03/19/2015 10:55 am ET | Updated May 19, 2015

4 Things to Know About Gene Therapy

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Four Things to Know About Gene Therapy

Gene therapy made its debut to much fanfare in the 1990s, but enthusiasm quickly abated after a young man died during treatment for liver disease in one clinical trial and patients with "bubble boy" disease developed treatment-related leukemia in other trials. Now, as a physician-scientist who has been involved in basic gene therapy research and the development of clinical trials since the 1980s, it is exciting to witness gene therapy making a comeback.

1. What is gene therapy?
Genes provide the blueprints that instruct cells to make the various proteins needed for all normal bodily functions. If a critical gene is mutated or absent, disease may ensue. In gene therapy, we use a vehicle, called a vector, usually a specially modified virus, to deliver the correct gene to the patient. Think of this as the viral vector acting like an unmanned drone delivering a package to fix, for example, the broken furnace in your house.

This is possible only in conditions for which we know which gene causes the disease and can also deliver the correct gene into the cells that cause the disease. With some diseases, we collect the patient's stem cells, add the gene-carrying vector in the laboratory, and then give the cells back to the patient. In other diseases, we deliver the vector directly into the bloodstream or affected organ.

Candidates for gene therapy trials include patients with diseases lacking effective standard therapies, as well as patients who are not good candidates for standard therapies - for example, patients who lack matched sibling donors for the conventional hematopoietic (blood) stem cell transplants used to treat some conditions.

2. What problems dramatically slowed progress in gene therapy after it debuted with fanfare more than two decades ago. Why is it experiencing a comeback now? Two main issues needed to be overcome. The first was the transition from animal models to humans. In the early days, optimism was very high because we were curing disease in mice, but when we applied the technology to humans it wasn't always up to the task. In particular, we found the efficiency with which our vectors could deliver their payload to the correct cell (like the correct address in the example above) was much less in humans than in mice.

The second problem was the occurrence of serious adverse events related to the technology itself. In 1999, Jesse Gelsinger, who had been treated at the University of Pennsylvania with gene therapy for ornithine transcarbamylase deficiency, a genetic disease of the liver, died from the vector's toxicity to the liver, into which it had been delivered. Other gene therapy trials in Europe, which used a different approach to treat X-linked severe combined immune deficiency (SCID-X1 or "bubble boy" disease), one quarter of patients developed leukemia directly due to the vector itself. Likewise, leukemia developed in several patients in trials using a similar viral vector to treat Wiskott-Aldrich Syndrome, a disease that affects immunity and decreases the body's ability to form blood clots, and chronic granulomatous disease, an immune deficiency disorder that affects the body's ability to fight fungal and bacterial infections. In all of these cases, the vector used to deliver the gene therapy inadvertently "turned on" tumor-promoting genes known as oncogenes.

Gene therapy is now experiencing a comeback because both the safety and technological efficiency of the vector systems have improved. For instance, scientists, including some here at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, have identified and removed the viral sequences from the vector that activated the oncogenes that appeared to trigger the leukemia seen in the earlier trials. In a recent article in the New England Journal of Medicine, my colleagues and I reported that the new vector appears to be both effective and safe.

Researchers have also developed new viral vector systems that significantly reduce the type of toxicities associated with the death of Jesse Gelsinger. In addition, as scientists' basic understanding of stem cell biology has improved over the past two decades, so has the ability to safely and effectively manipulate hematopoietic stem cells outside the bone marrow and prepare them to accept the gene transfer.

3. What diseases have been in clinical trials for gene therapy?
Proof-of-principle successes in the application of gene therapy targeting hematopoietic stem cells has been shown in multiple severe, fatal genetic diseases that affect children, including the disorders noted above as well as childhood cerebral adrenoleukodystrophy and metachromatic leukodystrophy, two degenerative neurological disorders. There is currently a great deal of attention and excitement about T-cell immunotherapy for leukemia patients - using gene therapy to reeducate the immune system's T cells to be more effective against antigens (foreign substances) expressed in tumor cells.

The trials have produced strikingly positive results in both adults and children with treatment-resistant leukemia. In addition, gene therapy using a different viral vector system that targets non-stem cells has been reported successful in treating Leber's congenital amaurosis (a retinal disease that causes blindness) and hemophilia B. Clinical trials in one genetic form of SCID -- adenosine deaminase deficiency or ADA SCID -- proved so successful that some insurance companies have recognized it to be as effective as the enzyme replacement therapy typically used to treat the disease and are beginning to cover treatment with gene therapy.

4. What are we learning and what's next?
We're learning which diseases you can potentially cure with gene therapy. We're starting to learn the parameters by which you can predict that someone with a given disease can or cannot be cured.

We're starting to learn the dosages of cells and genes that are needed to be effective. We're also learning which vector technologies or platforms work best for particular diseases. These are things that you can't study in an animal model. You have to study in humans.

I think we'll soon learn that for some diseases gene therapy may be even better than conventional stem cell transplantation, the standard of care for several diseases now in gene therapy trials, because we can actually express the missing gene at higher levels than in normal donor cells. This may lead to more effective treatment.

We're still early in the field, so even in diseases for which the outcomes from gene therapy appear as good as standard therapies, until we have more experience with gene therapy we will continue to rely on standard therapies.