Group A articles

o The New York Times – Patient Dies During a Trial of Therapy Using Genes http://query.nytimes.com/gst/fullpage.html?sec=health&res=9E06EED8173EF93AA1575AC0A96F958260

o Fox News – Boy Living in Bubble Develops Leukemia From Experimental Therapy http://www.foxnews.com/story/0,2933,317225,00.html

o The New York Times – 2nd Cancer is Attributed to Gene Used in FDA Test http://query.nytimes.com/gst/fullpage.html?res=9801E7DB1F31F934A25752C0A9659C8B63

o ABC News – Patient Death Latest Setback for Gene Therapy http://abcnews.go.com/Health/Story?id=3421869&page=1

o The New York Times – Trials are Halted on a Gene Therapy http://query.nytimes.com/gst/fullpage.html?res=9C01E7D9163BF937A35753C1A9649C8B63

September 29, 1999

Patient Dies During a Trial Of Therapy Using GenesBy NICHOLAS WADE

A patient has died while undergoing gene therapy in a trial study at the University of Pennsylvania in Philadelphia.

If the treatment itself should prove to be the cause of his death it would probably be the first by someone undergoing gene therapy and could be a severe setback for the experimental technique, whose fulfillment has long fallen short of its high promise.

The patient, Jesse Gelsinger, was an 18-year old from Arizona who suffered from a genetic defect that prevents the correct metabolism of ammonia. He was part of a group of 18 patients who were being tested with different doses of a virus carrying a corrective gene. He and another patient, who was unaffected, received the highest dose being given in the trial.

Mr. Gelsinger died on Sept. 17, four days after a dose of genetically engineered virus was injected into one of the main arteries of his liver, so as to deliver the highest possible dose of a corrective gene to the cells where it was needed.

The virus, known as adenovirus, is one of the causes of the common cold and usually causes only a mild fever. It has been used in many previous gene therapy trials. Mr. Gelsinger's death was first reported in Tuesday's editions of The Washington Post.

''We're all devastated by this,'' said Rebecca Harmon, a spokesperson for the University of Pennsylvania. ''Jesse truly was a hero in advancing the cause of science.''

Ms. Harmon said Mr. Gelsinger's was the first death to have occurred among the 130 patients who have been treated at the university's Institute of Gene Therapy. The institute, headed by Dr. James M. Wilson, is one of the leading gene therapy centers in the United States.

Dr. Steve Raper, the principal scientist in charge of the trial, said that the timing of the treatment and Mr. Gelsinger's death suggested a possible relationship but that the cause had not yet been determined.

''The major impact of Jesse's sacrifice,'' Dr. Raper said, is that safer viruses may need to be developed. ''Gene therapy,'' he said, ''still holds tremendous promise for a variety of diseases.''

To get corrective genes into cells, gene therapists have to rely on viruses, which specialize in exactly this task.

Adenovirus is used partly because it causes such a mild gene. Results have been generally disappointing, however, because the body's immune system usually roots out and destroys the virus after six weeks, along with the beneficial genes it has inserted. Well before Mr. Gelsinger's death, gene therapists had been trying to develop more suitable viruses as vectors.

Mr. Gelsinger's disease, ornithine transcarbamylase deficiency, is usually inherited but Mr. Gelsinger had a rare form in which his gene mutated after birth.

Mr. Gelsinger's father, Paul Gelsinger, 47, a licensed handyman in Tucson, Arizona, said his son became interested in the experimental gene therapy after he had begun to rebel against the restrictive nonprotein diet and the 50 pill-a-day regimen that mitigated his symptoms. He faced a life of increasingly larger doses of medication.

''He was a a rebellious teenager who thought he could manage his own illness,'' his father said.

Jesse was especially interested in the gene trial since it promised dramatic improvement.

Jesse was also interested because the particular phase of the trial he was in might benefit newborns who get the worst form of the disease that kills in the first year.

Paul Gelsinger and Jesse, who at 18 was the actual person giving consent for the trial, were told the largest risks from the trial would come from possible hepatitis and blood clots. The cause of death has not been determined, Mr. Gelsinger said, ''but it's obvious it had to have been the procedure itself.''

Mr. Gelsinger does not have hard feelings toward the doctors in the trial. ''The doctors are as devastated as I am. It was because of these men that I had my son for 18 years.''

Jesse died on Sept. 17, when artificial life support was discontinued, but his vital signs began to fail the second day after the introduction of the modified gene on Monday, Sept. 13.

Boy Living in Bubble Develops Leukemia From Experimental TherapyPublished December 18, 2007 by Fox News

London Times

One of the first children in Britain to receive pioneering gene therapy for an immune system disorder

has developed leukemia as a result of his treatment.

The boy, 3, is the first gene therapy patient in Britain to fall ill with leukemia, a known risk of the

treatment. A similar gene therapy program in France has caused four cases of the blood cancer, and

one death.

The child, who has not been named, was born with X-linked severe combined immunodeficiency (X-

SCID), a genetic condition in which the immune system fails to develop. It is often known as “bubble

baby syndrome," as sufferers are shielded against germs in a sterile pouch.

Two years ago, he became the eighth patient to be treated with the gene therapy program at the

U.K.'s Great Ormond Street Hospital. The program uses a genetically modified virus to correct the

faulty DNA that causes X-SCID.

His immune system responded “extremely well” to the procedure but leukemia was diagnosed last

month, the hospital said. This is an acknowledged risk of gene therapy, as inserting the replacement

DNA can trigger another gene that promotes cancer.

None of the other 14 children to have had gene therapy for X-SCID and a similar condition, known as

ada-SCID, has developed leukemia so far, the hospital said. The cancer, however, has been

diagnosed in four of the 11 patients involved in a French trial, one of whom has died while three are in

remission.

Professor Adrian Thrasher and professor Bobby Gaspar, who treated the boy, said in a statement:

“Our first thoughts are to secure the best treatment for this child and to support his family at this very

difficult time. This unfortunate event is the first such development on our program. As with any

medical treatment there are associated side-effects. The development of leukemia is now a

recognized side-effect in this study, though the risks are balanced by the severity of the condition and

the lack of good alternative treatments for X-SCID.

They pointed out that 80 percent of children with leukemia made a full recovery, and there was every

chance that the child would survive the cancer and be cured of X-SCID.

The immune system disorder is always fatal without treatment. The only alternative to gene therapy is

a bone marrow transplant, which rarely achieves satisfactory results unless a fully matching donor is

available.

January 17, 2003

2nd Cancer Is Attributed To Gene Used In F.D.A. TestBy ANDREW POLLACKCorrection Appended

The second case of a leukemia-like disease in a gene therapy patient in France appears to have the same basic cause as the first one, a scientist investigating the incident said yesterday.

In both cases, it appears the gene inserted into the boys' cells to cure their disease accidentally landed on or near a cancer-causing gene and switched it on, said the scientist, Dr. Christof von Kalle of Cincinnati Children's Hospital Medical Center, who is collaborating with the French researchers.

Dr. von Kalle said his preliminary assessment, which is still to be verified, suggested that the problem might be restricted to the particular gene therapy regimen in France. ''This is something that is so specific and unique I would say it would not have been possible to predict this,'' he said.

The Food and Drug Administration on Tuesday suspended 27 clinical trials of gene therapy after learning of the second case of leukemia. The halt was another setback to the fledgling field of gene therapy because the French experiment, in which 9 of 11 boys were essentially cured of a fatal immune deficiency, had been considered the first unequivocal success for the technique.

But three years after their treatment, two of those nine boys have developed uncontrolled growth of blood cells characteristic of leukemia. They are responding to chemotherapy, according to the National Institutes of Health.

In both cases, the gene inserted into the boys' blood-forming stem cells landed on or near an oncogene, or cancer-promoting gene, called LMO-2, which can spur childhood leukemia. In the first case the gene landed inside LMO-2 and the second landed near enough to turn on the gene, Dr. von Kalle said.

The gene therapy used viruses to carry the therapeutic cells into the children's blood-forming stem cells. The virus lands at random on the cell's DNA. So scientists have long known there was a risk that the virus could land on a cancer-spurring gene, but it was thought that the chances of its happening were small.

Dr. von Kalle said the chance of a virus landing on LMO-2 was about 1 in 100,000. But since each child was given about one million cells, the probability is very high that a child received at least one cell in which the virus landed on the gene. That makes it important to monitor the other children closely, he said.

But Dr. von Kalle said scientists believed that turning on just one oncogene would not be a problem because it usually requires multiple genetic changes to turn a cell cancerous.

''There's no human cancer model where you can see that one gene got turned on and it gave you a cancer,'' he said.

Dr. von Kalle's hypothesis is that a second genetic change came from the therapeutic gene itself. The gene put into the French children was designed to spur growth of infection-fighting blood cells, since the boys suffered from a lack of such cells, meaning they would be killed by infections. It is possible that the therapeutic gene combined with the activated oncogene to cause a surge of such blood cells, Dr. von Kalle said.

If this hypothesis is confirmed, it would indicate that gene therapy treatments in which the inserted gene is not a growth-promoting one would not face the same risk, he said.

Patient Death Latest Setback for Gene TherapyTragedy May Raise Public Fear Over Clinical Trials for Promising Treatments

By DAN CHILDSABC News Medical Unit

July 27, 2007 —

The death of a patient enrolled in the clinical trial of an experimental gene therapy is the third black mark for the treatment approach since 1999 -- and one that doctors fear has the potential to stall future research.

The death has spurred the U.S. Food and Drug Administration (FDA) to halt the trial and begin safety reviews of 28 other gene therapy trials around the country.

According to an FDA press release issued Thursday, the Seattle-based Targeted Genetics Corp., which conducted the trial, informed the FDA of the death July 24.

The trial was designed to test the effectiveness of a treatment for active inflammatory arthritis called tgAAC94.

It is not yet clear whether the drug being used directly led to the patient's death, or whether other causes are to blame. Still, in response to the death, the FDA has launched an investigation of the trial, which began in October 2005 and involved 127 subjects who may have received the drug.

According to the FDA statement, none of the other subjects are reported to have experienced similar complications, and the patient's illness was related in time to the receipt of a second injection of the product.

But gene therapy researchers say they are already worried that the death could represent a major setback for the technology, regardless of the results of the investigation.

"Gene therapy may be an important future effort, and it is disconcerting that something like this has happened," said Dr. Lee Simon, associate clinical professor of medicine at Harvard Medical School, who called the announcement "interesting and troubling."

Other doctors agreed.

"It is certainly a troubling development," said Dr. David Fox, chief of rheumatology at the University of Michigan Medical School. "It will be important to determine what caused this patient's death and whether it was due to the gene therapy treatment."

Dr. Michael Becker, a rheumatologist at the University of Chicago Medical Center, said that his first reaction to news of the trial was "sadness at the death of the patient and concern about its implications relevant to gene therapy."

Gene Therapy Promise -- and Pitfalls

A number of diseases and conditions are caused by defective genes in the patient's cells. The idea behind gene therapy is to replace these defective, disease-causing genes in a patient's body with normal genes, thus alleviating the source of many genetic diseases.

In order to do this, scientists need a way to get the replacement genes into the patient's cells. The tool of choice is usually a virus that has been modified to carry the new gene. In the same way that a normal virus would infect a cell with its own genetic material, the designer virus -- known as a vector -- infiltrates the cell and delivers the replacement gene.

In recent years, the possibilities of such treatments have heartened disease researchers. But periodic tragedies have blighted development of such treatments.

In 1999, 18-year-old Jesse Gelsinger of Arizona died while participating in a gene therapy trial. He died from multiple organ failures four days after starting the treatment, and investigators believe a severe immune response to the modified virus used in the trial led to his death.

The next blow came in January 2003, when a seemingly successful gene therapy treatment being tested in France for the immune condition commonly known as "bubble baby syndrome" led to a child in the study developing a leukemia-like disorder. A similar condition had occurred in August 2002 in another child who received the gene therapy treatment.

But despite past tragedies, what all of the diseases for which gene therapy shows promise have in common is that they have few, if any, effective treatments available.

"The devastating progression of organ or joint destructive disease in autoimmune disease can justify aggressive trials including gene therapy, or biologic therapies," said Dr. Stephen Mitchell, professor of medicine and pediatrics at Georgetown University.

And because patients in these trials are often already sick from their conditions, determining the exact cause of death can be a challenge.

"People with [rheumatoid arthritis] are at increased risk of dying from heart attacks, for example, and causes of death unrelated to the clinical protocol need to be considered," Fox said.

Informed Consent Key

Regardless of the cause, physicians agreed that the FDA's action is warranted.

"I agree that the FDA has acted appropriately to suspend this trial for the time being, until much more is understood about what happened," Fox said.

And Dr. Robert Yood, chief of rheumatology at Fallon Clinic, said the case underscores the potential problems that patients should consider before enrolling in a clinical trial.

"My reaction to the announcement is that anyone considering an experimental treatment for any medical problem must be informed of all known and potential risks and benefits and then make an informed decision about participation," Yood said.

"It is only through experimental trials that we advance in medicine. I am pleased that the FDA is reacting quickly to this particular issue and halting the trial until more is known."

Copyright © 2014 ABC News Internet Ventures

October 4, 2002

TRIALS ARE HALTED ON A GENE THERAPYBy SHERYL GAY STOLBERG

WASHINGTON, Oct. 3— Officials in the United States and France said today that they had suspended four gene therapy experiments because the treatment, which cured a 3-year-old boy of a fatal immune deficiency, may have given him an illness similar to leukemia.

Scientists conducting the research said it was not clear whether the boy, who was treated as an infant in France, was made sick by the therapy. But officials at the Food and Drug Administration said they suspected that the experiment, which until now had been hailed as the only unequivocal gene therapy success, was responsible.

''It is not absolutely a definitive thing, but the preliminary data that we have leads us to suspect that it surely isn't a coincidence,'' said Dr. Philip Noguchi, the agency official who oversees gene therapy research. ''It's a sobering experience, but we are doing what should be done.''

The experiments -- one in France, three in the United States -- were suspended in early September. But the news was not made public until today, authorities said, to give the researchers time to notify the families of 14 children enrolled in the trials.

The move is yet another major setback for the fledgling field of gene therapy, which involves using viruses to introduce healthy genes into cells. The field is still reeling from the death of Jesse Gelsinger, 18, who lost his life three years ago while undergoing gene therapy at the University of Pennsylvania.

Scientists have long theorized that retroviruses, which were used in the suspended experiments, could trigger cancer. The risk was that the virus, which integrates itself into the patient's DNA, would lodge in or near a cancer-causing gene.

But researchers said they had never seen this before, either in animals or humans, even though hundreds of people have received retroviruses in gene therapy experiments for a number of diseases. Experts said it was too soon to tell whether other children treated for immune deficiency were at risk.

''This has been a spectacularly successful endeavor up to this point,'' said Dr. Savio Woo, former president of the American Society of Gene Therapy. ''This is a new enemy that we have discovered. We know that there is a theoretical possibility, but it has never been seen before.''

The suspended trials sought to cure severe combined immune deficiency, a disorder that leaves infants without working immune systems. Abbreviated as SCID, but commonly called ''bubble boy disease,'' it is extremely rare and is fatal in the first year of life if left untreated.

In the most severe form, the disease affects boys who have faulty X-chromosomes. The only treatment is bone marrow transplant. But the transplants fail in as many as 40 percent of all children who lack a perfect donor match, so scientists looked to gene therapy as an alternative.

In April 2000, Dr. Alain Fischer and his colleagues at the Necker children's hospital in Paris announced that they had used gene therapy to successfully insert corrective genes into the bone marrow stem cells of three babies with X-linked SCID. Coming on the heels of Mr. Gelsinger's death, Dr. Fischer's study was hailed as long-sought proof that gene therapy could work.

Dr. Fischer went on to treat six more babies and a teenager, who survived because he had a partial immune deficiency. ''Up until now, all these patients, more than three and a half years after treatment, are doing well,'' he said. All had ''close to normal immune functions,'' he said.

But last spring, Dr. Fischer said, one of the boys showed elevated levels of a particular type of white blood cell, known as a T-lymphocyte, though he had no symptoms. Subsequently, though, the boy developed chickenpox. By August, Dr. Fischer said, he had a ''significant increase'' in the white cell counts, as well as an enlarged spleen, anemia and a drop in platelets.

When scientists examined the child's cells, Dr. Fischer said, they could see that the genetic material of the retrovirus had inserted into a particular gene on the 11th chromosome that controls the proliferation of cells. But he said he was not yet convinced the gene therapy was entirely to blame.

Other factors, including the chickenpox infection and a family history of cancer, could also be at work, Dr. Fischer said. But Dr. W. French Anderson, a professor at the University of Southern California who was among the first scientists to use gene therapy to treat SCID, said the gene therapy was likely responsible.

''We knew it would happen sooner or later,'' he said. But even if it turns out that gene therapy causes the disease, Dr. Anderson and other experts said gene therapy might still be used to treat SCID because the illness was so devastating.

The child does not have leukemia per se, Dr. Fischer said. There is no name for his proliferation of cells because scientists have never seen it before, so Dr. Fischer is calling it ''lymphoproliferation.''

The boy is being treated with chemotherapy and is responding, Dr. Fischer said. But the abnormal cells have not disappeared, he said.

Dr. Fischer said he notified French authorities, as well as the F.D.A. and his colleagues in the field, right after Labor Day, as soon as he knew the problem was serious.

The food and drug agency immediately put what it calls ''a clinical hold'' on three trials in the United States, two at Children's Hospital in Los Angeles and one at the National Institutes of Health in Bethesda, Md. The N.I.H. study, and one of the Los Angeles studies, have yet to enroll any patients, he said.

The other Los Angeles study is being run by Dr. Donald Kohn, president-elect of the American Society of Gene Therapy. The four children Dr. Kohn and his collaborators have treated all have a form of SCID that is not the X-linked type. But Dr. Kohn said the F.D.A. was correct in suspending his research. ''The clinical hold, I think, is the only ethical and responsible course of action until we have more answers,'' he said.

The F.D.A. will convene a meeting of outside experts next week to discuss the trials, Dr. Noguchi said. He added that other SCID trials had been going on in England and Germany. The German studies have been suspended, but the British research is continuing, he said.

At Cincinnati Children's Hospital Medical Center, researchers said they were collaborating with Dr. Fischer to try to determine what, if anything, went wrong in the study.

But Dr. Christof von Kalle, who is leading the effort, said it could take months, if not years, for a definitive determination.

Today's announcement came as a panel of independent experts released a study of the safety of clinical trials that was prompted by Mr. Gelsinger's death. The panel, at the Institute of Medicine, called for major reforms, including a federal law that would require all research organizations to develop patient protection programs.

Dr. Daniel Federman, a professor of medicine at Harvard Medical School who was chairman of the panel, said the panel was especially concerned about financial conflicts of interest in research. He spoke of a ''hodgepodge of protections'' that was so haphazard it was impossible to catalog how many Americans were enrolled in research experiments, and how many had been harmed by them.

''At the present time, a lot of people are trying to do a good job, and almost certainly are,'' Dr. Federman said. ''What we are trying to do is raise the level of the system as a whole.''

Mr. Gelsinger's father, Paul, who has become an advocate for patient protection and reviewed the study in advance of its publication, applauded the work.

''I have always felt like what happened to Jesse blew the lid off the can of worms of medical research,'' Mr. Gelsinger said. ''The system needs to be looked at, it needs to be unraveled. This study goes a long way toward doing that.''

Group B articleso Biology News Net – Gene Therapy Shows Promise as Weapon Against HIV

http://www.biologynews.net/archives/2009/02/23/gene_therapy_shows_promise_as_weapon_against_hiv.html

o New Scientist - Gene Therapy Cures “Bubble Boy” http://www.newscientist.com/article/dn2124-gene-therapy-cures-bubble-boy.html

o The New York Times – More Than Human http://www.nytimes.com/2005/07/03/books/chapters/0703-1st-naam.html

o New Scientist – Gene Therapy is First Deafness ‘Cure’ http://www.newscientist.com/article/dn7003

o Stanford University Medical Center – Gene Therapy for Muscular Dystrophy Fixes Frail Muscle Cells in Animal Model http://www.eurekalert.org/pub_releases/2005-12/sumc-gtf122205.php

o USA Today – Gene Therapy Experiments Improve Vision in Nearly Blind http://www.usatoday.com/tech/science/2008-04-28-3714044875_x.htm

Gene therapy shows promise as weapon against HIV

February 23, 2009 02:05 PM

A new UCLA AIDS Institute study has found that gene therapy can be developed as a safe and active technique to combat HIV.

Researchers involved in this first-of-its-kind study found that cell-delivered gene transfer has the potential to be a once-only treatment

that reduces viral load, preserves the immune system and avoids lifelong antiretroviral therapy. The study appears in the current online

edition of the journal Nature Medicine.

Though modest, the results do show some promise that gene therapy can be developed as a potentially effective treatment for HIV,

said lead investigator Dr. Ronald Mitsuyasu, professor of medicine and director of the Center for Clinical AIDS Research and Education

(CARE) at the David Geffen School of Medicine at UCLA.

"It is the first randomized controlled study done with gene therapy in HIV," said Mitsuyasu, who is also an associate director of the

UCLA AIDS Institute. "What we were able to demonstrate was that the patients who received the gene-modified cells had a somewhat

better suppression of their HIV viral replication after discontinuing their highly active antiretroviral therapy (HAART) treatment,

compared with the controls."

This was the first randomized, double-blind, placebo-controlled gene-transfer clinical trial and involved 74 HIV-positive adults.

The patients received their own blood stem cells, either untreated or modified to carry a molecule called OZ1, which prevents viral

replication by targeting a key HIV gene. OZ1 was safe, causing no adverse effects over the course of the 100-week trial.

At the primary end-point, the difference in viral load between the OZ1 and placebo group at weeks seven and eight, after they had

stopped HAART treatment, was not statistically significant. But other viral parameters did demonstrate better HIV suppression and

improvement in the counts of CD4+ lymphocytes — the cell population that is depleted by HIV.

The technique still needs to be developed further and perfected, Mitsuyasu said.

"Part of the reason that we didn't see a larger effect is that the persistence of the anti-HIV gene in the patient's blood was not as long as

we would have liked," he said. "We need to find better ways to get the genes into the patients and maintain them, which could include

using different vectors to get the gene into the cells or conditioning the patients prior to gene transfer."

Still, the results indicate that gene therapy could eventually be a useful tool in the fight against AIDS, said study co-author Dr. Thomas

C. Merigan, the George and Lucy Becker Professor of Medicine emeritus at the Stanford University School of Medicine. He agrees that

more needs to be done to perfect it.

"But in the way we set up the trial with randomized placebo controls, we could dissect out that there was a positive effect in patients

who had the gene successfully installed," Merigan said. "This could be a first step in developing a new method of controlling a chronic

infectious disease."

Source : University of California - Los Angeles

Gene therapy cures "bubble boy"

17:00 03 April 2002 by Sophie Petit-ZemanGene therapy has cured Welsh baby Rhys Evans of the fatal "bubble boy" disease. "His progress seems nothing short of a miracle," says his mother Marie. Another boy treated more recently continues to improve.

The treatment, carried out at London's Great Ormond Street Hospital, is one of only a handful of successful gene therapy trials in people. It is also only the third trial of gene therapy for severe combined immunodeficiency or SCID.

Alain Fischer's team at the Necker Hospital in Paris reported the first-ever treatment in 2000, of two boys, while an Italian-Israeli team recently reported promising initial results with two people who have another form of the disease.

Nine people in total have had gene therapy at the Necker Hospital, and seven of them are doing well. But the researchers at Great Ormond Street think they have developed a better way of delivering the gene to correct the fault that causes the disease.

Solitary confinementThe type of SCID that the Welsh baby had is "X-linked", caused by a fault in a gene on the X chromosome that makes an immune protein called interleukin-2. The disease affects boys because they only have one X chromosome. The faulty gene stops the development of T cells, a key part of the immune system.

Children must be kept in isolation to protect them from catching infections and usually die young. A bone marrow transplant can cure the disease, but suitable donors are only found in a third of cases.

To treat the boys, the Great Ormond Street team took the stem cells that give rise to immune cells from the two boys' bone marrow. Then they used a modified form of a retrovirus found in gibbons to add a normal copy of the faulty gene to the stem cells. The virus has altered spikes on its surface which may mean it binds better to stem cells and transfers the gene to them more efficiently, team leader Adrian Thrasher told New Scientist.The engineered stem cells were then returned to the boys' bodies. Rhys Evans is now back at home, with normal T cell levels, seven months after treatment. The second child, treated just three months ago, continues to improve at home. The Great Ormond Street researchers say they are planning to treat another four boys over the next two years.

 

July 3, 2005'More Than Human'By RAMEZ NAAM

In 1989, Raj and Van DeSilva were desperate. Their daughter Ashanti, just four, was dying. She was born with a crippled immune system, a consequence of a problem in her genes.

Every human being has around thirty thousand genes. In fact, we have two copies of each of those genes-one inherited from our mother, the other from our father. Our genes tell our cells what proteins to make, and when. Each protein is a tiny molecular machine. Every cell in your body is built out of millions of these little machines, working together in precise ways. Proteins break down food, ferry energy to the right places, and form scaffoldings that maintain cell health and structure. Some proteins synthesize messenger molecules to pass signals in the brain, and other proteins form receptors to receive those signals. Even the machines inside each of your cells that build new proteins-called ribosomes-are themselves made up of other proteins.

Ashanti DeSilva inherited two broken copies of the gene that contains the instructions for manufacturing a protein called adenoside deaminase (ADA). If she had had just one broken copy, she would have been fine. The

other copy of the gene would have made up the difference. With two broken copies, her body didn't have the right instructions to manufacture ADA at all.

ADA plays a crucial role in our resistance to disease. Without it, special white blood cells called T cells die off. Without T cells, ADA-deficient children are wide open to the attacks of viruses and bacteria. These children have what's called severe combined immune deficiency (SCID) disorder, more commonly known as bubble boy disease.

To a person with a weak immune system, the outside world is threatening. Everyone you touch, share a glass with, or share the same air with is a potential source of dangerous pathogens. Lacking the ability to defend herself, Ashanti was largely confined to her home.

The standard treatment for ADA deficiency is frequent injections of PEG-ADA, a synthetic form of the ADA enzyme. PEG-ADA can mean the difference between life and death for an ADA-deficient child. Unfortunately, although it usually produces a rapid improvement when first used, children tend to respond less and less to the drug each time they receive a dose. Ashanti DeSilva started receiving PEG-ADA injections at the age of two, and initially she responded well. Her T-cell count rose sharply and she developed some resistance to disease. But by the age of four, she was slipping away, no longer responding strongly to her injections. If she was to live, she'd need something more than PEG-ADA. The only other option at the time, a bone-marrow transplant, was ruled out by the lack of matching donors.

In early 1990, while Ashanti's parents were searching frantically for help, French Anderson, a geneticist at the National Institutes of Health, was seeking permission to perform the first gene-therapy trials on humans. Anderson, an intense fifth-degree blackbelt in tae kwon do and respected researcher in the field of genetics, wanted to show that he could treat genetic diseases caused by faulty copies of genes by inserting new, working copies of the same gene.

Scientists had already shown that it was possible to insert new genes into plants and animals. Genetic engineering got its start in 1972, when geneticists Stanley Cohen and Herbert Boyer first met at a scientific conference in Hawaii on plasmids, small circular loops of extra chromosomal DNA in which bacteria carry their genes. Cohen, then a professor at Stanford, had been working on ways to insert new plasmids into bacteria. Researchers in Boyer's lab at the University of California in San Francisco had recently discovered restriction enzymes, molecular tools that could be used to slice and dice DNA at specific points.

Over hot pastrami and corned-beef sandwiches, the two Californian researchers concluded that their technologies complemented one another. Boyer's restriction enzymes could isolate specific genes, and Cohen's techniques could then deliver them to bacteria. Using both techniques researchers could alter the genes of bacteria. In 1973, just four months after meeting each other, Cohen and Boyer inserted a new gene into theEscherichia coli bacterium (a regular resident of the human intestine).

For the first time, humans were tinkering directly with the genes of another species. The field of genetic engineering was born. Boyer would go on to found Genentech, the world's first biotechnology company. Cohen would go on to win the Nobel Prize in 1986 for his work on cell growth factors.

Building on Cohen and Boyer's work with bacteria, hundreds of scientists went on to find ways to insert new genes into plants and animals. The hard work of genetically engineering these higher organisms lies in getting the new gene into the cells. To do this, one needs a gene vector-a way to get the gene to the right place. Most researchers use gene vectors provided by nature: viruses. In some ways, viruses are an ideal tool for ferrying genes into a cell, because penetrating cell walls is already one of their main abilities. Viruses are cellular parasites. Unlike plant or animal cells, or even bacteria, viruses can't reproduce themselves. Instead, they penetrate cells and implant their viral genes; these genes then instruct the cell to make more of the virus, one protein at a time.

Early genetic engineers realized that they could use viruses to deliver whatever genes they wanted. Instead of delivering the genes to create more virus, a virus could be modified to deliver a different gene chosen by a scientist. Modified viruses were pressed into service as genetic "trucks," carrying a payload of genes loaded onto them by researchers; these viruses don't spread from cell to cell, because they don't carry the genes necessary for the cell to make new copies of the virus.

By the late 1980s, researchers had used this technique to alter the genes of dozens of species of plants and animals-tobacco plants that glow, tomatoes that could survive freezing, corn resistant to pesticides. French Anderson and his colleagues reasoned that one could do the same in a human being. Given a patient who lacked a gene crucial to health, one ought to be able to give that person copies of the missing gene. This is what Anderson proposed to do for Ashanti.

Starting in June of 1988, Anderson's proposed clinical protocols, or treatment plans, went through intense scrutiny and generated more than a little hostility. His first protocol was reviewed by both the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Over a period of seven months, seven regulatory committees conducted fifteen meetings and twenty hours of public hearings to assess the proposal.

In early 1990, Anderson and his collaborators received the final approval from the NIH's Recombinant DNA Advisory Committee and had cleared all legal hurdles. By spring, they had identified Ashanti as a potential patient. Would her parents consent to an experimental treatment? Of course there were risks to the therapy, yet without it Ashanti would face a life of seclusion and probably death in the next few years. Given these odds, her parents opted to try the therapy. As Raj DeSilva told the Houston Chronicle, "What choice did we have?"

Ashanti and her parents flew to the NIH Clinical Center at Bethesda, Maryland. There, over the course of twelve days, Anderson and his colleagues Michael Blaese and Kenneth Culver slowly extracted some of Ashanti's blood cells. Safely outside the body, the cells had new, working copies of the ADA gene inserted into them by a hollowed-out virus. Finally, starting on the afternoon of September 14, Culver injected the cells back into Ashanti's body.

The gene therapy had roughly the same goal as a bone-marrow transplant-to give Ashanti a supply of her own cells that could produce ADA. Unlike a bone-marrow transplant, gene therapy carries no risk of rejection. The cells Culver injected back into Ashanti's bloodstream were her own, so her body recognized them as such.

The impact of the gene therapy on Ashanti was striking. Within six months, her T-cell count rose to normal levels. Over the next two years, her health continued to improve, allowing her to enroll in school, venture out of the house, and lead a fairly normal childhood.

Ashanti is not completely cured-she still takes a low dose of PEG-ADA. Normally the dose size would increase with the patient's age, but her doses have remained fixed at her four-year-old level. It's possible that she could be taken off the PEG-ADA therapy entirely, but her doctors don't think it's yet worth the risk. The fact that she's alive today-let alone healthy and active-is due to her gene therapy, and also helps prove a crucial point: genes can be inserted into humans to cure genetic diseases.

From Healing to Enhancing

After Ashanti's treatment, the field of gene therapy blossomed. Since 1990, hundreds of labs have begun experimenting with gene therapy as a technique to cure disease, and more than five hundred human trials involving over four thousand patients have been launched. Researchers have shown that it may be possible to use gene therapy to cure diabetes, sickle-cell anemia, several kinds of cancer, Huntington's disease and even to open blocked arteries.

While the goal of gene therapy researchers is to cure disease, gene therapy could also be used to boost human athletic performance. In many cases, the same research that is focused on saving lives has also shown that it can enhance the abilities of animals, with the suggestion that it could enhance men and women as well.

Consider the use of gene therapy to combat anemia. Circulating through your veins are trillions of red blood cells. Pumped by your heart, they serve to deliver oxygen from the lungs to the rest of your tissues, and carry carbon dioxide from the tissues back out to the lungs and out of the body. Without enough red blood cells, you can't function. Your muscles can't get enough oxygen to produce force, and your brain can't get enough oxygen to think clearly. Anemia is the name of the condition of insufficient red blood cells. Hundreds of thousands of people worldwide live with anemia, and with the lethargy and weakness that are its symptoms. In the United States, at least eighty-five thousand patients are severely anemic as a result of kidney failure. Another fifty thousand AIDS patients are anemic due to side effects of the HIV drug AZT.

In 1985, researchers at Amgen, a biotech company based in Thousand Oaks, California, looking for a way to treat anemia isolated the gene responsible for producing the growth hormone erythropoietin (EPO). Your kidneys produce EPO in response to low levels of oxygen in the blood. EPO in turn causes your body to produce more red blood cells. For a patient whose kidneys have failed, injections of Amgen's synthetic EPO can take up some of the slack. The drug is a lifesaver, so popular that the worldwide market for it is as high as $5 billion per year, and therein lies the problem: the cost of therapy is prohibitive. Three injections of EPO a week is a standard treatment, and patients who need this kind of therapy end up paying $7,000 to $9,000 a year. In poor countries struggling even to pay for HIV drugs like AZT, the added burden of paying for EPO to offset the side effects just isn't feasible.

What if there was another way? What if the body could be instructed to produce more EPO on its own, to make up for that lost to kidney failure or AZT? That's the question University of Chicago professor Jeffrey Leiden asked himself in the mid-1990s. In 1997, Leiden and his colleagues performed the first animal study of EPO gene therapy, injecting lab monkeys and mice with a virus carrying an extra copy of the EPO gene. The virus penetrated a tiny proportion of the cells in the mice and monkeys and unloaded the gene copies in them. The cells began to produce extra EPO, causing the animals' bodies to create more red blood cells. In principle, this was no different from injecting extra copies of the ADA gene into Ashanti, except in this case the animals already had two working copies of the EPO gene. The one being inserted into some of their cells was a third copy; if the experiment worked, the animals' levels of EPO production would be boosted beyond the norm for their species.

That's just what happened. After just a single injection, the animals began producing more EPO, and their red-blood-cell counts soared. The mice went from a hematocrit of 49 percent (meaning that 49 percent of their blood volume was red blood cells) to 81 percent. The monkeys went from 40 percent to 70 percent. At least two other biotech companies, Chiron and Ariad Gene Therapies, have produced similar results in baboons and monkeys, respectively.

The increase in red-blood-cell count is impressive, but the real advantage of gene therapy is in the long-lasting effects. Doctors can produce an increase in red-blood-cell production in patients with injections of EPO itself-but the EPO injections have to be repeated three times a week. EPO gene therapy, on the other hand, could be administered just every few months, or even just once for the patient's entire lifetime.

The research bears this out. In Leiden's original experiment, the mice each received just one shot, but showed higher red-blood-cell counts for a year. In the monkeys, the effects lasted for twelve weeks. The monkeys in the Ariad trial, which went through gene therapy more than four years ago, still show higher red-blood-cell counts today.

This is a key difference between drug therapy and gene therapy. Drugs sent into the body have an effect for a while, but eventually are broken up or passed out. Gene therapy, on the other hand, gives the body the ability to

manufacture the needed protein or enzyme or other chemical itself. The new genes can last for a few weeks or can become a permanent part of the patient's genome.

The duration of the effect depends on the kind of gene vector used and where it delivers its payload of DNA. Almost all of the DNA you carry is located on twenty-three pairs of chromosomes that are inside the nuclei of your cells. The nucleus forms a protective barrier that shields your chromosomes from damage. It also contains sophisticated DNA repair mechanisms that patch up most of the damage that does occur.

Insertional gene vectors penetrate all the way into the nucleus of the cell and splice the genes they carry into the chromosomes. From that point on, the new genes get all the benefits your other genes enjoy. The new genes are shielded from most of the damage that can happen inside your cells. If the cell divides, the new genes get copied to the daughter cells, just like the rest of your DNA. Insertional vectors make more or less permanent changes to your genome. . . . 

Excerpted from More Than Human by Ramez Naam Copyright © 2005 by Ramez Naam. Excerpted by permission.All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Gene therapy is first deafness 'cure'

10:35 14 February 2005 by Andy CoghlanA pioneering form of gene therapy has apparently cured deafness in guinea pigs, raising hopes that the same procedure might work in people.

"It's the first time anyone has biologically repaired the hearing of animals," says Yehoash Raphael at the University of Michigan in Ann Arbor, Michigan, and head of the US-Japanese team that developed the technique.

The therapy promotes the regrowth of crucial hair cells in the cochlea, the part of the inner ear which registers sound. After treatment, the researchers used sensory electrodes around the animals' heads to show that the auditory nerves of treated - but not untreated - animals were now registering sound.

Deafness is a major problem in people: millions of people worldwide become deaf or hearing impaired every year. This can occur if a person's inner-ear hair cells are destroyed by exposure to loud noise, to some antibiotic drugs, or simply through old age. The hair cells act like miniature microphones, capturing sound vibrations from fluid in the ear and translating the movement into nerve signals.

Raphael says one future possibility would be to use the therapy to improve hearing in people who already wear cochlear implants. These electrical devices are of some help to people lacking hair cells, but the regrowth of even some hairs could boost their hearing further. Raphael says that the next experiments in guinea pigs will focus on this combination.

Gene smuggler

Raphael's team first gave the guinea pigs antibiotics which destroyed their inner-ear hair cells. They then apparently repaired the damage by injecting them with genetically engineered adenoviruses.

The viruses had been engineered to be harmless while also smuggling a gene called Atoh1 into cells lining the scala media - the key chamber of the cochlea, containing the hair cells. Atoh1, also known as Math1, makes a signalling molecule known to orchestrate the development of hair cells in embryos.

The experiment worked beyond expectation. "The recovery of hair cells brought the treated ears to between 50% and 80% of their original hearing thresholds," says Raphael. Even more surprising, the team found that the hair cells were created from cells lining the scala media which, according to biological orthodoxy - should not be able to turn into other cells.

Stem cells to hair cells

Raphael warns that there are many obstacles to overcome before the procedure could be used in people. For example, the scala media is buried deep within human skulls, making it virtually inaccessible by surgery. And there is also a possibility that human immune systems could react against the viruses.

Another approach to regrowing the hair cells is to use embryonic stem cells, with research in this area led by Stefan Heller and colleagues at the Massachusetts Eye and Ear Infirmary in Boston, US.

Heller's team produced the inner-ear hair cells by exposing embryonic cells in the lab to chemical factors which steer the natural development of hair cells. The team then implanted them into chicken embryos and the cells continued to develop just like the native hair cells already present in the chick embryo.

Raphael's work is "extremely important", says Heller, as it shows the hairs can regrow and improve hearing. "There are now at least two possibilities for the development of a cure for deafness. It is highly likely that both approaches or a combination of those will find their way into the clinic within the next decade," he told New Scientist.Journal reference: Nature Medicine   (DOI: 10.1038/nm1193)

Contact: Amy Adamsamyadams@stanford.edu650-723-3900Stanford University Medical Center 

Gene therapy for muscular dystrophy fixes frail muscle cells in animal model, Stanford study findsA new gene therapy technique that has shown promise in skin disease and hemophilia might one day be useful for treating muscular dystrophy, according to a new study by researchers at Stanford University School of Medicine.

In the study, scheduled to be published online in the Proceedings of the National Academy of Sciences the week of Jan. 2, the researchers used gene therapy to introduce a healthy copy of the gene dystrophin into mice with a condition that mimics muscular dystrophy. The dystrophin gene is mutated and as a result produces a defective protein in the roughly 20,000 people in the United States with the most common form of the disease.

Using gene therapy to treat muscular dystrophy isn't a new idea. Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences, said that researchers have tried several different techniques with variable success. One hurdle is getting genes into muscle cells all over the body. Another is convincing those cells to permanently produce the therapeutic protein made by those genes.

The gene therapy technique Rando and postdoctoral fellow Carmen Bertoni, PhD, used was developed by Michele Calos, PhD, associate professor of genetics. One of the main advantages of this method is that it could potentially provide a long-term fix for a variety of genetic diseases, including muscular dystrophy.

In muscular dystrophy, the muscle cells break down and are slowly replaced by fat. Eventually people with the disease are confined to a wheelchair and usually die in their 20s. There is currently no effective treatment for the disease, which explains why gene therapy remains a hope despite the significant hurdles.

Rando said the PNAS paper highlights an additional requirement for any gene therapy to be successful: the introduced gene must produce healthy dystrophin protein in large quantities in order to repair the entire muscle cell. Previous muscular dystrophy gene therapy studies did not look at whether the introduced dystrophin spread along the entire length of the muscle cell, which can be many millimeters long in mice or inches long in humans.

In the upcoming paper Bertoni used a standard gene therapy method to introduce two genes - dystrophin and a gene that makes a glowing protein - into mice with a mouse version of muscular dystrophy. She found that in mice producing insufficient dystrophin, she could see the glowing protein slowly leak out of the cell. This leakiness is a sign that the cell is not healed. In contrast, when she used Calos' gene therapy technique to introduce the genes, the muscle cell contained high levels of dystrophin distributed along the length of the cell and the glowing protein stayed within the cell, suggesting that the abundant dystrophin repaired the ailing muscle.

"If you have a single cell that's a foot long and you only correct a few inches, you've done very little," Rando said, "Whereas if you correct it from end to end, you truly cure the disease in that cell."

Both Rando and Calos point out that the road to a gene therapy cure for muscular dystrophy is still a long one. However, Calos is confident that her technique will be a part of the journey towards a cure for the disease and for other diseases such as hemophilia and the skin disease, epidermolysis bullosa. Early trials using her approach have looked promising in animal models of both of these diseases.

"I think our approach has a lot of potential to overcome issues that have slowed the field of gene therapy," Calos said.

Calos said her approach has two advantages: one is that in her method the gene gets inserted directly into the cell's own DNA, which is why the correction is permanent. In some other methods the gene stays outside the DNA and slowly breaks down. The second advantage is that her method doesn't rely on a virus to disperse the DNA and therefore avoids some of the issues, including cancer and an immune reaction, that have turned up in viral gene therapy trials. Instead this approach uses naked DNA that travels through the bloodstream to cells of the body.

For his part, Rando said that no matter how well gene therapy works in an isolated muscle, researchers still must figure out how to get that gene to muscles throughout the body. Despite the remaining hurdles, both Rando and Calos said that their study is a step towards eventually treating muscular dystrophy and other diseases using gene therapy.

Other researchers who contributed to this work include research assistants Sohail Jarrahian and Yining Li, postdoctoral scholar Thurman Wheeler, MD, and graduate student Eric Olivares, PhD. The project was supported by grants from the Muscular Dystrophy Association.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.

Gene therapy experiments improve vision in nearly blindPosted 4/28/2008 4:26 PM | Comment  | Recommend E-mail | Print |

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AP

This

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released

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shows

Steven

Holwarth,

18,

playing

guitar

at

his

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ome

Bolton,

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on

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gene

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four

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children.

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results

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(AP

Photo/BBC)By Stephanie Nano, Associated Press Writer

NEW YORK — Scientists for the first time have used gene therapy to dramatically improve sight in people with a rare form of blindness, a development experts called a major advance for the experimental technique.

Some vision was restored in four of the six young people who got the treatment, teams of researchers in the United States and Britain reported Sunday. Two of the volunteers who could only see hand motions were able to read a few lines of an eye chart within weeks.

"It's a phenomenal breakthrough," said Stephen Rose, chief research officer of the Foundation Fighting Blindness, which helped pay for one study done at Children's Hospital of Philadelphia.

If successful in larger numbers, experts said, the technique has the potential to reverse blindness from other kinds of inherited eye diseases.

"I think this is incredibly exciting," said Dr. Jean Bennett, a professor of ophthalmology at the University of Pennsylvania and a leader of the Philadelphia study. "It's the beginning of a whole new phase of studies."

The research was published online Sunday by the New England Journal of Medicine in conjunction with presentations at a medical meeting in Florida.

The two teams of scientists, working separately, each tested gene replacement therapy in three patients with a form of a rare hereditary eye disease called Leber's congenital amaurosis. There's no treatment for the disease, which appears early in infancy and causes severe vision loss, especially at night.

An estimated 2,000 Americans have the form of the disease they targeted, Bennett said.

Gene therapy -- replacing faulty genes with a normal version -- has been studied in humans for over 15 years with limited success. The field suffered a setback with the 1999 death of Jesse Gelsinger, 18, in an experiment for a liver disorder at Penn. And some children treated for an immune disorder called the "bubble boy disease" later developed leukemia.

The early results of the eye experiments should give the field a boost, some experts said.

"I think it's really a big shot in the arm for gene therapy and for medicine in general," said Dr. Ronald Crystal, head of genetic medicine

at Weill Cornell Medical College in New York.

Each of the study participants had mutations in a gene that makes a protein needed by the retina, which senses light and sends images to the brain. Those without the gene gradually lose sight until they are blind in early adulthood.

The retina itself stays in relatively good shape for a while, making it a good candidate for gene therapy, said Robin Ali, a professor at University College London, who led the British team. He likened the defective gene to a missing spark plug in a car engine.

"The whole engine can be absolutely fine, but if it doesn't have a spark plug, the car's not going to work," said Ali.

For the experiment, the scientists injected millions of copies of a working gene beneath the retina in the back of the eye. Only one eye was treated -- the worst one -- in case anything went wrong; the untreated eye was used for comparison. After the treatment, their eyesight and light sensitivity were measured periodically; mobility was tested in a maze or an obstacle course.

All three of those treated in Philadelphia showed significant improvement in their vision, the researchers said. The volunteers -- two women, 19 and 26, and a man, 26 -- were from Italy, where they had been screened by researchers there. The longest follow-up was six months.

Besides reading lines on an eye chart, they could see better in dim lit, Bennett said.

"We were not expecting to restore their vision to 20/20," she said.

In the British group, the treatment only worked in 18-year-old Steven Howarth, whose disease was less advanced than the other two -- a girl, 17; and a man, 23, who was followed for a year.

Howarth said he used to rush home from school because he was worried about getting around in the dark, according to remarks issued by the university.

"Now, my sight when it's getting dark or it's badly lit is definitely better. It's a small change -- but it makes a big difference to me," said Howarth, who lives in Bolton, near Manchester.

After the injection last July, Howarth said his eye felt like sandpaper. It was better after a week, and his eyesight gradually improved. He was able to negotiate a dimly lit maze in 14 seconds without bumping into any obstacles; before it took him 77 seconds with eight errors.

There were no serious side effects reported in either group. One of the patients in Philadelphia developed a hole in his retina which didn't affect his eyesight. The researchers think the hole was related to the surgery and not the injected gene.

The researchers said there was no evidence that the altered virus used to ferry the gene into the retina's cells had traveled outside the eye to other areas of the body.

The groups have each treated a fourth patient, including a preteen in England. The researchers hope to see better results with higher doses and in younger patients with less eye damage.

The National Eye Institute is funding a third similar study at the University of Florida.

The research in Philadelphia and London was paid for by a variety of government agencies and private foundations. An employee of Targeted Genetics Corp., which made the altered virus used in London, is a co-author of their report. Four of the Philadelphia researchers, including Bennett, have either applied for or have patents related to gene therapy. Ali and another British researcher have also applied for a patent for the procedure.

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AP Science Writer Malcolm Ritter contributed to this report.

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