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Gene therapy’s growing pains

Once hailed as the mightiest magic bullet since antibiotics, gene therapy quickly hit technical and ethical roadblocks. But the lessons learned are helping to guide the next generation of genetic research


The paradigm was profound in its simplicity: if a faulty or missing gene causes a disease, just replace that gene with a good working copy. Conceptualized in the 1960s, it was in the early ’90s that gene therapy began generating hopeful headlines on conditions ranging from cardiac arrhythmias and cancers to cystic fibrosis, muscular dystrophy and immune deficiency. Typical was a news story in 1990 in the Washington Post: “New Hope in Treating Hereditary Illness: Researchers Seek to Replace Defective Gene in Blood Cells.”

The idea was to identify the offending gene, engineer a functional clone with recombinant DNA technology, and insert it into the patient – via lab-modified tissue or a disabled virus containing the new gene that would correctively “infect” the targeted cells. But technical and ethical problems soon arose and, for a time, this biotech wunderkind seemed to quit the therapeutic stage.

“As with many things in science, gene therapy turned out to be much more difficult than the enthusiasts originally thought,” says genetics researcher Jacques Tremblay, a professor at Université Laval specializing in muscular dystrophy. It became clear that a great deal more painstaking laboratory and animal work needed to be done before a gene-based treatment could reverse diseases in human patients.

But all is not lost – gene therapy is making a comeback in a new role. “The areas of gene transfer and regenerative stem-cell applications are now merging,” says Jonathan Kimmelman, a former molecular geneticist and a professor in the biomedical ethics unit of McGill University’s faculty of medicine. “Today, there are many gene-based studies under way in humans and some are very promising.”

So what happened to dampen the early hope, hype and hyperbole? “One of the biggest problems with gene transfer is random integration,” says Dr. Tremblay, meaning that the inserted genes do not necessarily go to the right segment of DNA. Adds Kathleen Hodgkinson, a geneticist specializing in inherited cardiac arrhythmias at Memorial University: “And when you do bash a gene in there, you don’t know what effect it will have on nearby genes.”

A case in point is a successful gene transfer trial in Paris, begun in 1999, in which 11 boys were treated for “bubble baby syndrome,” a severe inherited immune deficiency. The corrective DNA was delivered into their bodies using a retrovirus, a carrier that has the ability to transcribe genetic material into a cell’s nucleus. Although the treatment restored immunity in nine of the boys, by 2002, two of them had developed leukemia.

“The vector inserted itself at a site preceding a cancer-promoting gene associated with leukemia and triggered the expression of this gene,” says Dr. Tremblay. In other words, the treatment inadvertently flicked on a cancer switch.

Viral carriers can also cause severe immune reactions. In 1999, gene therapy suffered a major setback with the death of Jesse Gelsinger, an American teenager with an enzyme deficiency causing liver disease. He suffered a raging immune response to a treatment using the adenoviral (common-cold virus) vector and died four days later of multiple organ failure.

These events dashed the hopes of both patients and over-enthusiastic researchers. Expectations about what this technology could achieve – and how quickly – were scaled back.

“But, from the outset, there were many good and skeptical scientists who recognized that it would take many more years to translate this technology into effective medical interventions,” says McGill’s Dr. Kimmelman, who is writing a book on gene therapy due out this fall. “Still, even today there is disappointment that this promising technology has not yet had a major clinical impact.”

As with all novel biotechnologies, problems abound. Apart from inexact targeting, immune reactions, cancer and toxicity, therapeutic genes may simply fail to integrate into a person’s genetic makeup. The patient may need multiple courses of therapy, thus raising the risk of stronger immune reactions due to repeated exposure to foreign vectors.

In addition, gene transfer raises ethically distinct issues that cry out for caution. For one thing, it can irrevocably modify a recipient’s cells. “With radiotherapy or drugs, if a patient has an adverse response, you can take him off the treatment. But with gene transfer, it is difficult, if not impossible, to remove the genes, and the patient lives with the risk of long-term latent adverse effects,” says Dr. Kimmelman.

Yet another problem is the impracticality of using gene transfer to target common multi-gene conditions, such as Alzheimer’s disease, arthritis, diabetes and hypertension, which affect millions of people. The best candidates remain the much rarer single-mutation disorders such as muscular dystrophy or a type of cardiac arrhythmia known as long QT syndrome.

Compounding the application’s technical limitations was the early and precipitous rush to start up gene-therapeutics firms. “The whole phenomenon suffered from a too-rapid business phase,” says cardiologist Evangelos Michelakis, director of the pulmonary hypertension unit at the University of Alberta. “A lot of excitement was generated based on very little solid evidence.”

When any glimmer of progress appeared, there was a competitive stampede to form a company and announce clinical trials to attract lavish funding. “Business and industry players outside of medicine were imposing an accelerated schedule before we really knew what we were dealing with,” says Dr. Michelakis.

In addition, he says, research was often simplistic, isolated and non-integrated. “You’d have one team doing cell work in Germany, another working on dogs in France, yet another studying rats in the U.S., and maybe a phase 1 clinical trial in humans starting in Canada.” There was no continuity, no overall strategic theme. “Each team only cared about a single, simple pathway,” he says.

Enter stem cells

So where do we stand now with gene therapeutics? “The future lies in the transfer of stem cells that have been gene-modified in the lab in culture,” says Dr. Tremblay. Testimony to this, he adds, is the plan by the American Society of Gene Therapy to change its name to the American Society of Gene and Cell Therapy.

Stem cells are generic master cells that have the ability to transform themselves into specific cell types that build or replenish specialized tissues in the body, such as the heart, brain and blood. There are two broad types of stem cells: embryonic stem cells that are the focus of much ethical debate because they are harvested from fetal tissue, and adult stem cells, which are found in adult tissues.

Working in Duchenne muscular dystrophy – caused by the absence of the normal gene for the crucial muscle protein dystrophin – Dr. Tremblay has been using adult stem cells called satellite cells. These cells, which have been modified to contain the genetic instructions to produce dystrophin, are cultured in the lab and then implanted into the muscle cells of the patients. In 2006, his team reported that after transplantation, 34 percent of muscle cells were expressing the dystrophin gene, the best therapeutic result to date in this disease using any approach.

However, in response to lessons learned from past clinical setbacks, Health Canada and the university’s ethics committee have imposed new restrictions that are making it nearly impossible for Dr. Tremblay’s group to recruit patients for a second confirmatory trial. In 2008, the Illinois-based International Society for Stem Cell Research also released tough new guidelines insisting on robust pre-clinical data, expert evaluation, independent oversight, thoroughly informed consent and transparency in reporting trial results.

Despite these obstacles, there is hope. “There are many promising and even exciting studies under way, and it won’t be long before the first gene-transfer products are licensed by drug regulatory bodies,” says Dr. Kimmelman. One product is already available in China – Gendicine, licensed to treat squamous cell cancer in the head and neck – and several companies in the West have submitted data in pursuit of licenses.

There are some new twists as well. Dr. Tremblay is very hopeful about the potential of induced pluripotent stem cells – adult cells that are gene-treated to turn them into embryonic-like stem cells without the ethical controversy attached to therapies using material from the unborn. At the beginning of March, scientists at Mount Sinai Hospital’s Samuel Lunenfeld Research Institute announced that they had done just that. The team, led by University of Toronto molecular genetics professor Andras Nagy, successfully reprogrammed adult skin cells to act like embryonic stem cells – without the use of a potentially cancer-causing viral carrier.

The field is also expanding to include the very promising area of genomic therapy – regulating a patient’s faulty genes with drugs or other novel technologies.

But has early hubris been replaced with humility in the research community? “I hope so,” says Dr. Kimmelman. He points to a greater appreciation today of the need for strong pre-clinical data, fully informed patient consent and the management of financial conflicts of interest. As well, there is definitely a more realistic expectation of the time it takes to translate scientific concepts into effective medical applications.

“These things don’t happen in three to five years,” he says. “Think how long it took with organ transplantation. People worked for decades before the development of immunosuppressive drugs made transplants feasible.”

Without wishing to raise false hopes, these researchers again predict a bright future for the triumvirate of gene, cell and genomic therapies. And with stricter guidelines and lessons learned, they will doubtless have a clearer script to follow.

Gene therapy milestones


The development of genetically marked cell lines gives birth to the concept of gene transfer.


Scientists propose gene “surgery” to remove faulty genes and replace them with functioning copies. Recombinant DNA technology produces lab-cloned genes and demonstrates that foreign genes can correct DNA defects in mammalian cells in the lab.


The University of California’s Martin Cline conducts the first gene-transfer research on two patients suffering from the blood disease thalassemia.


Researchers at Baylor College of Medicine inject an enzyme-producing gene into cells and propose that gene transfer could cure people with Lesch-Nyhan disease, a syndrome characterized by gout, poor muscle control and retardation.


A U.S. gene therapy trial transfers gene-marked white blood cells into five patients with terminal melanoma.


A four-year-old girl undergoes gene therapy for a disorder of the immune system caused by a deficiency of the crucial enzyme adenosine deaminase.


More than 100 U.S. clinical trials of gene therapy have been approved. Wall Street predicts that a gene therapy “product” will hit the market by the following year (none does).


A 66-year-old Toronto man with terminal brain cancer dies in the antiviral-drug stage of a viral-vector gene transfer trial.


Gene therapy suffers another blow with the death from an acute immune reaction of an 18-year-old Philadelphia man treated for an enzyme deficiency.


Paris researchers announce that two of 11 boys successfully treated with retrovirus-vectored gene transfer for severe immune deficiency developed leukemia.


The U.S. Food and Drug Administration declares a moratorium on gene studies using retroviral vectors in humans.


University of Michigan scientists cure deafness in guinea pigs with a genetically engineered adenovirus.


U.S. National Cancer Institute scientists re-engineer white blood cells to attack advanced metastatic melanoma – the first positive treatment of cancer with gene therapy in humans.


UK researchers announce sight improvement in patients following gene therapy for the rare inherited eye disease Leber’s congenital amaurosis.


There are currently nearly 1,500 gene therapy trials underway. Canada ranks fourth in gene transfer research. No gene transfer products are yet on the market in the West.

Diana Swift
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