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13-Jan-2014

Contact: Mary Martialay martim12@rpi.edu 518-276-2146 Rensselaer Polytechnic Institute

Troy, N.Y. A team including researchers from Rensselaer Polytechnic Institute have discovered that a specific gene may play a major role in the development of a life-threatening birth defect called congenital diaphragmatic hernia, or CDH, which affects approximately one out of every 3,000 live births.

The hallmark of CDH is a rupture of the diaphragm that allows organs found in the lower abdomen, such as the liver, spleen, and intestines, to push their way into the chest cavity. The invading organs crowd the limited space and can lead to abnormal lung and heart development or poor heart and lung function, which, depending on the severity of the condition, can cause disability or death.

In a paper published recently in the Journal of Clinical Investigation, lead authors at the University of Georgia, along with colleagues from the Rensselaer and the University of California at San Diego, demonstrated for the first time that the gene NDST1 plays a significant role in the proper development of the diaphragm, and that abnormal expression of the gene could lead to CDH.

"We now have a really good picture of this abnormality in mice, and we suspect it is very similar in humans," said Fuming Zhang, a research professor in the laboratory of Robert J. Linhardt, the Ann and John H. Broadbent Jr '59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering, and a member of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer. "What this gives us is a total view, from the genetic level, to the molecular level, to the cellular or tissue level, to something that a physician would see a hernia in a newborn."

The discovery began with the observation that mice bred without the NDST1 gene, which produces the eponymous NDST1 enzyme, are more likely to develop CDH than ordinary mice. The enzyme NDST1 is one of four isoforms a group of molecules that are chemically similar, but show subtle functional differences. In mice lacking the NDST1 gene, and therefore the NDST1 enzyme, nature substitutes with an NDST1 isoform (NDST2, NDST3, and NDST4), but the results like substitutions in cooking are noticeable.

In the absence of NDST1, blood vessels supplying the developing diaphragm muscles formed inconsistently, leading to weak points in the muscle tissues that make them prone to hernia. Researchers knew that the NDST1 enzyme is involved in the synthesis of heparan sulfate, so the group turned to the Linhardt's research team at Rensselaer experts in heparan sulfate and glycosaminoglycan analysis to pinpoint the biochemical basis for the abnormality.

"There are two molecules in the interaction that leads to proper blood vessel formation in the diaphragm NDST1 biosynthesized heparan sulfate and the protein SLIT3," said Zhang. "In order for those interactions to be successful, and for blood vessels to form properly, everything must be accomplished within a specific time frame and having a specific structure. We were able to investigate the interactions between the two."

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Congenital diaphragmatic hernia traced from genetic roots to physical defect

The Slow and Steady Revival of Gene Therapy
The Slow and Steady Revival of Gene Therapy.

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The Slow and Steady Revival of Gene Therapy - Video

By Steven Reinberg HealthDay Reporter

THURSDAY, Jan. 9, 2014 (HealthDay News) -- A new, preliminary treatment involving triple-gene therapy appears safe and effective in helping to control motor function in Parkinson's disease patients, according to new research.

The therapy, called ProSavin, works by reprogramming brain cells to produce dopamine, the chemical essential for controlling movement, the researchers said. Lack of dopamine causes the tremors, limb stiffness and loss of balance that patients with the neurodegenerative disease suffer.

"We demonstrated that we are able to safely administer genes into the brain of patients and make dopamine, the missing agent in Parkinson's patients," said researcher Kyriacos Mitrophanous, head of research at Oxford BioMedica in England, the company that developed the therapy and funded the study.

ProSavin also helps to smooth out the peaks and valleys often produced by the drug levodopa, the current standard treatment, Mitrophanous said.

The treatment uses a harmless virus to deliver three dopamine-making genes directly to the area of the brain that controls movement, he explained. These genes are able to convert non-dopamine-producing nerve cells into dopamine-producing cells.

Although the study results are promising, the researchers suggest they should be "interpreted with caution" because the perceived benefits fall into the range of "placebo effect" seen with other clinical trials.

Hoping to improve on their results, the researchers have since re-engineered the therapy. "We have a new version which makes more dopamine in patients, and this new version is undergoing safety studies before we initiate trails in patients," he said.

Experts reacted positively but cautiously to the findings, which were published online Jan. 10 in The Lancet. While the treatment seems safe, its potential as a replacement for current therapy still must be proved, they noted.

"The ProSavin study was a positive and important first step for a potential gene therapy for Parkinson's disease," said Dr. Michael Okun, national medical director at the National Parkinson Foundation. "The results of this preliminary study revealed a promising safety profile, and it will be interesting to observe longer-term benefits and how ProSavin will compare to other therapies such as deep brain stimulation."

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Gene therapy may hold promise for advanced Parkinson's disease

One of the main problems with gene therapy is that there is a very low possibility that the plasmid with the new piece of DNA will be correctly inserted into the DNA in the human DNA for several reasons: a) The host cell (bacteria, virus or liposome which has been more recently used) has difficulties in travelling successfully to the human cell in the specific organ or tissue. (e.g.: lungs) If the host cell is a virus, the body can easily destroy them because as the virus touches the surface of the membrane, antibodies will attack it as the cell membrane has glycocalyx which are carbohydrates that can recognize molecules or cells that are not common in the body.

b) It is also because the new piece of DNA has to enter the DNA strand in the correct place. Usually, in a part where the bases are not coding for any protein.

Another negative effect might be that when the new piece of DNA enters the human DNA strand, it can have a terrorific effect on it. This happens when it successfully enters the DNA strand but it replaces or simply disrupts the sequence of amino acids which code for an important protein. (This has occured in the 1980s with the X-SCID disease)

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Gene Therapy - the impossible dream?
Gene Therapy - the impossible dream?

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The ProSavin treatment uses an inert virus to carry corrective genes directly into the striatum region of the brain that controls movement.

It is designed to convert ordinary nerve cells into factories for making dopamine, the signalling chemical that is lost in Parkinson's patients.

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Lack of dopamine activity leads to the common Parkinson's symptoms of tremor, slow movement and rigidity.

The trial tested the safety, tolerability and effectiveness of three different doses of ProSavin in 15 patients aged 48 to 65 with advanced Parkinson's disease who were not responding to conventional treatments.

A standard system of rating motor functions was used, covering speech, tremors, rigidity, finger taps, posture, gait, and slow movement. Lower scores indicated better muscle control and co-ordination.

Significant score improvements were seen after six months and a year in all patients not taking medication.

Reporting their findings in The Lancet medical journal, the researchers led by Professor Stephane Palfi, from Les Hopitaux Universitaires Henri-Mondor in Creteil, France, wrote: "ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients."

They stressed that, while promising, the results at this stage were still limited and should be "interpreted with caution".

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Gene therapy for Parkinson's produces promising results in first patient trial

10/01/2014 - 07:15:45Back to World Home

A gene therapy for Parkinsons disease has produced promising results in its first patient trial, say researchers.

The ProSavin treatment uses an inert virus to carry corrective genes directly into the striatum region of the brain that controls movement.

It is designed to convert ordinary nerve cells into factories for making dopamine, the signalling chemical that is lost in Parkinsons patients.

Lack of dopamine activity leads to the common Parkinsons symptoms of tremor, slow movement and rigidity.

The trial tested the safety, tolerability and effectiveness of three different doses of ProSavin in 15 patients aged 48 to 65 with advanced Parkinsons disease who were not responding to conventional treatments.

A standard system of rating motor functions was used, covering speech, tremors, rigidity, finger taps, posture, gait, and slow movement. Lower scores indicated better muscle control and co-ordination.

Significant score improvements were seen after six months and a year in all patients not taking medication.

Reporting their findings in The Lancet medical journal, the researchers led by Professor Stephane Palfi, from Les Hopitaux Universitaires Henri-Mondor in Creteil, France, wrote: ProSavin was safe and well tolerated in patients with advanced Parkinsons disease. Improvement in motor behaviour was observed in all patients.

They stressed that, while promising, the results at this stage were still limited and should be interpreted with caution.

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Gene therapy provides hope for Parkinson's sufferers

PARIS: A closely-watched prototype therapy to inject corrective genes into the brain to treat Parkinson's disease has cleared an important safety hurdle, doctors said Friday.

Tested on 15 volunteers with an advanced form of the degenerative nerve disease, the technique proved safe and the results were encouraging, they said.

The experiment aims to reverse the lack of a brain chemical called dopamine, which is essential for motor skills.

It entails tucking three genes into a disabled horse virus of the family lentiviruses.

The modified virus is then injected directly into a specialised area of the brain, where it infiltrates cells. In doing so, it delivers corrective pieces of DNA, prompting defective brain cells to once again start producing dopamine.

Called ProSavin, the British-designed treatment was authorised for tests on humans after it was tried on lab monkeys.

It is being closely watched by specialists to see if it works better than conventional therapies -- the veteran drug levodopa or electrical stimulation of the brain -- or another experimental gene technique which uses a modified cold virus.

French neurosurgeon Stephane Palfi, who led the early-stage trial published in The Lancet, said 15 patients aged 48-65 were given the genes in one of three doses.

They developed better coordination and balance, had less muscle twitching and improved speech.

Assessed at least 12 months after the injection, "motor symptoms remained improved in all the patients," Palfi said.

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Novel gene therapy for Parkinson's clears hurdle

Jan. 8, 2014 Currently, doctors use chromosome markers and gene mutations to determine the best treatment for a patient with acute myeloid leukemia (AML). But a new study suggests that a score based on seven mutated genes and the epigenetic changes that the researchers discovered were present might help guide treatment by identifying novel subsets of patients.

The findings, published in the Journal of Clinical Oncology, come from a study led by researchers at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James).

The epigenetic change used in the study is DNA methylation. It involves the addition of methyl groups to DNA, which can reduce or silence a gene's activity, or expression. Abnormal DNA methylation alters normal gene expression and often plays an important role in cancer development.

Overall, the findings suggest that patients with a low score -- indicating that one or none of the seven genes is overexpressed in AML cells -- had the best outcomes, and that patients with high scores -- that is, with six or seven genes highly expressed -- had the poorest outcomes.

"To date, disease classification and prognostication for AML patients have been based largely on chromosomal and genetic markers," says principal investigator Clara D. Bloomfield, MD, Distinguished University Professor, Ohio State University Cancer Scholar and Senior Adviser.

"Epigenetic changes that affect gene expression have not been considered. Here we show that epigenetic changes in previously recognized and prognostically important mutated genes can identify novel patient subgroups, which might better help guide therapy," says Bloomfield, who is also the William Greenville Pace III Endowed Chair in Cancer Research at Ohio State.

The seven-gene panel was identified in 134 patients aged 60 and older with cytogenetically normal acute myeloid leukemia (CN-AML) who had been treated on Cancer and Leukemia Group B (CALGB)/Alliance clinical trials.

The researchers computed a score based on the number of genes in the panel that were highly expressed in patients' AML cells, and retrospectively tested the score in two groups of older patients (age 60 and up) and two groups of younger patients (age 59 and under).

Patients with a low score -- indicating that one or none of the seven genes is overexpressed -- had the best outcomes. Patients with high scores -- that is, with six or seven genes highly expressed -- had the poorest outcomes.

"For this seven-gene panel, the fewer highly expressed genes, the better the outcome," says first author Guido Marcucci, MD, professor of medicine and the associate director for translational research at the OSUCCC -- James. "In both younger and older patients, those who had no highly expressed genes, or had one highly expressed gene had the best outcomes."

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AML score combining genetic, epigenetic changes might help guide therapy

A new biotech company with formidable founders and funding has joined a lawsuit that accuses the University of Pennsylvania of misappropriating key technology behind its breakthrough therapy for leukemia.

The company, Juno Therapeutics Inc., was launched early last month by three major cancer institutes - including Memorial Sloan-Kettering Cancer Center - with a massive $120 million investment from leading venture capital firms.

Juno's debut ups the ante in the high-stakes race to commercialize novel therapies that use the patient's immune "T cells" to fight cancer. While the approach is still highly experimental - it has worked primarily against certain blood malignancies - results of early clinical testing at Penn and other leading centers have electrified researchers, the biopharma industry, and patients.

Indeed, Penn entered a much-publicized partnership with the global pharmaceutical giant Novartis in 2012, based on results from just the first three leukemia patients.

Penn's T-cell therapy and its development deal are at the heart of the lawsuit that Juno Therapeutics has joined.

Juno, based in Seattle, is a partnership of Sloan-Kettering, Fred Hutchinson Cancer Research Center, and Seattle Children's Research Institute. Last month, Juno signed a licensing agreement to commercialize T-cell technology patented by St. Jude Children's Research Hospital in Memphis, according to legal papers.

The technology involves a "chimeric antigen receptor," or CAR - a synthetic genetic structure that programs the patient's T cells to target and attack cancer.

St. Jude is suing Penn, accusing the university of breaching an agreement to share St. Jude's CAR and infringing on St. Jude's patent.

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Biotech firm joins suit against Penn's cancer therapy

Sultans of Swing - Gene Therapy and the Chromosomes
Cover of Dire Straits #39; classic #39;Sultans of Swing #39;, performed by Gene Therapy and the Chromosomes at Hayfield Con Club on Saturday 28th Dec, 2013.

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Jan. 1, 2014 A novel breast-cancer therapy that partially reverses the cancerous state in cultured breast tumor cells and prevents cancer development in mice, could one day provide a new way to treat early stages of the disease without resorting to surgery, chemotherapy or radiation, a multi-institutional team led by researchers from the Wyss Institute of Biologically Inspired Engineering at Harvard University reported January 1 in Science Translational Medicine.

The therapy emerged from a sophisticated effort to reverse-engineer gene networks to identify genes that drive cancer. The same strategy could lead to many new therapies that disable cancer-causing genes no current drugs can stop, and it also can be used to find therapies for other diseases.

"The findings open up the possibility of someday treating patients who have a genetic propensity for cancer, which could change people's lives and alleviate great anxiety," said Don Ingber, M.D., Ph.D., Wyss Institute Founding Director. "The idea would be start giving it early on and sustain treatment throughout life to prevent cancer development or progression." Ingber is also the Judah Folkman Professor of Vascular Biology at Boston Children's Hospital and Harvard Medical School, and Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences.

Between breast self-exams, mammograms, MRIs, and genetic tests, more women than ever are undergoing early tests that reveal precancerous breast tissue. That early diagnosis could potentially save lives; however, few of those lesions go on to become tumors and doctors have no good way of predicting which ones will. As a result, many women currently undergo surgery, chemotherapy and radiation who might never develop the disease. What's more, some women with a high hereditary risk of breast cancer have chosen to undergo preemptive mastectomies.

A therapy that heals rather than kills cancerous tissue could potentially help all these patients, as well as men who develop the disease. But to date the only way to stop cancer cells has been to kill them. Unfortunately, the treatments that accomplish that, including surgery, chemotherapy, and radiation therapy, often damage healthy tissue, causing harsh side effects.

The Wyss Institute researchers thought they could do better by spotting new genes that drive breast cancer and developing targeted genetic therapies to block them. First they had to identify the culprit genes among the thousands that are active in a cell at any moment. Molecular biologists typically convict these culprits through guilt by association; for example, when looking for cancer-causing genes, they search for individual genes that become active as cancer develops. But because genes in cells work in complex networks, that approach has led to some false convictions, with innocent genes being fingered for crimes they did not commit.

To improve the odds of finding the real culprits, Ingber teamed up with Wyss Institute Core Faculty member Jim Collins, Ph.D., a systems biology expert who has developed a sophisticated mathematical and computational method to reverse-engineer bacterial gene networks. Collins is a Core Faculty member at the Wyss Institute for Biologically Inspired Engineering and the William F. Warren Distinguished Professor at Boston University, where he leads the Center of Synthetic Biology.

First, Hu Li, Ph.D. a former Wyss Institute postdoctoral fellow who is now an Assistant Professor of Systems Pharmacology at the Mayo Clinic, honed the computational network to work for the first time on the more complex gene networks of mice and humans. The refined method helped the scientists spot more than 100 genes that acted suspiciously just before milk-duct cells in the breast begin to overgrow. The team narrowed their list down to six genes that turn other genes on or off, and then narrowed it further to a single gene called HoxA1 that had the strongest statistical link to cancer.

The researchers wanted to know if blocking the HoxA1 gene could reverse cancer in lab-grown cells from mouse milk ducts. Amy Brock, Ph.D., a former Wyss Institute postdoctoral fellow who is now an Assistant Professor of Biomedical Engineering at the University of Texas, Austin, grew healthy mouse or human mammary-gland cells in a nutrient-rich, tissue-friendly gel. Healthy cells ensconced in the gel formed hollow spheres of cells akin to a normal milk duct. But cancerous cells, in contrast, packed together into solid, tumor-like spheres.

Brock treated cancerous cells with a short piece of RNA called a small interfering RNA (siRNA) that blocks only the HoxA1 gene. The cells reversed their march to malignancy, stopping their runaway growth and forming hollow balls as healthy cells do. What's more, they specialized as if they were growing in healthy tissue.

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Novel non-invasive therapy prevents breast cancer formation in mice

Amid somewhat of a renaissance in drug development for orphan diseases, another gene therapy company announced funding today for a potential treatment for a rare neurodegenerative condition called Friedreichs ataxia (FRDA).

Agilis Biotherapeutics said its raised $8 million and will work with synthetic biology company Intrexon Corp. to develop gene therapies and genetically modified cell therapies for FRDA. Whereas current treatments focus on minimizing symptoms of the disease, the partners expect their drugs to be able to target the underlying disease mechanisms.

FRDA is caused by a genetic defect that results in limited production of frataxin, a protein thought to help assemble clusters of iron and sulfur molecules in cells that are necessary for the function of many other proteins. When cells are deficient of frataxin, they may not function properly, causing damage to the nervous system and problems with movement. Most people with the disease become wheelchair-bound within two decades of diagnosis, and many die early due to weakened heart muscles.

The goal for Agilis and Intrexon is to use Intrexons gene switch technology to develop drugs that will repair the defective gene and enable increased production of the frataxin protein. Under the options of the deal, Agilis and Intrexon could add another rare genetic disease to the collaboration.

Ahead of the pair in developing new treatments for the rare disease are ViroPharma, which is in Phase 1 development of a small molecule drug for FA, and Edison Phamaceuticals, which is conducting a Phase 2 study of its drug.

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Rare disease biotech picks up $8M, drug development partner for DNA-based therapies

Gene therapy introduces or alters genetic material to compensate for a genetic mistake that causes disease. It is hoped that gene therapy can treat or cure diseases for which no other effective treatments are available. However, many unique technical and ethical considerations have been raised by this new form of treatment, and several levels of regulatory committees have been established to review each gene therapy clinical trial prior to its initiation in human subjects. Ethical considerations include deciding which cells should be used, how gene therapy can be safely tested and evaluated in humans, what components are necessary for informed consent, and which diseases and/or traits are eligible for gene therapy research.

Germ Line Versus Somatic Cell Gene Therapy

Virtually all cells in the human body contain genes, making them potential targets for gene therapy. However, these cells can be divided into two major categories: germ line cells (which include sperm and eggs) and somatic cells. There are fundamental differences between these cell types, and these differences have profound ethical implications.

Gene therapy using germ line cells results in permanent changes that are passed down to subsequent generations. If done early in embryologic development, such as during preimplantation diagnosis and in vitro fertilization, the gene transfer could also occur in all cells of the developing embryo. The appeal of germ line gene therapy is its potential for offering a permanent therapeutic effect for all who inherit the target gene. Successful germ line therapies introduce the possibility of eliminating some diseases from a particular family, and ultimately from the population, forever. However, this also raises controversy. Some people view this type of therapy as unnatural, and liken it to "playing God." Others have concerns about the technical aspects. They worry that the genetic change propagated by germ line gene therapy may actually be deleterious and harmful, with the potential for unforeseen negative effects on future generations.

Somatic cells are nonreproductive. Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. In other words, the therapeutic effect ends with the individual who receives the therapy. However, this type of therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived. Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over the course of the individual's life span are required to maintain the therapeutic effect. Transporting the gene to the target cells or tissue is also problematic. Regardless of these difficulties, however, somatic cell gene therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy, cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero, potentially correcting or treating a life-threatening disorder that may significantly impair a baby's health or development if not treated before birth.

Research Issues

Scientific and ethical discussions about gene therapy began many years ago, but it was not until 1990 that the first approved human gene therapy clinical trial was initiated. This clinical trial was conducted on a rare autoimmune disorder called severe combined immune deficiency. This therapy was considered successful because it greatly improved the health and well-being of the few individuals who were treated during the trial. However, the success of the therapy was tentative, because along with the gene therapy the patients also continued receiving their traditional drug therapy. This made it difficult to determine the true effectiveness of the gene therapy on its own, as distinct from the effects of the more traditional therapy.

Measuring the success of treatment is just one challenge of gene therapy. Research is fraught with practical and ethical challenges. As with clinical trials for drugs, the purpose of human gene therapy clinical trials is to determine if the therapy is safe, what dose is effective, how the therapy should be administered, and if the therapy works. Diseases are chosen for research based on the severity of the disorder (the more severe the disorder, the more likely it is that it will be a good candidate for experimentation), the feasibility of treatment, and predicted success of treatment based on animal models. This sounds reasonable. However, imagine you or your child has a serious condition for which no other treatment is available. How objective would your decision be about participating in the research?

Informed Consent

A hallmark of ethical medical research is informed consent. The informed consent process educates potential research subjects about the purpose of the gene therapy clinical trial, its risks and benefits, and what is involved in participation. The process should provide enough information for the potential research subjects to decide if they want to participate. It is important both to consider the safety of the experimental treatment and to understand the risks and benefits to the subjects. In utero gene therapy has the added complexity of posing risks not only to the fetus, but also to the pregnant woman. Further, voluntary consent is imperative. Gene therapy may be the only possible treatment, or the treatment of last resort, for some individuals. In such cases, it becomes questionable whether the patient can truly be said to make a voluntary decision to participate in the trial.

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Gene Therapy: Ethical Issues: Information from Answers.com

Neurotrophin Gene Therapy for Repair of the Injured Spinal Cord
George M. Smith, PhD | Shriners Hospitals Pediatric Research Center and Temple University 2013 Rare Neuro-Immunologic Disorders Symposium Repair and Recovery, Today and in the Future | October...

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Neurotrophin Gene Therapy for Repair of the Injured Spinal Cord - Video

Gene therapy is a novel approach to treat, cure, or ultimately prevent disease by changing the expression of a persons genes. Gene therapy is in its infancy, and current therapies are primarily experimental, with most human clinical trials still in the research stages.

How does gene therapy work? Genes are composed of DNA that carries information needed to make proteins the building blocks of our bodies. Variations in the DNA sequence or code of a gene are called mutations, which often are harmless but sometimes can lead to serious disease. Gene therapy treats disease by repairing dysfunctional genes or by providing copies of missing genes.

To reverse disease caused by genetic damage, researchers isolate normal DNA and package it into a vehicle known as a vector, which acts as a molecular delivery truck. Vectors composed of viral DNA sequences have been used successfully in human gene therapy trials. Doctors infect a target cell usually from a tissue affected by the illness, such as liver or lung cellswith the vector. The vector unloads its DNA cargo, which then begins producing the proper proteins and restores the cell to normal. Problems can arise if the DNA is inserted into the wrong place in the genome. For example, in rare instances the DNA may be inserted into a regulatory gene, improperly turning it on or off, leading to cancer.

Researchers continue to optimize viral vectors as well as develop non-viral vectors that may have fewer unexpected side effects. Nonviral gene delivery involves complexing DNA with an agent that allows it to enter a cell nonspecifically. DNA delivered in this manner is usually expressed for only a limited time because it rarely integrates into the host cell genome.

Initial efforts in gene therapy focused on delivering a normal copy of a missing or defective gene, but current programs are applying gene delivery technology across a broader spectrum of conditions. Researchers are now utilizing gene therapy to :

What diseases could be treated with gene therapy? About 4,000 diseases have been traced to gene disorders. Current and possible candidates for gene therapy include cancer, AIDS, cystic fibrosis, Parkinsons and Alzheimers diseases, amyotrophic lateral sclerosis (Lou Gehrig's disease), cardiovascular disease and arthritis.

In cases such as cystic fibrosis or hemophilia, disease results from a mutation in a single gene. In other scenarios like hypertension or high cholesterol, certain genetic variations may interact with environmental stimuli to cause disease.

Has gene therapy been successfully used in humans? Gene therapy is likely to be most successful with diseases caused by single gene defects. The first successful gene therapy on humans was performed in 1990 by researchers at the National Institutes of Health. The therapy treated a four-year-old child for adenosine deaminase (ADA) deficiency, a rare genetic disease in which children are born with severe immunodeficiency and are prone to repeated serious infections.

Since 1990, gene therapy had been tested in human clinical trials for treating such diseases as severe combined immunodeficiency disease (SCID), cystic fibrosis, Canavan's disease, and Gaucher's disease. In 2003, more than 600 gene therapy clinical trials were under way in the United States but only a handful of these are in advanced stages. SCID, in which children lack natural defenses against infection and can only survive in isolated environments, remains the only disease cured by gene therapy.

Are genetic alterations from gene therapy passed on to children? Gene therapy can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene therapy, the patients genome is changed, but the change is not passed along to the next generation. In germline gene therapy, the patients egg or sperm cells are changed with the goal of passing on changes to their offspring. Existing gene therapy treatments and experiments are all somatic.

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Gene Therapy - American Medical Association

Please choose from the following list of questions for information about gene therapy, an experimental technique that uses genetic material to treat or prevent disease.

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Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patients cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including:

Replacing a mutated gene that causes disease with a healthy copy of the gene.

Inactivating, or knocking out, a mutated gene that is functioning improperly.

Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures.

MedlinePlus from the National Library of Medicine offers a list of links to information about genes and gene therapy.

Educational resources related to gene therapy are available from GeneEd.

The Genetic Science Learning Center at the University of Utah provides an interactive introduction to gene therapy.

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Gene Therapy - Genetics Home Reference

BIO. "Biotechnology in Perspective." Washington, D.C.: Biotechnology Industry Organization, 1990. Altered Genes Each of us carries about half a dozen defective genes. We remain blissfully unaware of this fact unless we, or one of our close relatives, are amongst the many millions who suffer from a genetic disease. About one in ten people has, or will develop at some later stage, an inherited genetic disorder, and approximately 2,800 specific conditions are known to be caused by defects (mutations) in just one of the patient's genes. Some single gene disorders are quite common - cystic fibrosis is found in one out of every 2,500 babies born in the Western World - and in total, diseases that can be traced to single gene defects account for about 5% of all admissions to children's hospitals.

In the U.S. and Europe, there are exciting new programs to 'map' the entire human genome - all of our genes. This work will enable scientists and doctors to understand the genes that control all diseases to which the human race is prone, and hopefully develop new therapies to treat and predict diseases.

On the other hand, if the gene is dominant, it alone can produce the disease, even if its counterpart is normal. Clearly only the children of a parent with the disease can be affected, and then on average only half the children will be affected. Huntington's chorea, a severe disease of the nervous system, which becomes apparent only in adulthood, is an example of a dominant genetic disease.

Finally, there are the X chromosome-linked genetic diseases. As males have only one copy of the genes from this chromosome, there are no others available to fulfill the defective gene's function. Examples of such diseases are Duchenne muscular dystrophy and, perhaps most well known of all, hemophilia.

Queen Victoria was a carrier of the defective gene responsible for hemophilia, and through her it was transmitted to the royal families of Russia, Spain, and Prussia. Minor cuts and bruises, which would do little harm to most people, can prove fatal to hemophiliacs, who lack the proteins (Factors VIII and IX) involved in the clotting of blood, which are coded for by the defective genes. Sadly, before these proteins were made available through genetic engineering, hemophiliacs were treated with proteins isolated from human blood. Some of this blood was contaminated with the AIDS virus, and has resulted in tragic consequences for many hemophiliacs. Use of genetically engineered proteins in therapeutic applications, rather than blood products, will avoid these problems in the future.

Not all defective genes necessarily produce detrimental effects, since the environment in which the gene operates is also of importance. A classic example of a genetic disease having a beneficial effect on survival is illustrated by the relationship between sickle-cell anemia and malaria. Only individuals having two copies of the sickle-cell gene, which produces a defective blood protein, suffer from the disease. Those with one sickle-cell gene and one normal gene are unaffected and, more importantly, are able to resist infection by malarial parasites. The clear advantage, in this case, of having one defective gene explains why this gene is common in populations in those areas of the world where malaria is endemic.

The most likely candidates for future gene therapy trials will be rare diseases such as Lesch-Nyhan syndrome, a distressing disease in which the patients are unable to manufacture a particular enzyme. This leads to a bizarre impulse for self-mutilation, including very severe biting of the lips and fingers. The normal version of the defective gene in this disease has now been cloned.

If gene therapy does become practicable, the biggest impact would be on the treatment of diseases where the normal gene needs to be introduced into only one organ. One such disease is phenylketonuria (PKU). PKU affects about one in 12,000 white children, and if not treated early can result in severe mental retardation. The disease is caused by a defect in a gene producing a liver enzyme. If detected early enough, the child can be placed on a special diet for their first few years, but this is very unpleasant and can lead to many problems within the family.

The types of gene therapy described thus far all have one factor in common: that is, that the tissues being treated are somatic (somatic cells include all the cells of the body, excluding sperm cells and egg cells). In contrast to this is the replacement of defective genes in the germline cells (which contribute to the genetic heritage of the offspring). Gene therapy in germline cells has the potential to affect not only the individual being treated, but also his or her children as well. Germline therapy would change the genetic pool of the entire human species, and future generations would have to live with that change. In addition to these ethical problems, a number of technical difficulties would make it unlikely that germline therapy would be tried on humans in the near future.

Before treatment for a genetic disease can begin, an accurate diagnosis of the genetic defect needs to be made. It is here that biotechnology is also likely to have a great impact in the near future. Genetic engineering research has produced a powerful tool for pinpointing specific diseases rapidly and accurately. Short pieces of DNA called DNA probes can be designed to stick very specifically to certain other pieces of DNA. The technique relies upon the fact that complementary pieces of DNA stick together. DNA probes are more specific and have the potential to be more sensitive than conventional diagnostic methods, and it should be possible in the near future to distinguish between defective genes and their normal counterparts, an important development.

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Newswise Working in mice, researchers at Washington University School of Medicine in St. Louis report developing a gene delivery method long sought in the field of gene therapy: a deactivated virus carrying a gene of interest that can be injected into the bloodstream and make its way to the right cells.

In this early proof-of-concept study, the scientists have shown that they can target tumor blood vessels in mice without affecting healthy tissues.

Most current gene therapies in humans involve taking cells out of the body, modifying them and putting them back in, said David T. Curiel, MD, PhD, distinguished professor of radiation oncology. This limits gene therapy to conditions affecting tissues like the blood or bone marrow that can be removed, treated and returned to the patient. Today, even after 30 years of research, we cant inject a viral vector to deliver a gene and have it go to the right place.

But now, investigators at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine say they have designed a targetable injectable vector a deactivated virus that homes in on the inner lining of tumor blood vessels and does not get stuck in the liver, a problem that has plagued past attempts.

The findings are reported Dec. 23 in PLOS ONE.

Building on their own previous work and others, the researchers engineered this viral vector to turn on its gene payload only in the abnormal blood vessels that help fuel and nurture tumor growth. But unlike most therapies aimed at tumor vasculature, the goal is not to destroy the cancers blood supply.

We dont want to kill tumor vessels, said senior author Jeffrey M. Arbeit, MD, professor of urologic surgery and of cell biology and physiology. We want to hijack them and turn them into factories for producing molecules that alter the tumor microenvironment so that it no longer nurtures the tumor. This could stop the tumor growth itself or cooperate with standard chemotherapy and radiation to make them more effective. One advantage of this strategy is that it could be applied to nearly all of the most common cancers affecting patients.

In theory, Arbeit pointed out, this approach could be applied to diseases other than cancer in which the blood vessels are abnormal, including conditions like Alzheimers disease, multiple sclerosis or heart failure.

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Gene Therapy Method Targets Tumor Blood Vessels

Gene therapy for inherited disorders
Gene therapy will be of great significance for patients with hereditary disorders and society at large, says Gerard Wagemaker.

By: youris.com - European Research Media Center

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