Category Archives: Gene Medicine

16-01-2012 03:57 http://www.telethon.it - Gene therapy is the technique that allows the prevention and treatment of diseases thanks to DNA transfer. In the case of genetic diseases in which one gene is defective or absent, gene therapy basically consists in transferring a functioning version of the gene into a patient's organism so as to remedy the defect. The idea at the basis of gene therapy is a simple one, but implementing it means negotiating an obstacle course. The more delicate aspects include the safety of the procedure, the efficiency of the transfer and the immune system's reaction, which can result in the elimination of the genetically modified cells and annul the effects of the treatment. The first success in gene therapy was achieved in Italy in 2002, thanks to Telethon research, curing the first two children suffering from ADA-SCID and therefore born with no immune defences. Today there are 14 children who have been totally cured and Telethon is working on making gene therapy available for everyone. To this one must add the success achieved by researchers at the Telethon Institute of Genetics and Medicine (TIGEM) at Naples' Second University and at the Children's Hospital in Philadelphia, with the treatment of 12 patients suffering from Leber's congenital amaurosis, the disease of the retina that leads to blindness.

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Gene therapy, a totally Italian success - Video

One of first examples of using personalised medicine for an infectious disease

By Lauren Paxman

Last updated at 3:28 PM on 3rd February 2012

Tuberculosis patients may soon receive treatments specially tailored to their DNA, an international research team from Oxford University, King's College London, Vietnam and the U.S. has revealed.

The idea of personalised medicine is already becoming familiar in the treatment of cancer. But this would be one of the first times where an individual's genetic profile can determine which drug will work best for them for an infectious disease.

The scientists found that people generate an immune response to tuberculosis that is 'too much', 'too little' or 'just right', according to what versions they have of the LTA4H gene.

Goldilocks effect: A scientists checks the results of a DNA test, as research reveals that people generate an immune response to tuberculosis according to what versions they have of the LTA4H gene (file photo)

This indicates that patients are likely to benefit from different drug treatments depending on their LTA4H gene profile.

Furthermore, the researchers show that steroids - used as part of the standard treatment for the most severe form of tuberculosis, TB meningitis - only benefit some patients.

The results of the study, part-funded by the Wellcome Trust, are published in the journal, Cell.

Tuberculosis is a major cause of death worldwide, with an estimated 9.4 million cases and 1.7 million deaths in 2009.

The disease is caused by Mycobacterium tuberculosis bacteria and differs according to where the infection takes hold.

Most TB affects the lungs, but around 40 per cent of cases involve disease elsewhere. In perhaps 1 per cent of cases, TB affects the brain. This form of the disease, TB meningitis, is the most serious. It is hard to diagnose and treat, and even with treatment it is often fatal.

The standard treatment for TB meningitis involves a range of antibiotics to try and kill the bacteria, and the steroid dexamethasone to dampen inflammation – the body's response to tuberculosis infection that can be almost as much of a problem.

An X-ray of a human chest showing pulmonary tuberculosis. Most TB affects the lungs, but around 40 per cent of cases involve disease elsewhere

The new study combines work on zebrafish at the University of Washington, to identify genes and biological pathways involved in the immune response to TB, with clinical research work in collaboration with Pham Ngoc Thach Hospital, the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit in Vietnam.

The scientists identified a gene in zebrafish associated with susceptibility to tuberculosis, which controlled the balance of the inflammatory response.

Variations in the DNA code in this gene could alter different biological pathways, leading either to too much inflammation or too little. Both too much and too little inflammation were problems, allowing the tuberculosis bacteria to thrive and multiply.

The researchers showed that blocking the appropriate biological pathway with drugs could restore just the right level of inflammatory response.

The researchers based in Vietnam then went back to samples from a previous clinical trial in over 500 patients with TB meningitis. They showed changes at a single position in the human LTA4H gene were associated with treatment response.

'Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right"'

Only those having LTA4H genes that led to too much inflammation benefitted from the use of the steroid dexamethasone.

There is some suggestion that the steroid could have an adverse effect for those whose LTA4H genes already lead them to have a reduced inflammatory response, though the result is not statistically significant.

Dr Sarah Dunstan, Head of Human Genetics at Oxford University Vietnam, said: 'It's like a "Goldilocks" gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right".'

She added: 'You are likely to benefit most from a treatment tailored to your own genes.'

Dr Guy Thwaites, of King's College London and who lead the clinical study in Vietnam on a Wellcome Trust Fellowship, says: 'This is a fundamental discovery. It is now possible to think about the use of simple but rapid genetic tests to determine how people will respond to tuberculosis infection and whether they would benefit from steroids.

'The findings could apply much more widely than just in TB meningitis, or other forms of tuberculosis,' adds Dr Thwaites.

'Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.

Professor Jeremy Farrar, who leads the Oxford University Clinical Research Unit in Vietnam, said: 'The idea that a patient's genes can determine what treatment they will benefit from is pretty novel outside of cancer.

'Nothing like this has been seen before in infectious disease.'

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'Goldilocks' gene used to find drug treatment that is 'just right' for TB patients

20-01-2012 17:36 Dr. James Wilson is a professor in the department of pathology and laboratory medicine, and the director of the gene therapy program, at the University of Pennsylvania. He is also the editor of Human Gene Therapy, a peer-reviewed journal published by Mary Ann Liebert, Inc. During this interview with GEN, Dr. Wilson discusses his concept of a disruptive technology and explains why he believes gene therapy falls into this category. In addition to this SKYPE interview, Dr. Wilson further elaborated on his view of gene therapy as a disruptive technology in a column in the January 2012 issue of Human Gene Therapy which can be viewed here: online.liebertpub.com

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James Wilson, MD, Ph.D., on Gene Therapy as a Disruptive Technology - Video

This is one of the first examples in infectious disease of where an individual's genetic profile can determine which drug will work best for them – the idea of personalised medicine that is gradually becoming familiar in cancer medicine.

The scientists found that people generate an immune response to tuberculosis that is 'too much', 'too little' or 'just right', according to what versions they have of the LTA4H gene.

The findings indicate that patients are likely to benefit from different drug treatments depending on their LTA4H gene profile.

Furthermore, the researchers show that steroids used as part of the standard treatment for the most severe form of tuberculosis, TB meningitis, only benefit some patients.

The results of the study, part-funded by the Wellcome Trust, are published in the journal Cell.

Tuberculosis is a major cause of death worldwide, with an estimated 9.4 million cases and 1.7 million deaths in 2009. The disease is caused by Mycobacterium tuberculosis bacteria and differs according to where the infection takes hold. Most TB affects the lungs, but around 40% of cases involve disease elsewhere. In perhaps 1% of cases, TB affects the brain. This form of the disease, TB meningitis, is the most serious. It is hard to diagnose and treat, and even with treatment it is often fatal.

The standard treatment for TB meningitis involves a range of antibiotics to try and kill the bacteria, and the steroid dexamethasone to dampen inflammation – the body's response to tuberculosis infection that can be almost as much of a problem.

The new study combines work in zebrafish at the University of Washington, Seattle to identify genes and biological pathways involved in the immune response to TB, with clinical research work in collaboration with Pham Ngoc Thach Hospital, the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit in Vietnam.

The scientists identified a gene in zebrafish associated with susceptibility to tuberculosis, which controlled the balance of the inflammatory response. Variations in the DNA code in this gene could alter different biological pathways, leading either to too much inflammation or too little. Both too much and too little inflammation were problems, allowing the tuberculosis bacteria to thrive and multiply.

The researchers showed that blocking the appropriate biological pathway with drugs could restore just the right level of inflammatory response.

The researchers based in Vietnam then went back to samples from a previous clinical trial in over 500 patients with TB meningitis. They showed changes at a single position in the human LTA4H gene were associated with treatment response.

Only those having LTA4H genes that led to too much inflammation benefitted from the use of the steroid dexamethasone.

There is some suggestion that the steroid could have an adverse effect for those whose LTA4H genes already lead them to have a reduced inflammatory response, though the result is not statistically significant.

'It's like a "Goldilocks" gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right",' explains Dr Sarah Dunstan Head of Human Genetics of Oxford University Vietnam. 'You are likely to benefit most from a treatment tailored to your own genes.'

Dr Guy Thwaites of King's College London and who lead the clinical study in Vietnam on a Wellcome Trust Fellowship says: 'This is a fundamental discovery. It is now possible to think about the use of simple but rapid genetic tests to determine how people will respond to tuberculosis infection and whether they would benefit from steroids.'

'The findings could apply much more widely than just in TB meningitis, or other forms of tuberculosis,' adds Dr Thwaites. 'Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.'

'This study highlights the power of really good clinical research supported through Wellcome Trust Fellowships and linked with some of the very best scientists in the world in Vietnam and the USA, which can bring immediate benefits to patients and also point the way to develop better, more targeted drugs to treat people with tuberculosis in the future,' says Professor Jeremy Farrar who leads the Oxford University Clinical Research Unit in Vietnam. 'The idea that a patient's genes can determine what treatment they will benefit from is pretty novel outside of cancer. Nothing like this has been seen before in infectious disease. Now we need to see if we can use this to help patients with this devastating disease'

More information: 'Host genotype-specific therapies can optimise the inflammatory response to mycobacterial infections', by David Tobin et al., Cell (2012).

Provided by King's College London (news : web)

Original post:
'Goldilocks' gene could determine best treatment for tuberculosis patients

Newswise — (SALT LAKE CITY)—A team of scientists from the University of Utah and the University of California at San Francisco has discovered that the mutation of a gene encoding a ketone body transporter triggers accumulation of fat and other lipids in the livers of zebrafish. This discovery, published in the Feb. 1, 2012, issue of Genes & Development, reveals that transport of ketone bodies out of the liver is a critical step in energy metabolism during fasting. It also provides a new approach for studying the development of fatty liver disease in humans.

Nonalcoholic fatty liver disease (NAFLD), or abnormally high accumulation of lipids in the liver, is the most common cause of chronic liver disease worldwide. Lipids are a broad group of molecules that include fats, triglycerides, and cholesterol. In some people, NAFLD causes no complications, but in others, excess fat in the liver can lead to inflammation or development of scar tissue, resulting in permanent liver damage or even liver failure. NAFLD may also increase the risk of heart disease in people who are overweight or obese.

The increasing prevalence of NAFLD in the United States is due, in large part, to the obesity epidemic. It is estimated that more than 6 million U.S. children already have fatty liver disease.

“Currently, there are a limited number of treatment options for decreasing excess fat in the liver and there are no methods for reversing damage to liver tissue due to NAFLD,” says Amnon Schlegel, M.D., Ph.D., investigator in the University of Utah Molecular Medicine program, assistant professor of internal medicine at the University of Utah School of Medicine, and senior author on the study. “By identifying and characterizing novel genes that regulate accumulation of lipids in the liver, we may be able to gain new insight into the physiological processes that lead to NAFLD.”

Previous research has shown that many of the proteins known to control lipid metabolism in humans are also present in zebrafish. Schlegel and his colleagues began by identifying a zebrafish mutant known as red moon (rmn), which developed abnormal lipid accumulation in liver cells, without evidence of associated liver inflammation or liver damage, when exposed to fasting conditions. Schlegel and his colleagues then used a molecular genetic technique called positional cloning to isolate the gene disrupted by the rmn mutation. They found that the rmn mutation inactivated slc16a6a, a gene thought to encode a protein required in the transport of nutrients during fasting.

“Until now, the activity of the Slc16a6a protein has not been functionally characterized in any organism,” says Schlegel, who’s also an adjunct assistant professor of biochemistry at the U medical school. “Our studies indicate that Slc16a6a is a protein involved in the transport of ?-hydroxybutyrate.”

?-hydroxybutyrate is a ketone body, a compound that is produced in the liver when blood glucose is low and fatty acids are broken down for energy. During periods of fasting, most body tissues can use fatty acids as an energy source, but the brain relies on ?-hydroxybutyrate and other ketone bodies for fuel. Schlegel and his colleagues discovered that, in rmn mutants deprived of nutrition, loss of Slc16a6a function disabled secretion of ketone bodies from liver cells and increased lipid accumulation in the liver. They also found that introducing the human form of the SLC16A6 protein into rmn mutant livers restored ketone body secretion.

“Our research has uncovered a previously unrecognized, but critical step, in the complicated physiology of fasting,” says Schlegel. “We still don’t know whether altered fasting liver metabolism influences the development of NAFLD, but knowing that Slc16a6a is required for secretion of ketone bodies from liver cells during fasting may have implications for our understanding and treatment of other medical conditions where ketone bodies play a role. These conditions include uncontrolled type 1 diabetes, obesity, and childhood metabolic disorders caused by defects in fatty acid metabolism.”

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Gene Mutation Linked to Inappropriate Lipid Buildup in Liver

EXTON, Pa.--(BUSINESS WIRE)-- Fibrocell Science, Inc. (OTCBB: FCSC.OB - News), a biotechnology company focused on the development of autologous (personalized) cell therapies for aesthetic, medical and scientific applications, announces that the June 2011 FDA approval of LAVIV™ (azficel-T) for the improvement of the appearance of “smile line” wrinkles was named the #3 top story of 2011 in cell and gene therapy and regenerative medicine at The 2012 Cell & Gene Therapy Forum in Washington, D.C. The award was voted by The Cell & Gene Therapy Forum survey responders, comprised of Director-level and above leaders in the cell and gene therapy and regenerative medicine industry. The meeting is organized annually by Phacilitate (www.phacilitate.co.uk), a specialist in the organization of exclusive events (www.phacilitate.co.uk/cgt) for leaders from the life sciences community.

“We are delighted and honored that industry leaders attending The 2012 Cell & Gene Therapy Forum have recognized the FDA approval of LAVIV and we hope we continue to impress the industry with our innovations in upcoming years,” said David Pernock, Fibrocell Science Chairman and CEO. “Fibrocell Science is committed to exploring the full therapeutic potential of our personalized fibroblast cellular treatment for use in diverse medical and aesthetic applications.”

About LAVIV™

Approved on June 21, 2011, LAVIV™ (azficel-T) is the first and only personalized cell therapy approved by the FDA for aesthetic use. It is indicated for the improvement of the appearance of moderate to severe nasolabial fold wrinkles (“smile lines”), in adults. The patented technology behind LAVIV is an advanced process that extracts a person’s collagen-producing fibroblast cells from a small skin sample and multiplies them in the Fibrocell Science lab. (The collagen produced by fibroblast cells helps give skin its tone, structure and overall quality. As people get older, the number of fibroblasts decreases and collagen breaks down, resulting in wrinkles and lost skin tone. ) LAVIV is the resulting formulation of a person’s own fibroblast cells, which is then injected into “smile line” wrinkles.

LAVIV is now available in major metropolitan areas throughout the U.S., exclusively through board-certified dermatologists and plastic surgeons who have been trained by Fibrocell Science on the treatment process. A list of trained and certified physicians is available at http://www.mylaviv.com and will be continually updated as new physicians are trained and begin offering LAVIV in their practice.

Important Safety Information About LAVIV™ (azficel-T)

LAVIV is made especially for you from your own skin cells. Using someone else’s cells can cause a serious reaction. Prior to injection, confirm with your physician that your information on the LAVIV vial is correct.

The most common side effects of LAVIV are at the injection-site, including redness, bruising, swelling, pain, bleeding, lumps, irritation, and itchiness. In clinical trials with LAVIV, most injection-site adverse reactions resolved within one week and most required no treatment.

Your health care provider will help you to decide whether you are a candidate for LAVIV and may help you avoid some of the adverse reactions from LAVIV. Before getting LAVIV, tell your healthcare provider if you have any medical problems including allergic reactions to any drugs or food, bleeding disorders or take blood-thinning medicines like aspirin, ibuprofen, or coumadin, keloids or excessive scarring, skin cancer or any malignancy, genetic disorders affecting your skin, immune problems or take medicines that affect your immune system, or any other illness or medical problem. The full Prescribing Information for LAVIV includes additional warnings about adverse reactions that occurred in less than 1% of patients following LAVIV treatment in clinical trials. Talk to your healthcare provider about these warnings.

Please tell your healthcare provider if you are allergic to the antibiotics amphotericin or gentamicin, bovine materials (products made from cattle), or dimethyl sulfoxide (DMSO). Do not use LAVIV if you have a skin infection on your face because LAVIV treatment can make the infection worse.

For more information about LAVIV, please see the Full Prescribing Information at http://www.mylaviv.com.

About Fibrocell Science, Inc.

Fibrocell Science, Inc. (OTCBB: FCSC.OB - News) is a biotechnology company focused on the development of regenerative cell therapy for aesthetic, medical and scientific applications. Fibrocell Science is committed to advancing the scientific, medical and commercial potential of autologous skin and tissue, as well as its innovative cellular processing technology and manufacturing excellence. For additional information, please visit http://www.fibrocellscience.com.

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Fibrocell Science, Inc. Announces Recognition for LAVIV™ (azficel-T) at The 2012 Cell & Gene Therapy Forum, Washington ...