How does gene therapy work?

May 13, 2008

Arthur Nienhuis, a hematologist at St. Jude Children’s Research Hospital in Memphis, Tenn., and president of the American Society of Gene Therapy, responds:

Gene therapy is the addition of new genes to a patient’s cells to replace missing or malfunctioning genes. Researchers typically do this using a virus to carry the genetic cargo into cells, because that’s what viruses evolved to do with their own genetic material.

The treatment, which was first tested in humans in 1990, can be performed inside or outside of the body. When it’s done inside the body, doctors may inject the virus carrying the gene in question directly into the part of the body that has defective cells. This is useful when only certain populations of cells need to be “fixed.” For example, researchers are using it to try to treat Parkinson’s disease, because only part of the brain must be targeted. This approach is also being used to treat eye diseases and hemophilia, an inherited disease that leads to a high risk for excess bleeding, even from minor cuts.

Early in-the-body gene therapies used a virus called adenovirus—the virus behind the common cold—but the agent can cause an immune response from the body, putting a patient at risk of further illness. Today, researchers use a virus called adeno-associated virus, which is not known to cause any disease in humans. In nature, this agent needs to hitch a ride with an adenovirus, because it lacks the genes required to spread itself on its own. To produce an adeno-associated virus that can carry a therapeutic gene and live on its own, researchers add innocuous DNA from adenovirus during preparation.

In-the-body gene therapies often take advantage of the natural tendency of viruses to infect certain organs. Adeno-associated virus, for example, goes straight for the liver when it is injected into the bloodstream. Because blood-clotting factors can be added to the blood in the liver, this virus is used in gene therapies to treat hemophilia.

In out-of-the-body gene therapy, researchers take blood or bone marrow from a patient and separate out immature cells. They then add a gene to those cells and inject them into the bloodstream of the patient; the cells travel to the bone marrow, mature and multiply rapidly, eventually replacing all of the defective cells. Doctors are working on the ability to do out-of-the-body gene therapy to replace all of a patient’s bone marrow or the entire blood system, as would be useful in sickle-cell anemia—in which red blood cells are shaped like crescents, causing them to block the flow of blood.

Out-of-the-body gene therapy has already been used to treat severe combined immunodeficiency—also referred to as SCID or boy-in-the-bubble syndrome—where patients are unable to fight infection and die in childhood. In this type of gene therapy, scientists use retroviruses, of which HIV is an example. These agents are extremely good at inserting their genes into the DNA of host cells. More than 30 patients have been treated for SCID, and more than 90 percent of those children have been cured of their disorder—an improvement over the 50 percent chance of recovery offered by bone marrow transplants.

A risk involved with retroviruses is that they may stitch their gene anywhere into DNA, disrupting other genes and causing leukemia. Unfortunately, five of the 30 children treated for SCID have experienced this complication; four of those five, however, have beaten the cancer. Researchers are now designing delivery systems that will carry a much lower risk of causing this condition.

Although there are currently no gene therapy products on the market in the U.S., recent studies in both Parkinson’s disease and Leber congenital amaurosis, a rare form of blindness, have returned very promising results. If these results are borne out, there could be literally hundreds of diseases treated with this approach.

link back url: http://www.sciam.com/article.cfm?id=experts-gene-therapy

Development of gene therapy for blood disorders

Arthur W. Nienhuis¹

¹ Division of Experimental Hematology, Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN

The concept of introducing genes into human cells for therapeutic purposes developed nearly 50 years ago as diseases due to defects in specific genes were recognized. Development of recombinant DNA techniques in the 1970s and their application to the study of mouse tumor viruses facilitated the assembly of the first gene transfer vectors. Vectors of several different types have now been developed for specific applications and over the past decade, efficacy has been demonstrated in many animal models. Clinical trials began in 1989 and by 2002 there was unequivocal evidence that children with severe combined immunodeficiency could be cured by gene transfer into primitive hematopoietic cells. Emerging from these successful trials was the realization that proto-oncogene activation by retroviral integration could contribute to leukemia. Much current effort is focused on development of safer vectors. Successful gene therapy applications have also been developed for control of graft-versus-host disease and treatment of various viral infections, leukemias, and lymphomas. The hemophilias seem amenable to gene therapy intervention and informative clinical trials have been conducted. The hemoglobin disorders, an early target for gene therapy, have proved particularly challenging although ongoing research is yielding new information that may ultimately lead to successful clinical trials.

linkback url: http://bloodjournal.hematologylibrary.org/cgi/content/short/
111/9/4431?rss=1

Gene Therapy: Medicine of the 21st Century

Gene Therapy: Medicine of the 21st Century

As scientists are unravelling the mystery of genes and pitching it as a ‘cure all’ medicine of the future, Nancy Singh traces the baby steps taken in the world of gene therapy.

The year is 3050. Enter a patient suffering from partial blindness. The doctor enters his ‘gene-lab’ and after selecting the appropriate vector introduces ‘normal’ genes that replace the unhealthy ones and the patient regains full vision. Sounds like a scene straight out of a sci-fi movie? Today - yes, but perhaps tomorrow a fact. As they say, today’s fiction is tomorrow’s reality.

Says Sanjeev Saxena, Chairman and CEO of Actis Biologics, a company engaged in gene therapy research, “Gene therapy or nanotechnology may today sound like sci-fi just as the thought of prevention or treatment of smallpox or polio would have to people in the last century. But science has progressed and we will see all the current research in gene therapy becoming a reality soon and India will be hopefully in the lead.”

Gradually surfacing from the world of theoretical fantasies to the realm of actuality, gene therapy has come a long way indeed to be popularly known as the ‘Medicine of 21st Century.’

Widespread application

It is estimated that as of today around 1,340 gene therapy clinical trials have been completed, or are ongoing or been approved worldwide. Gene therapy is considered as treatment for common diseases, as well as cystic fibrosis, Severe Combined Immunodeficiency (SCID), haemophilia, muscular dystrophies, and so on.

“For terminal systemic disorders such as paralysis or Parkinson’s Disease, gene therapy has had reduced success, but for localised states like disc regeneration or spinal fusion, gene therapy can be an extremely powerful tool,” opines Dr Farzana Farzeh, Professor & Chair, Molecular Medicine, Kings College, London & President, International Society of Cell & Gene Therapy for Cancer.

Gene therapy received a significant push after the human genome project. Scientists have recognised exact alterations in the DNA sequences that play causative roles in an array of common diseases that include type 1 and type 2 diabetes, bipolar disorder, schizophrenia, inflammatory bowel disease, glaucoma, and rheumatoid arthritis. Clinical trials and research have also expanded to incorporate cardiovascular, neurological, and pulmonary disorders, cancer, infectious diseases such as AIDS, and monogenic disorders like haemophilia and cystic fibrosis. “Short-term therapy markets such as cardiovascular diseases and cancer will probably be the first to reap financial benefits from gene therapy,” says Dr Sara Collins, Cork Cancer Research Centre, Cork, Ireland.

However, worldwide experts say that gene therapy’s current status is similar to that of monoclonal antibodies 15 years ago, and this market is estimated to be worth over $20 billion.

Gene Therapy for Cancer

Around 70 per cent of more than 400 clinical gene therapy studies initiated are targeted at cancer. Scientists are using multi-pronged gene therapy strategies to fight cancer. One approach is to directly target cancer cells to annihilate them or stop their growth. In another, researchers replace altered or missing genes with healthy ones. “For instance, gene p53 may cause cancer: substituting ‘working’ copies of those genes may be used to treat cancer,” explains Dr Farzeh.

Researchers are also studying methods to enhance the body’s immune response to cancer. Here, gene therapy is used to stimulate the body’s natural ability to attack cancer cells.

In one technique that is currently under investigation, researchers obtain a small blood sample from a patient and insert genes that cause each cell to produce T-cell Receptors (TCR). The TCR recognises and attaches to certain molecules that are present on the surface of the tumour cells. Finally, the TCRs activate the white blood cells to attack and kill the tumour cells.

Research is currently on to insert genes into cancer cells to make them more sensitive to radiation therapy, chemotherapy or other treatment forms. In other studies, researchers are investigating removing healthy blood-forming stem cells from the body, then inserting a gene that will make these cells highly resistant to the side effects of drugs.

Another well-known strategy is inserting ’suicide genes’ into a patient’s cancer cells. A pro-drug (an inactive form of a toxic drug) is then administered to the patient. The pro-drug is activated in cancer cells that contain these ’suicide genes’, which leads to the destruction of those cancer cells. Other research is focused on the use of gene therapy to prevent cancer cells from angiogenesis.

Says Dr Adrian Thrasher, Professor of Paediatric Immunology, Molecular Immunology Unit, Institute of Child Health, UK, “Most early clinical trials have been primarily designed to study safety, applicability and toxicity. Several phase I and II studies have shown partial remission of tumours and, in exceptional cases, complete remission, although complete cure has not yet been shown.”

Mouse Tests

The driver of growth for gene therapy in cancer has been the substantial increase in the understanding of the pathogenesis and various gene expressions on these cancer cells.

Most recently, researchers at the University of Kentucky have created a mouse resistant to cancer. The research has been published in the October 2007 edition of the journal Cancer Research.

This breakthrough originates from a discovery by UK’s College of Medicine’s Professor of Radiation Medicine Dr Vivek Rangnekar and his team of researchers who hit upon a tumour-suppressor gene called ‘par-4′ in the prostate. Dr Rangnekar serves as the Associate Director, Translational Research, at the Markey Cancer Centre. The study was funded by several donations from the National Institutes of Health.

The team found that this ‘par-4′ gene kills cancer cells, but not normal cells. There are very few such molecules known, giving it a potentially therapeutic application. This study is unique in that the mice born carrying this gene are not developing tumours. They grow normally without any defects, and in fact actually live a few months longer than the control animals, indicating no toxic side effects. While originally discovered in the prostate, par-4 is not limited to this location. The gene is expressed in every cell type that the researchers looked at.

To further investigate the prospective therapeutic benefits of this gene, Dr Rangnekar’s team in October 2007 implanted the gene into the egg of a mouse. That egg was then introduced into a surrogate mother. The results were quite promising. The mouse itself does not express many copies of this gene, but the infants do. Hence, scientists have been able to transfer this activity to generations in the mouse.

The potential application for humans is that through Bone Marrow Transplant (BMT), the par-4 molecule could be used to fight cancer cells in patients without any damaging side effects of chemotherapy or radiation therapy.

The next logical step is of course to apply it to humans. “But there needs to be much more work done before any sort of human trial starts,” cautions Dr Farzeh. Nevertheless, a significant step has been taken in the right direction.

Gene Therapy for Immunodeficiency

As of now, the only claim to fame for gene therapy is its undisputed success in Severe Combined Immunodeficiency (SCID) or ‘bubble syndrome’ as it is commonly known.

This is a severe form of heritable immunodeficiency that affects about 1 in 1,00,000 live births. Since 1999, gene therapy has managed to restore the immune systems of at least 17 children (in a US, UK and French trial) with two forms (X-SCID and ADA-SCID) of the disorder.

The first ever gene therapy trials were started in 1990 by Dr William French Anderson in the US. The patient was a four-year-old girl called Ashanti. In her case, the disease was caused by the absence of the enzyme Adenosine Deaminase (ADA). This deficiency prevented her body from producing lymphocytes. The most common treatment for SCID is BMT, which requires matched donors.

Of late, gene therapy has proved useful. Transduction of the missing gene to haematopoietic stem cells by using viral vectors is being tested in ADA-SCID and X-linked SCID. In 2000, the first gene therapy ’success’ resulted in SCID patients with a functional immune system. These trials were terminated when it was discovered that two out of 10 patients in one trial had developed leukaemia resulting from the insertion of the gene carrying retrovirus near an oncogene. Till 2007, four of the 10 patients are believed to have developed leukaemia. Work is currently on to focus on correcting the gene without triggering an oncogene. In trials of ADA-SCID, no leukaemia cases have yet been reported.

Hope Ahead

Further trials were initiated in which bone marrow cells or umbilical cord blood cells were used as targets. The modification of the stem cells present did result in the long-term production of a small number of ADA-positive lymphocytes. However, the ADA levels produced by the cells were low and it is not clear whether the patients would survive without concurrent ADA-PEG treatment.

In 2002, there was a major breakthrough in ADA gene therapy. It resulted from the use of a technique known as non-myeloblative conditioning, in which bone marrow in the SCID patient is partially killed in order to give the modified stem cells the chance to proliferate. Another important factor was that none of the children in this trial had been treated with ADA-PEG. It is believed that enzyme treatment may have contributed to the lack of success in previous trials.

The first patient was a two-year-old Palestinian child named Salsabil who had never received ADA-PEG therapy. The new treatment seems to have cured her condition and she is enjoying a comparatively normal life. Her body is producing antibodies that even managed to fight chicken pox, which would almost certainly have killed her months earlier.

Gene therapy for the Heart

To date, most gene therapy studies are accomplished in the laboratory and the earliest experiments seem promising for treatment of cardiovascular diseases in the future. A case in point is the use of gene therapy to help increase blood flow to ischemic tissue.

The body’s first response to decreased blood flow to the heart is to grow small new ‘collateral’ vessels to help blood flow around the blockage. For unspecified reasons, this process of angiogenesis eventually switches off.

There are some angiogenic proteins in the body that are known to help trigger new blood vessel growth. These include the endothelial growth factors, Vascular Endothelial Growth Factor (VEGF), Hepatocyte Growth Factor (HGF) and Fibroblast Growth factor (FGF).

In gene therapy trials, scientists have used a variety of different ways to deliver the genes for VEGF-1, VEGF-2 and FGF4 into the hearts of patients suffering from advanced myocardial ischemia. After gene therapy, patients reported less severe angina. Similarly, after gene delivery of VEGF to patients with limb ischemia, the blood supply improved and leg sores healed better. In fact, gene therapy has prevented below-knee amputation in some patients for whom it had been recommended.

Researchers at Johns Hopkins have successfully transferred a gene for the ‘G protein’ to cells of the AV node in pigs having atrial fibrillation, which has resulted in a therapeutic slowing of the heart rate. In Germany, scientists transported a gene in the heart muscle of rabbits and rats that was shown to increase the heart’s ability to contract forcefully. The gene transfers in these two animal studies were done by transfecting the target cells with a virus carrying the desired DNA.

Gene therapy has also been a success in preventing re-blockage or re-occlusion of coronary artery bypass grafts and in maintaining arteries open after angioplasty. Though gene therapy looks very promising, it still needs improvement before it becomes a routine treatment in the clinic for cardiovascular diseases, experts point out.

But several indispensable concepts of genetic therapy, by virtue of successful trials, have now been validated. Says Dr David Klatzmann, Director, Biotherapy Centre, Pierre & Marie Curie University, France, “If the field continues to advance briskly over the next few years, we may be able to apply genetic therapy to problems such as coronary artery disease, cardiomyopathy and certain cardiac arrhythmias.”

Obstacles to Overcome

The possibilities are limitless, but so are the challenges. Things are not as hunky-dory as theory would make it seem. Difficulties arise when the genes get out of the controlled laboratory environment and have to be tested in practical waters.

Gene therapy has suffered some grave setbacks in the past few years and its success graph has been considerably slower than many people, particularly investors, had anticipated.

The first Blow: Immune Response The industry as a whole suffered in 1999 when 18-year-old Jesse Gelsinger died from organ failure just four days after initiating a gene therapy trial at the University of Pennsylvania. He had a rare liver disorder, and died of complications from an inflammatory response shortly after receiving a dose of experimental adenovirus vector. His death halted all gene therapy trials in the US as it raised many questions concerning the safety of experimental gene therapy treatments. Dr Ramani Iyer, Chief Scientific Officer, Actis Biologics, argues, “I don’t understand why there is such a big hue and cry when these patients really required the drug and had no other recourse.”

The Next Setback: Wrong Location Researchers tested a gene therapy treatment to restore the function of a crucial gene, gamma c, to cells of the immune system, in children with X-linked SCID. Initially, this treatment appeared very successful, restoring immune function for seven out of 10 children. But, two years later, two of the children developed leukaemia.

The virus that was used to deliver the newly transferred gamma c gene had stitched itself into the wrong place, interrupting the function of a gene that normally helps regulate the rate at which cells divide, and activated an oncogene.

The Most Recent Bad News - Targeted Genetics

One patient died in a Phase 1/2 trial of gene therapy drug candidate tgAAC4 for treatment of rheumatoid arthritis, from a fungal infection (Histoplasmosis) due to suppressed immune response. tgAAC4 works as a local anti-TNF-alpha gene therapy treatment, which is delivered only to the affected joint(s) of arthritis patients.

The DNA vector had the potential to cause systemic immune suppression. However, preliminary testing results from three tissue sites revealed that the level of vector DNA from tgAAC94 present in the patient’s system was too low to have a systemic effect or cause suppression of the immune system. Also, the patient who died in this study was on systemic arthritis medications, which are known to cause immune system suppression. Hence, there are still expectations that the FDA may allow the trial to continue.

Technical Hurdles

There are many pre-clinical technical hurdles as these involve manufacturing under high-level bio-safety precautions and things get tougher keeping in mind strong FDA oversight on its clinical applications. “International standards for drug testing are rigorous, time-consuming and expensive, but they are crucial to protect patients,” says Dr Iyer.

An additional roadblock for the technology is the short-lived nature of the therapeutic DNA that is introduced into cells and the human body’s immune system response.

However, with more researchers joining the bandwagon and many promising drugs in clinical trials expected to surface in the market, the potential applications for gene therapy are increasing.

High Costs

Lack of appropriate finances is also another stumbling block, especially if you consider the fact that such large-scale studies involve billions of dollars.

Almost 75 per cent of research in gene therapy is mainly at academic institutional level and they too require appropriate and timely grants to flourish. While there are companies who have a strong base for gene therapy research and future products, they generally aren’t money-spinning operations yet. Celera, for example, reported a $20 million loss in early 2004. But their future products hold promise.

After 12 unprofitable years, Avigen Inc decided to stop funding its experimental gene therapy platform and focus its limited funds on developing traditional pharmaceuticals. It agreed to sell its AAV gene therapy assets to Genzyme in December 2005 for an upfront cash payment of $12 million, with additional milestone payments and royalty payments on all products developed under this portfolio, including the current Parkinson’s disease programme.

However not all news is bad news. Some companies have received notable grants that infuse a feeling of optimism. Celladon, developing gene therapy for congestive heart failure, received $30 million in a Series B round. Ceregene, focusing on several prevalent central nervous system diseases, such as Parkinson’s, Alzheimer’s, and ALS, received $32 million. Virxsys, developing a lentiviral vector gene delivery technology for HIV/AIDS, raised a total of almost $52 million in 2005/2006 financings.

Lessons Learned

Experience is the best teacher, they say. This statement can be best applicable to gene therapy. Dr Iyer agrees, “Today, the innovators need to capitalise on the significant progress that has been achieved in the discovery area, be it the choice of vectors, manufacturing, RCV Analysis, etc.”

He suggests, “No drug is either 100 per cent good or 100 per cent bad— it comes down to a clear risk-benefit analysis for a particular patient population for a given indication. Hence, focus initially on a patient population in whom the highest possible benefit may be shown. This may entail compromising on ‘blockbuster’ market potential, but may prove worthwhile in the long run. Finally, be willing to go the extra mile on safety issues and work closely with the regulator.”

Despite the troubles, if companies singlehandedly pursue their current lines of studies, applications for gene therapy are nearly limitless.

There is huge unmet need in the world of incurable diseases and this is where gene therapists are aggressively working hard trying to bridge the supply-demand gap even if that means reaching the unknown. The high prevalence of untreatable diseases drives the demand for this new treatment.

The moments of agony have not been without their share of ecstasy. This market has witnessed both devastating clinical failures as well as incredible breakthroughs for the treatment of severe diseases. On the positive side, the risks historically associated with gene therapy are lessening, largely through scientific advances in gene delivery.

Several products are in the pipeline with the regulatory approval hoped for in the next three years. “The market does face huge challenges in terms of patient recruitment, or the development of clinical success, but when these are overcome, the results will pave the way to a new era of medicine,” predicts Saxena.

The bottom line is that any kind of biomedical research depends on its relevance. Regardless of the excitement gene therapy can lead to, the field is yet in its infancy. Several clinical trials of gene therapy have been completed or are under way. They can provide information that cannot be concluded from tests in animals. Although this therapy has been theoretically good in principle, it has proved cumbersome to demonstrate its efficacy in practice. Thus, the success rate in clinical trials has been relatively low. “Such results can reduce the enthusiasm for genetic approaches, but the field is still new and the pace and surprises of new discoveries are amazing,” says Dr Farzeh.

The gene therapy market is currently going through an exciting transition phase from infancy to its adolescence and gradually taking slow steps to lay the foundation of the medicine for generations yet to come.

nancy.singh@expressindia.com

linkback url: http://www.expresshealthcaremgmt.com/200804
/knowledge01.shtml

Keeping the faith for Parker

Keeping the faith for Parker
Canadian boy will return to Italy for treatment of his rare disease
By Mariella Policheni

Parker DesLauriers, 2, will be returning to the San Raffaele Hospital in Milan in May for further testing.
Parker, with his blond page-boy hair cut and the energy typical of children his age, is afflicted with a rare disease known as Severe Combined Immunodeficiency Disease (Ada-Scid) a disease without a cure that makes him vulnerable to virus, bacteria, and fungus.
“However, there are experimental treatments available, like the one administered by Doctor Alessandro Aiuti at San Raffaele in Milan, which we had our Parker undergo with the hope of seeing some positive results,” says Parker’s mother Tracy DesLaurier. “It will take a lot of time, maybe years, before we know for sure if Parker is cured, but in May we’re heading to Milan to learn, through a series of tests, if the treatment works.”
Severe Combined Immunodeficiency Disease (Ada-Scid) is so rare that in the past 20 years only 15 children have been treated for it at Sick Children’s Hospital in Toronto.
We wanted to try Doctor Aiuti’s treatment, which has proven to be successful on many other children,” adds DesLauriers. If he succeeds in overcoming the disease, Parker will be able to lead a normal life, he’ll be able to attend school, interact with others and live like a normal child, whereas for now, we have to limit his interactions, his time outdoors, and we have to provide a home environment that is as sterile as possible.”
Parents Tracy and Kevin DesLauriers are full of hope for their son Parker who has had to live a sheltered first two years of life under extreme safety measures.
“We have always been positive and continue to be so,” says Tracy DesLauriers, “with test results from gene therapy, which ended last September showing that the number of lymphocytes is increasing although they are obviously not at the level they should be. This is encouraging news for us, although we remain with our feet planted to the ground, so that we don’t get overly optimistic.”
To be near Parker, his parents have had to quit their teaching positions and move to Italy for seven months, facing many challenges.
“The language, being away from our families and our home, and the financial challenge of not having worked in months has naturally affected our situation,” says DesLaurier. “But we have friends and family who help us, and in Milan we’ve come to know and appreciate Doctor Aiuti’s team, who have been marvelous, as has been all the hospital staff. We wanted to try out this treatment with the hope of guaranteeing a normal life for our son. We’re confident and are making this second trip to Italy with much hope – with the hope that everything is moving in the right direction.”
In a show of support, family and friends of the DesLauriers have organized a fundraiser, Golfing ‘Fore’ Parker, to be held June 1 at Four Seasons Golf Club (www.2golf.ca) at 1 p.m.

Anyone wanting to buy tickets, donate prizes, help organize the event, or who wants to get further information, can write to golfingforparker@gmail.com. For donations visit the blog at www.scidada.blogspot.com.

linkback url: http://www.tandemnews.com/viewstory.php?storyid=8176&page=1

Professor innovates gene therapy

TGRx provides jobs, brings revenue

J.J. Alcantara

Issue date: 3/25/08 Section: News

Richard Cooper, veterinary science professor, is leading students and professionals to research and develop treatments for certain genetic diseases.

Cooper, TransGenRx executive vice president of research and development, expands and enhances the way gene therapy works.

Gene therapy is used to treat individuals with single-disorder genes such as cystic fibrosis, sickle-cell anemia and certain types of diabetes.

Cooper said his technology has made gene therapy more efficient than previous methods.

“Every gene therapy trial that’s been started has been shut down because people are dying because they use viruses to transfer the genes,” said Bill Fioretti, co-founder and president of TGRx. “Those viruses have a habit of integrating to cancer-causing genes, if they integrate at all.”

Fioretti said TGRx’s gene therapy is different because Cooper’s technology has the ability to know which specific genes to change and will not cause cancer if it fails.

“[It does] it at a rate … of 100 more times efficient than traditional gene transfer technologies,” Fioretti said. “You know where it’s going to integrate and it does not cause cancer.”

Fioretti said the TGRx is the only company using this form of gene therapy because the technology is patented.

Fioretti co-founded TGRx in 2002 to license Cooper’s technology but the University also benefits.

Cooper said the University owns shares of the company and has a royalty agreement with TGRx.

“Both the AgCenter and the main campus are in the top-tier of royalty-producing income,” Fioretti said.

He said TGRx’s technology helps increase the University’s revenue because they own part of the license.

TGRx also produces protein drugs such as insulin and growth hormones for 10-20 times cheaper than the current costs using Cooper’s technology.

Cooper said TGRx uses chickens and chicken eggs to develop the protein.

He said TGRx engineers chickens to produce human proteins in their eggs.

Fioretti said TGRx’s first commercial product is a derivative of a human growth hormone.

“We will be making intermediate pharmaceutical ingredients,” Fioretti said. “We will sell that to someone who further processes it and sells it.”

TGRx partnered with the University and the AgCenter to develop this technology.

Fioretti said this partnership allows the company and the University to benefit.

He said TGRx first looks to the University before they advertise elsewhere to find graduates to work for the company.

Today, Fioretti said TGRx employs about 10 scientists who graduated from the University and about 12 student workers.

“Most [graduates] come out of biological sciences,” Cooper said. “But we’ve had a few come out animal sciences with an emphasis in poultry.”

Fioretti said as the company continues to expand, he will broaden his search for business, accounting and management graduates.

“We want to give graduates that are getting degrees in areas like molecular biology and biochemistry a place to work when they stay here,” Cooper said.

Fioretti said his long-term goal is to establish TGRx as an anchor for a viable biotech industry in Louisiana - specifically around Baton Rouge.

He said TGRx will attract support services and businesses like companies that raise poultry and purify and finish protein drugs.

“As we grow, there’ll be not just the jobs that we can provide,” Fioretti said. “Other companies that move in to provide services for us will be hiring people as we go.”

Fioretti said another goal of TGRx is to be a large-scale contract manufacturer.

“The companies that we partner with would have an interest to putting small- to medium-sized operations down here,” Fioretti said. “The whole thing goes toward not just attracting or keeping students and graduates in the state but bringing companies that will bring their workforce with them as well.”

Fioretti said this goal will help the biotech industry grow faster in Louisiana.

TGRx is currently located at the Wilson Laboratories but will soon move to the Louisiana Emerging Technology Center.

Fioretti said once the move to LETC is complete, TGRx will be able to increase their workforce.

“It’s really good for our company to have that kind of opportunity to expand in size and bring everybody together,” Fioretti said. “There’s something to be said about working in contact with all your peers and exchang[ing] ideas.”

—-
Contact J.J. Alcantara at jalcantara@lsureveille.com

linkback url: http://media.www.lsureveille.com/media/storage/paper868/news/
2008/03/25/News/Professor.Innovates.Gene.Therapy-3281223.shtml

Way to target genes devised for gene therapy

Way to target genes devised for gene therapy

By Roger Highfield, Science Editor
Last Updated: 10:01pm GMT 17/03/2008

A way to carry out genetic surgery has been devised by a British Nobel prizewinner that is already under test on diabetic patients and being readied for use to treat Aids, blocked blood vessels and chronic pain.

So called gene therapy was hailed as a medical revolution two decades ago but progress has been slow, the successes have been hard to come by, and there have been a few deaths.

One key problem is that it has been hard to control where newly introduced genes end up in the genetic makeup of the patient - one fear is that they damage existing genes, or the way they are used.
advertisement

Now Sir Aaron Klug, a Nobel laureate working at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, has developed a more efficient way to target genes, so gene therapy can be done with surgical precision.

His team reports a new application of the gene fingers in the Proceedings of the National Academy of Sciences that it has have modified a piece of natural cellular machinery called “zinc fingers”.

These are zinc-containing proteins that bind to DNA and control how the genetic code - and the genes it contains - are read in our cells, so that a liver cell is different from a brain cell.

They have devised synthetic versions, called zinc-fingered nucleases, which have the capacity to recognise specific sequences of DNA which makes them extremely good at latching on to a specific spot, targeting particular genes without affecting others, so they can carry out genetic surgery to knock out genes or introduce new ones.

The new method is already being tested on more than 100 young diabetic patients who have lost sensation, a common complication, by the Californian company Sangamo BioSciences, after encouraging results in preliminary tests of the method to introduce a gene encoding a growth factor that can help restore sensation.

The work, backed by the Juvenile Diabetes Research Foundation, will be extended to see if it can help treat spinal injury.

Animal trials are already under way to use the same targetted gene therapy to reduce chronic pain and to knock out a gene called CCR5, the docking point used by the Human Immunodeficiency Virus to invade white blood cells, called T-cells, in AIDS patients, leading to a supply of non-infectable T-cells, which will combat HIV and the other infections which occur in AIDS patients.

Clinical trials are also in progress for stimulating the growth of new arteries in patients suffering from obstruction of the blood vessels in the limbs, which can lead to gangrene and amputations.

The new study shows they are effective at knocking out harmful genes too, also a fundamental tool for animal research to work out what genes do.

Sir Aaron explains: “The beauty of zinc-finger nucleases lies in their simplicity. Where other methods are long, arduous and often messy, it is relatively easy to switch off genes using this method.

“The zinc-finger design allows us to target a single gene, while the nuclease disrupts the gene. The single step process is extremely quick and reliable and opens up exciting possibilities for research and gene therapy.”

linkback url: http://www.telegraph.co.uk/earth/main.jhtml?xml=/
earth/2008/03/17/scigene117.xml

New hope for Ajax ‘bubble boy’

TheStar.com - Ontario - New hope for Ajax ‘bubble boy’

var imageL= ‘/images/a8/94/2c9b4b844abfa0f62a522d57bb31.jpeg’ if(imageL) { document.write(’‘); } else{ document.write(’‘); }

RICK EGLINTON/TORONTO STAR

Cutting-edge therapy done in Milan appears to be boosting child’s immune system

March 03, 2008

Joseph Hall
Health Reporter
Tracy Kulas-DesLauriers holds her son firmly by the shoulders and pleads with him, with exasperated bemusement, to please stop spinning.

“It will make you dizzy, Parker. It will make you fall down!”

But when she lets go, he’s a human top again; twirling, twirling, running toddler circles around his kneeling mother and around all that medical expertise that said he likely wouldn’t do what he has so obviously and gleefully done.

Parker DesLauriers has ADA-deficient severe combined immunodeficiency – a form of “bubble boy” disease.

With the frenzied energy of a 2-year-old bent on being naughty, he has every appearance of brimming health.

But his immune system remains massively compromised and Parker, who celebrated his second birthday in January, is a virtual prisoner in his antiseptic Ajax home.

“We’ve been confined, basically for two years and it’s taxing. I mean it gets to you after a while,” his mother says.

Basically, the only time he leaves the house is for twice-monthly visits to the Hospital for Sick Children, she says.

The disease, a rare genetic ailment caused by one malfunctioning gene on chromosome 20, leaves him with almost no working T and B blood cells, which are essential to a body’s immune system. Without these white blood cell components, Parker is almost entirely unable to fend off any harmful virus or bacteria he encounters.

But there’s hope in his mother’s voice now, and a rising confidence that one day, maybe soon, her little boy will enjoy a normal childhood.

Because, deep in Parker’s bone marrow, a seeding of genetically modified stem cells may be sprouting a new immune system.

“We have reason to believe that it’s definitely working,” Kulas-DesLauriers says of the cutting-edge gene therapy her son received in Italy.

The process, which took place in Milan last May, involved harvesting Parker’s bone marrow, from which doctors removed a number of the stem cells that can produce every type of blood cell, including the disease-fighting cells Parker lacks.

Then, using a virus as a transporting vector, they inserted a healthy gene into the stem cells to counteract its defective counterpart. That gene produced an enzyme known as ADA, which is critical in protecting T cells from rapid destruction in the body. Without T cells, antibody-producing B cells do not perform properly either, leaving the entire immune system in shambles.

The genetically altered stem cells were reintroduced into Parker’s marrow. Now, some nine months later, his T and B blood cells have substantially improved.

When he was born, Parker had a lymphocyte count of 80, his mother says. Now it fluctuates between 700 and 900, she says. A normal count would be about 2,000, doctors say.

“The main thing now is the fact that he is producing these cells, something he was never able to do on his own before,” she says.

Parker will return to Italy this May for a one-year follow-up. Meanwhile, the quarantine of the outside world from the family’s Ajax home must be maintained.

“He can’t play with his little cousins or anything … little kids are bacteria carriers,” says grandfather Roy Kulas, who, with his wife, Parker’s fraternal grandparents and the boy’s parents, are the only people allowed to pick the toddler up.

“Still, he’s a good happy lad, and a joy to be around,” Kulas says.

Financially, the disease has been devastating for his parents, who both had to quit their jobs as teachers – with their professional obligation to be around kids and germs – after Parker was born.

They’ve been living off savings, fundraising events and support from family and friends. “I had a nice house, I had a great job, I had everything going for me and now all of a sudden, I’m in this position where I need to ask for help,” Parker’s mother says. “I’m going to lose this house. I’m going to lose everything that we’ve worked so hard to get.”
The family will be holding a fundraising golf tournament June 1 at the 4 Seasons Golf Club in Claremont. Anyone wishing to buy tickets or donate can email golfingforparker@gmail.com.

linkback url: http://www.thestar.com/News/Ontario/article/308771

Debate over Safety of Gene Therapy Trials Focuses on Issue of Informed Consent

New Rochelle, NY, January 22, 2008—Can a patient who agrees to participate in a safety study of a gene therapy protocol give truly informed consent and understand the risks involved when the consent forms are highly technical and the physician or institution seeking their consent has a stake in the study and its outcome? The continuing debate over informed consent and the acknowledgement of risk and responsibility in gene therapy trials are the focus of a series of probing and provocative commentaries published in the January 2008 issue (Volume 19, Number 1) of Human Gene Therapy, a peer-reviewed journal published by Mary Ann Liebert, Inc. The commentaries are available free online.

In the Editorial, James M. Wilson, MD, PhD, Editor-in-Chief and Head of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, at the University of Pennsylvania School of Medicine, in Philadelphia, calls on the gene therapy, regulatory, and research communities to re-explore the issue of informed consent as it relates to the safety of viral vector-based gene transfer therapies and the appropriateness of having physicians and others with an interest in the trials and their outcomes recruit patients and obtain the necessary informed consent.

“I encourage the professional gene therapy societies and various related foundations to work together in the new year to undertake a critical review of the conduct of our clinical trials…it behooves us to get ahead of this issue and put in place more effective ways to assure that research subjects who courageously give of themselves can do so with a full and unbiased understanding of the risks and benefits of their participation,” writes Dr. Wilson.

This issue of the Journal also includes five stimulating commentaries that discuss the key controversies related to patient recruitment and trial management. They explore the question of whether patients are able to comprehend the lengthy and often highly technical study descriptions and consent forms to the extent needed to make an informed decision about enrolling in a trial. The authors also present suggestions and innovative strategies for improving the recruitment and informed consent process.

Dr. Arthur Caplan, Professor of Bioethics, Chair of the Department of Medical Ethics, and Director of the Center for Bioethics at the University of Pennsylvania, authored a commentary entitled, “If It Is Broken Shouldn’t it Be Fixed? Informed Consent and Initial Clinical Trials of Gene Therapy.” Another, entitled, “Case of Leukaemia Associated with X-Linked Severe Combined Immunodeficiency Gene Therapy Trial in London,” was prepared by the Board of the European Society of Gene and Cell Therapy, Executive Committee of the Clinigene Network of Excellence, and Executive of the Consort Integrated Project. Dr. Jeffrey Kahn, Director and Professor, Center for Bioethics, at the University of Minnesota Medical School, presents his perspectives in, “Informed Consent in Human Gene Transfer Clinical Trials.” Also contributing a commentary is Dr. Tomas Jose Silber, Chair of the Institutional Review Board and Director of the Office of Ethics at Children’s National Medical Center, in Washington, D.C. It is entitled, “Human Gene Therapy, Consent, and the Realities of Clinical Research: Is It Time for a Research Subject Advocate? ” Ms. Suzanne Pattee, Vice President of Regulatory and Patient Affairs for the Cystic Fibrosis Foundation authored, “Protections for Participants in Gene Therapy Trials: A Patient’s Perspective.”

linkback url: http://www.liebertpub.com/prdetails.aspx?pr_id=611