potential of this promising vaccine candidate.”

Dr. J. Joseph Kim, Inovio’s President and CEO, said: “After recently announcing best-in-class immunogenicity data from our clinical trial for our cervical cancer DNA vaccine using the same technology platform, we are pleased to again see very strong T-cell immune responses from this vaccine platform for a different disease, and particularly a disease with unmet needs like HIV. They are amongst the highest immune responses seen in other HIV vaccine trials either with DNA or other vaccine platforms including proteins and viral vectors. However, unlike viral vectors, DNA vaccines do not induce unwanted immune responses against the carrier. Taken together these results further support the prospect that Inovio’s DNA vaccine and delivery platform could play an important role in developing new vaccines and therapies for major diseases like cancer and HIV.”

In addition to the interim ICS results presented at the meeting, the complete immunogenicity data including data from the few remaining unanalyzed samples and additional antibody and T-cell results based on ELISpot assays as well as the end-of-study safety data are expected in 2Q 2011.

DNAWellnessinfo.com Resource:  http://www.drugs.com/clinical_trials/inovio-pharmaceuticals-hiv-dna-vaccine-achieves-strong-t-cell-immune-responses-phase-human-trial-10673.html

Possible Genetic ‘Switches’ for Blood Sugar Control Detected

But applications for diabetes years away, researchers say.

TUESDAY, Nov. 2 (HealthDay News) — A new genetic analysis has uncovered specific regions in the DNA of certain human pancreatic cells that appear central to the regulation of insulin and other functions of the pancreas.

The new effort — conducted by researchers at the National Human Genome Research Institute (NHGRI) — takes scientists a step closer towards understanding the complex genetic underpinnings of insulin deficiency and the onset of type 2 diabetes, which accounts for most of the 23 million cases of diabetes among Americans and the more than 170 million cases worldwide.

By honing in on clusters of hormone-producing pancreatic cells known as islets, the investigators were able to detect about 18,000 “molecular on-off switches” (or so-called “promoters”) that control gene behavior. Several hundred of these gene-adjacent switches were previously unknown.

In a U.S. National Institutes of Health (NIH) news release, study co-author Michael Stitzel explained that previous gene-mapping work has pointed out some genetic differences between type 2 diabetic and non-diabetic individuals in specific regions of the genome.

“But substantial efforts are required to understand how these differences contribute to disease,” he said. “Defining regulatory elements in human islets is a critical first step to understanding the molecular and biological effects for some of the genetic variants statistically associated with type 2 diabetes.”

Stitzel and colleagues from the NIH Intramural Sequencing Center, Duke University in Durham, N.C., and the University of Michigan in Ann Arbor report their findings in the Nov. 3 issue of Cell Metabolism.

The new work has also enabled the authors to identify another 34,000 regulatory “modules” located slightly farther away (than the 18,000 on-off switches) from the genes they control. They believe that these distinct “regulatory elements” may be critical to proper blood glucose levels.

Upwards of 50 genetic abnormalities believed to have an association with islet-related pancreatic dysfunction were also uncovered.

“These findings represent important strides that were not possible just five years ago, but that are now realized with advances in genome sequencing technologies,” Dr. Eric D. Green, NHGRI director, noted in the NIH news release.

“Very exciting” is how Dr. Stuart Weiss, an endocrinologist at New York University Medical Center and a clinical assistant professor at the NYU School of Medicine in New York City, described the current effort.

“It’s clearly the future of medicine,” he said. “However, the fact of the matter is that all sorts of factors are involved in the development of diabetes, and different people require different treatments. And just when you think that you understand it, another curve comes at you. So it’s very difficult to think that we’re going to find a magic bullet. And I would think that the clinical applications from any of this are probably years and years away.”

More information

For more on genetics and diabetes, visit the American Diabetes Association.

SOURCES: U.S. National Institutes of Health, news release, Nov. 2, 2010; Stuart Weiss, M.D., endocrinologist, clinical assistant professor, NYU School of Medicine, New York City

Copyright © 2010 HealthDay. All rights reserved.

DNAWellnessinfo.com Resource:  http://www.doctorslounge.com/index.php/news/hd/15338

TGen-Mayo Clinic study discovers role of DNA methylation in multiple myeloma blood cancer

Science Centric | 1 October 2010 11:18 GMT

DNA methylation – a modification of DNA linked to gene regulation – is altered with increasing severity in a blood cancer called multiple myeloma, according to a study by Mayo Clinic and the Translational Genomics Research Institute (TGen).

And at specific points of DNA, ‘global hypomethylation,’ in which many genes lose the modification, may be associated with the step-by-step development of myeloma, according to a scientific paper published this month in the journal Cancer Research.

‘This is the first study to show that hypomethylation occurs early in the development of multiple myeloma and increases through disease progression,’ said Dr Bodour Salhia, a TGen cancer researcher and the paper’s lead author.

DNA methylation suppresses the expression of viral genes and other harmful elements incorporated over time into an individual’s genome. In cancer, hypermethylation at certain genomic locations can turn tumour suppressing genes off, while hypomethylation in some instances may lead to the over-expression of oncogenes, or those genes that give rise to cancer, and is linked to chromosomal instability.

However, there is still much to learn about the consequences of altered methylation.

In this study, researchers examined the methylation status of more than 1,500 CpGs. This is shorthand for C-phosphate-G, or cytosine and guanine – two of the four chemicals that comprise DNA – separated by a phosphate group, which links the two nucleosides together.

Researchers used a high-throughput universal bead array technology to examine CpG methylation at different stages of multiple myeloma, evaluating DNA methylation events associated with the progression of tumours.

They performed DNA methylation profiling analysis for more than 800 genes, including tumour suppressors, oncogenes, and genes involved in cancer-related cellular processes. This process contrasts with previous studies that focused on the analysis of a single gene.

They found only a few genes that were hypermethylated, but importantly found many more hypomethylated genes, even in the earliest stages of multiple myeloma.

‘Our data suggest that the overall degree of methylation may have some prognostic value, and further studies are needed to determine the functional and clinical significance of our findings,’ said Dr John Carpten, Director of TGen’s Integrated Cancer Genomics Division and the paper’s senior author.

Dr Salhia, added, ‘This study represents the most comprehensive examination to date of the role of methylation in multiple myeloma, and is expected to lead to an improved understanding of the biological mechanisms involved in the development of this type of cancer.’

The study of DNA methylation falls under epigenetics – an emerging field in cancer research. Unlike the study of genetics, epigenetics refers to the study of gene activity that does not involve hardwiring alterations in the genetic code. These epigenetic events, which lay atop the genome, are an intricate and heritable mechanism of regulating the expression of genes.

‘Understanding the full spectrum of epigenetic modifications will be key to improving the clinical management of the disease, and studies should continue to find new ways of treating multiple myeloma by targeting the multiple myeloma epigenome. This study also emphasises that hypomethylating strategies may not be the next necessary steps in drug development.’ said Rafael Fonseca, M.D., Deputy Director of Mayo Clinic Cancer Centre in Arizona.

Source: TGen

DNAWellnessnessinfo.com Resource:  http://www.sciencecentric.com/news/10100122-tgen-mayo-clinic-study-discovers-role-dna-methylation-multiple-myeloma-blood-cancer.html

ADHD Genetic Link: Is Attention Deficit All in the Genes?

October 1, 2010 8:51 AM  -  cbsnews.com
Posted by David W Freeman

CBS) What causes attention-deficit hyperactivity disorder, or ADHD?

A new study points the finger not at bad parenting or too much sugar in the diet but at heredity.

Scientists at Cardiff University in Wales compared the DNA of 366 children with ADHD to that of 1,047 kids without the condition. They found that kids with ADHD were more likely to have small segments of DNA that were duplicates or missing.

“We hope that these findings will help overcome the stigma associated with ADHD,” Professor Anita Thapar, the study’s lead author, said in a written statement. “Too often, people dismiss ADHD as being down to bad parenting or poor diet. As a clinician, it was clear to me that this was unlikely to be the case. Now we can say with confidence that ADHD is a genetic disease and that the brains of children with this condition develop differently to those of other children.”

The study was published online in The Lancet, the English medical journal.

Worldwide, about one in 50 children have ADHD. The condition – which makes kids restless, impulsive, and easily distracted – is incurable but can often be controlled with medication and therapy.

DNAWellnessinfo.com Resource: http://www.cbsnews.com/8301-504763_162-20018239-10391704.html

Cancer treatment found among junk DNA

September 27, 2010

AAP

Australian scientists have found a new and potent way to fight cancer among what was once thought of as junk DNA.

The experimental technique, proven to shrink tumours in mice, involves “microRNA”.

Dr Alex Swarbrick said this new class of genes was until recently considered to be junk DNA, the term used to describe the bulk of information contained in the genome that has no apparent purpose.

But far from being junk, he said one specific type of microRNA (microRNA 380) has been found to play a pivotal role in allowing certain types of cancer to grow.

Dr Swarbrick and his research colleagues also found that blocking the action of this microRNA in mice with neuroblastoma cancers caused their tumours to shrink.

“The revolutionary thing about this finding is that it’s the first time anyone has blocked the growth of a primary tumour by the simple delivery of a microRNA inhibitor…,” Dr Swarbrick, from Sydney’s Garvan Institute of Medical Research, said.

“That, of course, makes this microRNA a potential therapeutic target for all cancers that depend on it.”

The discovery points to a new way to combat cancer that could be as simple as a twice-weekly injection of a microRNA inhibitor.

MicroRNA 380 has its cancer-promoting effect on the body by disabling another gene (P53), which is known as the “guardian of the genome” because of its role in suppressing tumour growth.

Dr Swarbrick said the studies in mice showed how their P53 gene was disabled by “overproducing” microRNA 380.

He said this microRNA served a necessary purpose in embryos when cells needed to divide quickly and it should play no role in a “normal adult’s cells”.

It was not yet known why it could become active and with cancer-causing effects later in life.

“By blocking it, you’re effectively returning cells to normal,” Dr Swarbrick said.

“We still don’t know why it gets switched on again in certain cancers.

“(However) understanding that certain cancers appear to be regulated like this gives us a new avenue to explore in their treatment.”

Dr Swarbrick said the technique could also be applied to treat brain tumours as well as melanoma, which are known to be caused by a disabled P53 gene.

The research was conducted along with Brisbane-based Dr Susan Woods from the Queensland Institute of Medical Research, and a colleague in the US.

The results are reported in the journal Nature Medicine on Monday.

© 2010 AAP

DNAWellnessinfo.com Resource:  http://news.smh.com.au/breaking-news-national/cancer-treatment-found-among-junk-dna-20100927-15sv8.html

DNA Mutation in c-Myb Gene linked to Leukaemia

thglobalherald.com

Australian researchers have uncovered a novel DNA mutation in the c-Myb gene that may be linked to the development of leukaemia, breast and colon cancer.

A team led by Dr Peter Papathanasiou from the John Curtin School of Medical Research at The Australian National University and Associate Professor Andrew Perkins from the Institute for Molecular Bioscience at The University of Queensland completed a three-year screening project to find the genes that control the development and turnover of stem cells.

“We’ve shown that blood stem cells with this genetic mutation behave the same way as those present in human bone marrow diseases, including diseases that can evolve into leukaemia,” said Dr Papathanasiou, who is also affiliated with the Australian Phenomics Facility at ANU.

“By understanding more about the genetic blueprint of these kinds of disorders, we can start to develop new ways of targeting diseases,” Dr Perkins said.

“Currently, there is no treatment for this group of blood diseases, but the discovery of this mutation provides new avenues for investigation.”

As a result of the screening project, the researchers have also identified five other abnormal blood stem cell profiles, adding to understanding of the genetic diversity of blood cells. The project has also led to a better understanding of how blood cells develop and how this process becomes corrupted.

“Given that the same genes that operate in stem cells also function in cancer cells – albeit with genetic mutation – this research also has potential implications for regenerative medicine, by understanding how to stimulate the growth of new blood cells,” Dr Papathanasiou said.

The project was the first in the world to mutate the mammalian genome in a specific search for novel genetic regulators of stem cells.

The following is taken from the research paper’s abstract:

Here we demonstrate that chemical mutagenesis of mice combined with advances in hematopoietic stem cell reagents and genome resources can efficiently recover recessive mutations and identify genes essential for generation and proliferation of definitive hematopoietic stem cells and/or their progeny.

We employed high-throughput FACS to analyze nine subsets of blood stem cells, progenitor cells, circulating red cells and platelets in >1,300 mouse embryos at embryonic day (E) 14.5. From 45 pedigrees we recovered six strains with defects in definitive hematopoiesis.

We demonstrate rapid identification of a novel mutation in the c-Myb transcription factor that results in thrombocythemia and myelofibrosis as proof-of-principal of the utility of our FACS-based screen.

The work was made possible by grants from the National Health & Medical Research Council, the Leukaemia Foundation, and by the Australian Government’s National Collaborative Research Infrastructure Strategy to establish the Australian Phenomics Network.

Get the full paper by visiting: http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2010-04-269951v1

DNAWellnessinfo.com Resource:  http://theglobalherald.com/science-dna-mutation-in-c-myb-gene-linked-to-leukaemia/5384/

DNA Test May Speed Colon Cancer Diagnosis

NICHOLAS WADE
Published: August 9, 2010
nytimes.com

A new generation of DNA tests for colon cancer seems likely to improve the detection both of cancers and of the precancerous polyps that precede them. The tests, if validated, could reduce the burden of disease substantially by detecting tumors at an early stage, including those not picked up by a colonoscopy.

Colorectal cancers tend to grow slowly and are easily removed if caught early. But many people over 50 do not comply with the recommendation to have a colonoscopy — a time-consuming procedure in which a tube is threaded up the intestine — and even colonoscopies do not catch everything. Colorectal cancer has become the second most common cancer in the United States; each year it causes more than 50,000 deaths and costs about $14 billion to treat.

Colon tumors provide considerable evidence of their presence by shedding blood and cells that are detectable in the stool. Tests for blood have reduced deaths from colorectal cancer only modestly, because they are not very sensitive to precancerous polyps, the stage at which cancer is best prevented.

Researchers turned to measuring mutations in DNA after Dr. Bert Vogelstein of Johns Hopkins University discovered the series of mutations by which a colon polyp advances to full cancer. But no single mutation predicts a patient’s risk, and the mutation tests, though more accurate than the blood tests, have not been a decisive improvement.

By 2004 it was clear that looking for the Vogelstein mutations was “neat biology but not a home run,” said Dr. David Ransohoff, an expert on colon cancer screening at the University of North Carolina.

A new generation of tests being developed depends on a different process in cancer cells. All cells switch off the genes they do not need by attaching small chemicals called methyl groups to certain sites along their DNA. In cancer cells, there is generally less methylation than usual, except for certain regions of DNA where the methylation process is taken to excess, perhaps because the cells need to shut down tumor suppressor genes. These and other genes are highly methylated in colon tumors and other kinds of cancer.

Exact Sciences, a company based in Madison, Wis., is developing a colon cancer test based on highly methylated DNA. Its researchers reported last month that by testing for methylated DNA at four markers, pieces of DNA drawn from specific genes, they could detect colon tumors and polyps, distinguishing them from normal tissue with 100 percent sensitivity and with no false positives.

The tests of methylated DNA were performed directly on tumors and are expected to be less accurate in the real world, in which they would have to work in stool samples. Almost all of the DNA in stool is from bacteria, and the methylated DNA is a fraction of the 0.01 percent that is human DNA.

Still, Kevin T. Conroy, chief executive of Exact Sciences, said he expected that the four-marker test, when applied to stool samples, would detect at least half of all precancerous polyps and 85 percent of actual cancers. Results of a trial now under way in 1,600 patients will be reported in October, he said.

The test would cost less than $300, and samples could be collected at home. Patients would be advised to take the test every three years. People with a positive result would then have a colonoscopy to verify and remove any polyps, with the result that colonoscopies could be focused on high-risk patients instead of the population at large.

Exact Sciences’ test is based on work by Dr. Vogelstein, Dr. Sanford Markowitz at Case Western Reserve University and Dr. David A. Ahlquist of the Mayo Clinic. Dr. Ahlquist, who is a scientific adviser to the company, identified some of the highly methylated genes the company is testing as markers for colon cancer.

Dr. Ahlquist said that if the test worked as well as hoped on stool samples, “this will be the first noninvasive test that will reliably detect malignant lesions.” Cervical cancer has been virtually eliminated by the Pap test, he said, and “we feel that colon cancer could be eliminated to the same extent.”

The four-marker test can pick up a kind of precancerous tissue called a serrated polyp which is often missed by colonoscopies, Dr. Ahlquist said. It also ignores most innocuous small polyps.

Using different sets of four markers, other kinds of cancer can be detected. “We can detect all of the cancers above the colon — pancreas, esophagus, stomach, bile duct,” Dr. Ahlquist said. Thus in principle, all the cancers of the gastrointestinal tract, which account for nearly a quarter of all cancer deaths in the United States, should be detectable from stool samples.

Dr. Vogelstein said tests for DNA mutations would be better in theory than tests for DNA methylation because “mutations are entirely specific and they are what is driving the tumor”; the methylation is less causative and increases naturally with age.

But the DNA methylation tests are promising in principle, he said, and it seems feasible for Exact Sciences to get a sensitivity of better than 90 percent and a false positive rate of only 5 to 10 percent. “We can tolerate 5 to 10 percent false positives because those people will just get colonoscopies,” he said.

For cancers above the colon, there are many enzymes that digest DNA, so whether such cancers can be detected efficiently can be answered only with experiments, Dr. Vogelstein said. And false positives would be more of a problem, since for these cancers there is no easy verification method like colonoscopy. “That’s when these false positives really start to be the devil,” he said.

Dr. Ransohoff said the Exact Sciences test was still at a preliminary point. “This is neat and it’s promising,” he said. “But we’ve been down this road before and we need to be hopeful without being carried away.”

DNAWellnessinfo.com Resource:  http://www.nytimes.com/2010/08/10/health/10cancer.html?_r=1

Smokeless tobacco may hurt DNA, enzymes

CHANDIGARH, India, June 18 (UPI) — A researcher in India warns smokeless tobacco use may damage the body’s DNA and key enzymes.

Krishan Khanduja of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, suggests smokeless tobacco not only may damage DNA, but may also affect the normal functioning of a key family of enzymes found in almost every organ.

Khanduja and colleagues found laboratory rats exposed to extracts of smokeless tobacco had altered DNA material in the liver, kidney and lungs — as well as changed function of the CYP-450 family of enzymes. This enzyme group affects many functions including the production of hormones such as estrogen and testosterone, the processing of cholesterol and vitamin D and the breaking down of prescription drugs and possibly toxic substances.

The study, published in Chemical Research in Toxicology, noted use of smokeless products is increasing not only among men but also among children, teenagers and women.

“These products are used around the world but are most common in Northern Africa, Southeast Asia, and the Mediterranean region,” the study authors said in a statement. “Most of the users seem to be unaware of the harmful health effects and, therefore, use smokeless tobacco to ‘treat’ toothaches, headaches, and stomachaches.”

DNAWellnessinfo.com Resource: http://www.upi.com/Health_News/2010/06/18/Smokeless-tobacco-may-hurt-DNA-enzymes/UPI-41481276902848/

UPDATE 1-Benefits trump risks of rotavirus vaccine-US panel

By Lisa Richwine

GAITHERSBURG, Md., May 7 (Reuters) – Benefits from rotavirus vaccines made by GlaxoSmithKline Plc (GSK.L) and Merck & Co Inc (MRK.N) outweigh any risk from recently discovered contamination with a pig virus, members of a U.S. advisory panel said on Friday.

Pieces of DNA from porcine circovirus (PCV) have been detected in Glaxo’s Rotarix and Merck’s Rotateq. The U.S. Food and Drug Administration said there was no evidence the virus harms people.

Several members of a Food and Drug Administration advisory panel said the vaccines carried impressive benefits from preventing rotavirus, which can cause fatal diarrhea, and agreed there was no sign so far of illness in people from PCV.
Any risks “are at best theoretical,” said Dr. Melinda Wharton, a panelist and deputy director of the Center for Disease Control and Prevention’s National Center for Immunization and Respiratory Diseases.

“Based on where we are with current knowledge, to me the known benefits clearly outweigh the risks,” she said.

The panel did not take any votes on formal recommendations to the agency.

In March the FDA advised doctors to stop using Rotarix after PCV-1 was found in the vaccine. Merck then tested its vaccine and the FDA announced on Thursday the company found pieces of DNA from PCV-1 and a related virus, PCV-2.

The FDA said it wanted the advisory panel’s input before making new recommendations on either vaccine. The agency will issue its latest advice “in the very near future,” said Karen Midthun, acting head of the FDA unit that reviews vaccines. “We need to consider this very expeditiously,” she told reporters.

Both PCV1 and PCV2 are common in pigs but neither is known to cause illness in humans, the FDA said. PCV2 is believed to cause postweaning multisystemic wasting syndrome in young piglets, marked by diarrhea and an inability to gain weight.

Advisory panel members urged further study to check for any long-term effects from PCV. Some also said parents needed to be told about the PCV finding.
“The fact that it poses no risk in the short term is certainly comforting. I don’t think that necessarily says it’s risk-free in the long term,” said panelist Stephen Hughes, head of the HIV drug resistance program at the National Cancer Institute.

Some panelists said they wanted to know more about PCV2. The committee heard less about that type as Merck’s finding was so recent. The meeting was originally scheduled just to discuss the Glaxo vaccine.

PCV1 apparently has been in Glaxo’s vaccine since it was first developed, the company said. Testing found DNA from the virus in master cells used to make the product.

The material may have come from a pig-derived enzyme called trypsin used early in development, Glaxo officials said.

“All available data support this is a manufacturing quality issue and not a safety issue. PCV1 does not pose a risk for infants vaccinated with Rotarix,” said Dr. Barbara Howe, a Glaxo vice president.

Glaxo said it planned to develop a rotavirus vaccine free from PCV1 but the process would take time.

Merck was not scheduled to speak at the meeting, but the company said on Thursday the levels of DNA from PCV were low in Rotateq and there was no sign it was harmful to people.

Vaccines against rotavirus have a troubled history. Wyeth’s Rotashield was pulled off the market in 1999 after it was linked with a rare but deadly bowel obstruction.

Rotavirus kills more than 500,000 infants each year, mostly in low- and middle-income countries. In the United States, deaths from the virus are rare but it caused more than 50,000 U.S. hospitalizations annually before Merck’s vaccine won FDA approval in 2006.

The World Health Organization and the European Medicines Agency have not recommended any changes in rotavirus vaccine use in Europe or developing countries.

In 2009, sales of Merck’s vaccine totaled $522 million, including $468 million from the United States.

Most of Glaxo’s rotavirus vaccine sales occur outside the United States. Worldwide sales in 2009 were $440 million, including $118 million from the United States. Glaxo’s vaccine won U.S. approval in 2008. (Reporting by Lisa Richwine, editing by Gerald E. McCormick and Carol Bishopric)

DNAWellnessinfo.com Resource: http://www.reuters.com/article/idUSN0712973220100507

DNA referees

By Amber Dance, Special to the Los Angeles Times

May 3, 2010

Your life story depends upon a combination of the DNA you’re stuck with plus your environment, including all the little choices and events that happen over that lifetime.

But in recent years, researchers have discovered that, while DNA lays out the options, many of those life experiences — the foods you eat, the stresses you endure, the toxins you’re exposed to — physically affect the DNA and tell it more precisely what to do.

The cause: a kind of secondary code carried along with the DNA. Called the “epigenome,” this code is a set of chemical marks, attached to genes, that act like DNA referees. They turn off some genes and let others do their thing. And although the epigenome is pretty stable, it can change — meaning lifestyle choices such as diet and drug use could have lasting effects on how the body works.

“The thing I love about epigenetics is that you have the potential to alter your destiny,” says Randy Jirtle, who studies epigenetics at Duke University Medical Center in Durham, N.C.

Twins provide an example of how environment can affect the actions of our DNA. Identical twins have identical genes, but sometimes one twin has autism or cancer while the other remains healthy. Studies show that as twins age, their epigenomes become less and less alike, probably causing a lot of those differences in fate.

Another provocative study: In 2009, researchers at Duke University Medical Center published a study in the journal BMC Medicine on epigenetics and autism. They found that some children with autism had extra DNA referees turning off a gene needed to respond to oxytocin, a hormone important in social interaction. The study was small, including only 40 children, but it suggests that turning off that one gene could cause the social problems people with autism have.

Many pharmaceutical companies are exploring the potential of epigenome-altering medicines: There are already a few cancer drugs that turn off cancer-promoting genes or turn on cancer-fighting ones. But since altering the epigenome could have far-reaching, unintended consequences, many scientists are wary of drugs targeted at less life-threatening conditions.

In short, the study of epigenetics is “booming,” says Dana Dolinoy, a toxicologist at the University of Michigan School of Public Health in Ann Arbor.

Pick and choose

The regular DNA genome carries the code for every recipe involved in making a human (or antelope, or philodendron or whatever) — it’s like “The Joy of Cooking.” But just as some chefs never crack, say, the veggies chapter, while they dog-ear every page on desserts, different parts of the body pick and choose the genes they need.

The epigenome is part of what tells different cells in the body which DNA recipes to read and which to ignore. The small chemicals that attach to the DNA may cover up or restrict access to genes that aren’t needed and keep others wide open and readable.

Jirtle compares the system to a computer: The DNA is the hardware — set and unchanging — and the epigenome is the software that tells it when, where and how to work.

Epigenetics might be especially important for pregnant women and infants, because much of the epigenetic code is laid down early in development. Dolinoy speculates that the time before puberty might also be important, since the genome and epigenome are gearing up to launch new genetic programs.

The chemicals that make up epigenetic codes ultimately come from diet. Folic acid, for example, is needed to produce epigenetic molecules that turn off many unwanted genes. Broccoli and garlic are good sources of other types of chemical tags that are part of the epigenome.

In a classic experiment published in 2003 in the journal Molecular and Cellular Biology, Jirtle showed how diet can affect these DNA referees. He studied certain mice that can have either brown or yellow pups. He showed that when pregnant mice eat lots of folic acid and other vitamins, they have mostly lean, brown pups. If those mothers instead eat a diet without the epigenome-enhancing supplements, they have more fat, yellow pups, which are prone to diabetes.

The DNA of the pups is the same — but mom’s diet determined how they used those genes.

Dolinoy used the same types of mice to examine how bisphenol A, a toxin common in hard plastics, affects the epigenome of unborn mice. In a 2007 paper in the Proceedings of the National Academy of Sciences, she reported that mice whose diet included bisphenol A produced more fat, yellow pups. But eating folic acid counteracted those negative effects.

Human mothers, not just rodent ones, affect their children’s epigenomes. In a study published last year in the American Journal of Respiratory and Critical Care Medicine, scientists at USC’s Keck School of Medicine found that if the mother smoked during pregnancy, there were long-lasting changes in her children’s epigenomes. The authors speculated that these changes could affect how the body turns on genes for cancer and development.

Dolinoy, who is expecting her second child in May, cautions that women concerned about epigenome changes in their kids should not base health decisions on this still-immature science. For example, she advises not to overdo it with prenatal supplements. While some folic acid is certainly good — it prevents birth defects — too much might alter the epigenome in unknown, undesirable ways.

“My philosophy is, everything in moderation,” she says.

The epigenome can also be altered after a person is born. For example, researchers from McGill University and the Douglas Mental Health University Institute in Montreal found that child abuse can affect DNA referees. In a 2009 paper in the journal Nature Neuroscience, the authors report that 12 people who were abused as children, and later committed suicide, had different DNA referees on a gene needed to cope with stress, compared with 24 people who were not abused. The research implies, although in no way proves, that diminished ability to cope with stress might have been a factor in the suicides.

Adult epigenomes are still somewhat malleable, but they are stable compared with those of developing fetuses and infants. So there’s no need to worry that every little action will alter it.

But there are also short-term referees that jump on or off the DNA at a moment’s notice. Many scientists consider these refs to be outside the classical definition of “epigenetics,” but those chemical changes do affect genes in similar ways. They may change in response to what you had for breakfast today, or the stress you feel after a tough day.

Genes are not just “on” or “off.” They can be on just a little bit, on a lot and everything in between. So referees, both the short-term and long-term types, tune genes up or down, rather like the dimmer switch for a lamp.

And many genes can be turned up or down by changes in behavior and environment. For example, researchers at the Preventive Medicine Research Institute in Sausalito, Calif., studied 30 men with prostate cancer. These men declined traditional medical treatment and instead underwent a three-month program that included a healthy diet, moderate exercise and daily stress management.

When the researchers examined gene activity in the men’s prostate biopsy samples, they found that 48 genes were turned up and 453 were turned down, compared with gene activity at the beginning of the study. The authors noted that the study, published in the Proceedings of the National Academy of Sciences in 2008, was small and needs to be repeated to be sure of the effects. They also suggested that similar changes might happen in healthy people too, when they alter their behavior.

Though the science of epigenetics is young, scientists think there’s good reason to think about how lifestyle choices may affect the epigenome.

It’s known already that some referees can be inherited from human parent to child. Praeder-Willi syndrome, for example, is caused when some of Dad’s DNA referees or genes are missing. Among other symptoms, people with the syndrome have an overactive appetite that can easily lead to obesity.

And though it hasn’t been proved, some scientists suspect that DNA referees laid down generations ago — in your grandparents, for example — are still active in your body today. That is, the epigenome may “remember” the environment Grandpa grew up in and set your genes to match it, even if you have different foods and activities than he did.

Such control over one’s DNA is a double-edged sword, Jirtle says. Healthy choices, such as eating right, could lead to helpful referees, but unhealthy activities, such as smoking, could have a negative effect on you — and your descendants.

“You now have a major responsibility … to optimize your epigenome,” he says.

health@latimes.com

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