Immune cells (dark purple) cluster around the fringes of transplanted cells - which they would normally invade
An unexpected discovery made by a Sydney scientist has potential to alter the body's response to anything it perceives as not 'self', such as a tissue or organ transplant.
Stacey Walters, an immunology researcher at the Garvan Institute of Medical Research, has found that by greatly boosting the levels of the hormone BAFF in mice, it is possible to alter their immune systems so that they will accept tissue transplants without the need for any immunosuppression.
The findings have just been published in the Journal of Immunology.
Specifically, Stacey has found that mice genetically engineered to produce large amounts of BAFF (B cell activating factor), don't reject transplants.
She has shown that increased numbers of B cells (caused by boosted BAFF levels) in turn stimulate the production of T regulatory cells, which then control T cells, the body's killer cells.
The surprising thing about the results is that B cells, which make antibodies, were not known to have any role in the production of T regulatory cells. Nor would it have been thought possible for them to influence the body's response to a transplant, which has been considered a function of T cells only.
"In normal situations, something has to turn the immune system off once your body's fought an invader, such as a virus. It's the T regulatory cells that come in and say 'enough's enough'," Stacey explained.
Just to make sure it was the B cells that were provoking the changes, Stacey repeated her experiments on a mouse in which B cells were genetically knocked out, but high BAFF levels preserved. She found that when there are no B cells, normal allograft rejection occurs.
Stacey's results give us insight into previously unknown interrelationships between various classes of immune cells. Manipulating these relationships may offer a way of preserving organ grafts in the future without the need for toxic immunosuppressive drugs.
The Garvan Institute of Medical Research was founded in 1963. Initially a research department of St Vincent's Hospital in Sydney, it is now one of Australia's largest medical research institutions with approximately 400 scientists, students and support staff. Garvan's main research programs are: Cancer, Diabetes & Obesity, Immunology and Inflammation, Osteoporosis and Bone Biology, and Neuroscience. The Garvan's mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan's discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.
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Bioengineered goats churn out medicines
Karen Kaplan / Los Angeles Times
Sunday, 18 January 2009
They have four legs, fuzzy faces and udders full of milk.
To the uninitiated, they look like dairy goats. To GTC Biotherapeutics Inc., they're cutting-edge drug-making machines.
The goats being raised on a farm in central Massachusetts are genetically engineered to make a human protein in their milk that prevents dangerous blood clots from forming. The company extracts the protein and turns it into a medicine that fights strokes, pulmonary embolisms and other life-threatening conditions.
GTC has asked the Food and Drug Administration (FDA) to OK the drug, called ATryn. An expert panel voted overwhelmingly on Friday that it is safe and effective, putting it on the verge of becoming the first drug from a genetically engineered animal to be approved in the United States. The agency is expected to make a final decision in early February.
If approved, the drug would be followed by perhaps hundreds of others made from milk produced by genetically engineered goats, cows, rabbits and other animals. Other products in the pipeline are designed to treat people with hemophilia, severe respiratory disease and debilitating swollen tissues.
“As soon as we were able to make genetically engineered animals, this was an obvious thing to do,” said James Murray, a geneticist and professor of animal science at the University of California, Davis. “It's totally cut and paste. This is kindergarten stuff with molecular scissors.”
The biotechnology industry is rooting for ATryn. The FDA's endorsement would signal to Americans that they have nothing to fear from the futuristic technology—and suggest that the millions of dollars they've invested in the technology could soon begin to pay off.
If the drug is approved, “it takes a big question mark off the table in terms of products that are developed from this technology,” said Samir Singh, president of US operations for Pharming Group, which is developing medicines using milk from genetically engineered cows and rabbits.
The public has had misgivings about eating food from genetically modified animals, and some vocal critics of such technology say the wariness could extend to medicines.
“I think many people are going to have the same revulsion,” said Jaydee Hanson, a policy analyst at the Center for Food Safety, an advocacy group in Washington, D.C., that opposed genetic manipulation of food and animals.
For scientists, the appeal is obvious. Many drugs are now synthesized in bioreactors by bacteria or Chinese hamster ovary cells, and they require extensive processing to be suitable for human use. Genetically engineering animals is a more straightforward alternative for producing proteins, which form the basis of all biological drugs.
“We're taking advantage of the fact that the mammary gland was designed by nature to make proteins,” said Tom Newberry, GTC's vice president for government relations.
The process of designing animal milk with human proteins starts by identifying the human gene containing instructions for making a medically useful protein. That human DNA or deoxyribonucleic acid, sequence is combined with pieces of animal DNA that regulate when and where the protein is produced. Those regulatory controls ensure that the human gene is only switched on in the mammary gland during lactation and doesn't interfere with any other part of the animal's body.
The DNA package can be injected into a single-cell animal embryo with a microscopic needle, though it's a hit-or-miss proposition. When the embryo divides, it may or may not incorporate the foreign DNA into its own genome. The embryo is then transferred to the womb of a surrogate mother, with a 1 percent to 3 percent chance that it will result in a healthy animal containing the human gene.
A more advanced alternative is to start with a normal animal cell and splice the DNA package directly into the cell nucleus. The modified cell can be cloned to create a new animal that expresses a human gene.
With three to five founder animals, a company could use traditional breeding methods to create an entire herd of genetically engineered cows, sheep or goats.
“Something like five or six cows can produce the world's requirement for some drugs,” Murray said. Demand for most drugs could be met with herds no bigger than 50 cows or 100 goats, he said.
Companies separate the components of engineered animals' milk based on their size, shape, electrical charge and other chemical characteristics. The process ultimately leads to vials of pure protein that carry out specific functions in the human body.
The species of animal used depends in part on the volume of protein needed or how quickly it needs to be produced.
The companies say it's cheaper to create the animals than to build and maintain expensive bioreactors. The technique could make it cost-effective for companies to develop drugs to treat diseases that affect relatively few patients.
To make ATryn, GTC used the microinjection technique to insert the human gene for antithrombin alfa into goat embryos. The protein is essential for preventing blood clots, but about one in every 3,000 to 5,000 people is born with a genetic defect that prevents them from making enough of it.
Most of the time, patients are treated with standard blood thinners like warfarin, which can be dangerous if people are undergoing surgery or childbirth. In those situations, patients are treated with antithrombin protein extracted from human-blood plasma.
But the supply is limited. If all the plasma donated in the US each year were used to make antithrombin, the most that could be produced is about 100 kilograms.
“We can match that with 150 goats,“ Newberry said.
GTC plans to expand the use of the protein beyond patients with the genetic defect to include people who have a short-term deficiency due to burns or other traumatic injuries, he said.
The European Commission approved ATryn for use there in 2006.
The company's scientists have made more than 100 proteins in the milk of genetically engineered animals, Newberry said. The company is considering clinical trials for factor VIIa and factor IX proteins to treat hemophilia, along with alpha-1 antitrypsin to treat severe respiratory problems, he said.
Pharming, based in the Netherlands, plans to seek US and European approval this year for Rhucin, made from a human protein purified from the milk of genetically engineered rabbits. The protein, C1 esterase inhibitor, helps control inflammation, and patients with hereditary angioedema have a genetic mutation that prevents their bodies from making enough of it. The result can be severe swelling, abdominal pain and airway obstruction.
Pharming is focusing on cows to make other proteins in larger quantities. The company is working with the US Army on cow milk containing human fibrinogen, a protein that helps blood to clot, Singh said.
Other companies are using genetic engineering to make milk with proteins for vaccines, a class of cancer drugs called monoclonal antibodies, and nutritional supplements.
Regulators will have their work cut out for them as they try to anticipate all the potential risks posed by genetically engineered animals and the medicines they produce, said Greg Jaffe, biotechnology director at the Center for Science in the Public Interest, a consumer-advocacy group in Washington, D.C. Hanson, of the Center for Food Safety, said he fears animals created through genetic engineering and cloning are inherently unhealthy due to the unnatural circumstances of their birth, despite FDA assessments that the animals are fine.
“We don't want a herd of sick animals being our source of a new biological drug,“ he said.
At the meeting on Friday, FDA biotechnology adviser Larisa Rudenko said the agency's Center for Veterinary Medicine found that GTC's goats were treated very well and posed no environmental risks.
Those assurances won't satisfy everyone, said Todd Winters, professor of animal physiology and biotechnology at Southern Illinois University, Carbondale. But he said people should not let fear stand in the way of potential cures.
“You've got to weigh whether you're going to save a life or not,” he said.
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President Bush Signs Landmark Genetic Nondiscrimination Information Act Into Law
Washington DC
May 21, 2008–
President Bush Signs Landmark Genetic Nondiscrimination Information Act Into Law
Washington, D.C. - The Coalition for Genetic Fairness (
http://www.geneticfairness.org/) commends President George W. Bush for signing into law today the first civil rights legislation of the new millennium, the Genetic Information Nondiscrimination Act (GINA). GINA is the
first and only federal legislation that will provide protections against discrimination based on an individual's genetic information in health
insurance coverage and employment settings.
"This is a tremendous victory for every American not born with perfect genes - which means it's a victory for every single one us," said Representative
Louise Slaughter (D-NY). "Since all of us are predisposed to at least a few genetic-based disorders, we are all potential victims of genetic discrimination."
"Today marks the beginning of a new era in health care," continued Slaughter. "Americans can finally take advantage of the tremendous potential of genetic research without the fear that their own genetic information will be used against them."
Just a few weeks ago, GINA received overwhelming support in both the Senate, with a unanimous vote of approval, and the House of Representatives, where the
legislation was passed by a landslide vote of 414-1.
"Individuals no longer have to worry about being discriminated against on the basis of their genetic information, and with this assurance, the promise of
genetic testing and disease management and prevention can be realized more fully," stated Sharon Terry, president of the Coalition and CEO of Genetic
Alliance (
http://www.geneticalliance.org/). "We applaud our champions on the Hill who have worked tirelessly to pass this important legislation. It is now our responsibility to make sure the public knows that these new protections are in place."
The health insurance protections offered by GINA are expected to roll out 12 months after the bill is signed, whereas the employment protections will be fully realized in 18 months.
"Now that GINA has been approved and signed into federal law by the President, American health care consumers and employees will no longer have to fear the
adverse effects of being tested to determine their risk status for genetic diseases," said Joann Boughman, Ph.D., executive vice president of the
American Society of Human Genetics
[http://www.ashg.org/] and a member of the Coalition's executive committee. "Once this legislation has taken effect, clinicians will be able to order genetic tests for patients and their families in a manner that ensures the full realization of the advantages of
personalized medicine models, while easing patients' concerns about the risk of genetic discrimination by insurance companies and employers based on this
data."
Specifically, the legislation protects against genetic discrimination by health insurers or employers by:
- Prohibiting group health plans and issuers offering coverage on the group or individual market from basing eligibility determinations or adjusting premiums or contributions on the basis of genetic information. They cannot request, require or purchase the results of genetic tests, or disclose genetic information.
- Prohibiting issuers of Medigap policies from adjusting pricing or conditioning eligibility on the basis of genetic information. They cannot
request, require or purchase the results of genetic tests, or disclose genetic information.
- Prohibiting employers from firing, refusing to hire, or otherwise discriminating with respect to compensation, terms, conditions or privileges
of employment. Employers may not request, require or purchase genetic information, and may not disclose genetic information. Similar provisions
apply to employment agencies and labor organizations.
The Coalition for Genetic Fairness is an alliance of advocacy organizations, health professionals, and industry leaders working to educate Congressional policymakers about the importance of legal protections for genetic information and ensure passage of meaningful genetic information nondiscrimination legislation.
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“Gene Therapy Shows Promise against Hereditary Lung Disease.”
Date: November 21, 2006
GAINESVILLE, Fla.—An experimental gene therapy to combat alpha-1 antitrypsin deficiency, a common hereditary disorder that causes lung and liver disease, has caused no harmful effects in patients and shows signs of being effective, University of Florida researchers say. In a clinical trial, researchers evaluated the safety of using a so-called gene vector—in this case an adeno-associated virus—to deliver a corrective gene to 12 patients who are unable to produce a protein essential for health called alpha-1 antitrypsin.
“The primary end point in the trial was to see whether it was safe to give patients this gene transfer vector and then to try to begin to see if we could get the dose into a range where we would begin to replace the missing protein in the blood,” said Dr. Terence Flotte, a pediatrician, geneticist and microbiologist with UF’s College of Medicine and a member of the Powell Gene Therapy Center and the UF Genetics Institute. “We found that we can use this agent safely and we also saw evidence in the patients’ blood that the higher doses successfully introduced the vector DNA. In one patient we saw evidence for a very brief period that some of the alpha-1 protein was being produced, but not at a high enough level to be beneficial.”
The findings appeared online today (Nov. 21) in the journal Human Gene Therapy. Physicians injected doses of the virus containing copies of the gene for alpha-1 antitrypsin into the patients’ upper arms. Essentially, the virus is intended to “infect” patients’ cells with replacement genes that will do the necessary work to produce alpha-1 protein. UF scientists have successfully developed the technique in animal models. The next step is to test the therapy with a different version of the adeno-associated virus; about 200 variations of the virus exist in nature.
“We have another version of the virus that appears in animal studies to be close to a thousandfold more potent at making protein,” Flotte said. “That’s very encouraging to us. So the next trial, which has already begun, is to use the new version of the virus and take patients through a similar range of doses, in a very similar scheme, and see if we can maintain the safety while pumping up the efficiency of the protein production.”
In most people, alpha-1 antitrypsin is made in the liver and protects the lungs by counteracting inflammatory products that destroy lung tissue. But about 100,000 Americans have alpha-1 antitrypsin deficiency, according to the Miami-based Alpha-1 Foundation, a national not-for-profit organization devoted to finding a cure. In addition, medical authorities suspect less than 5 percent of affected individuals are diagnosed, often not until they are in their mid- to late-30s, after extensive lung damage occurs. Shortness of breath, wheezing, chronic cough and recurring chest colds are signs of the disease.
It is important that alpha-1 patients avoid cigarette smoke, said Dr. Mark Brantly, a professor of medicine and molecular genetics and microbiology at UF’s College of Medicine who develops clinical research programs aimed at developing therapies for alpha-1 patients. Alpha-1 deficiency can in some patients lead to emphysema and cirrhosis, both progressive diseases that can be fatal.
Alpha-1 patients with symptoms of emphysema can be treated through weekly intravenous injections of alpha-1 protein derived from human plasma. The injections must continue throughout a patient’s life, according to the American Lung Association. It does not cure, but it does appear to slow the progression of this disease.
Patients in the clinical trial—10 men and two women who ranged from 42 to 69—were asked to discontinue their replacement therapy 28 days before receiving the gene therapy. One volunteer who had not been on protein replacement therapy exhibited low-level expression of alpha-1 antitrypsin, which was detectable 30 days after receiving an injection. However, residual levels of alpha-1 antitrypsin from the replacement therapy in the other patients obscured whether the alpha-1 gene had begun to express protein.
“As the authors conclude, the results set up the more interesting approach of using other AAV serotypes more suited for muscle delivery as an alternative with the same transgene in the next trial,” said Richard J. Samulski, a professor of pharmacology and director of the University of North Carolina’s Gene Therapy Center. “These studies are important milestones that allow the potential for gene correction of AAT to advance, as well as the (gene therapy) field in general. They also represent the step-by-step process established by the FDA and research community to ensure that safe and good clinical studies are employed in these early days, and I applaud Terry Flotte and his group for being cautious and thorough in their clinical design.”
The trial is funded by a National Institutes of Health grant, and the Alpha-1 Foundation played a crucial role in helping to build the infrastructure to support the research, Flotte said. UF holds an equity interest in Applied Genetic Technologies Corp., a company formed by UF researchers to develop gene therapies.
Credits: Contact John Pastor, jpastor@vpha.health.ufl.edu.
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