X-linked severe combined immunodeficiency

In recent years, research on gene therapy has yielded successes that offer much hope to patients suffering from a spectrum of diseases. I expect great advances in the coming years, but researchers still face obstacles.

One sign of the field's development is the growth of related professional societies. The American Society of Gene Therapy grew 115% between 1999 and 2002, from 1,443 to 3,102 members. Gene therapy societies in other countries have shown similar growth. National Institutes of Health funding for gene therapy research grew 8% between 2002 and 2003, from $379.7 million to $409.8 million.

About 80% of gene therapy trials occur in the United States. Cancer research accounts for 63% of trials, followed by studies of monogenetic disease (12.3%). Yet we're clearly in the early stages of gene therapy research: 66% of trials are in phase I and another 21% are between phases I and II. Only about 3,500 patients have been treated so far.

Despite these small numbers, advances in several important areas have occurred in recent years.

Early research in gene therapy focused on severe combined immunodeficiency (SCID). This led to break-throughs in treating several forms of this disorder, most notably in treating X-linked SCID (X-SCID) through use of a retrovirus to deliver the corrected gene into the patient's hematopoietic stem cells.

Gene therapy has also led to progress in hemophilia treatment. Phase I trial results using an adeno-associated virus injected into muscle to provide factor IX provide hope for patients with this disease.

There has been some success in using gene therapy in the treatment of cystic fibrosis. In a phase II trial, researchers used an adeno-associated virus to deliver the cystic fibrosis transmembrane conductance regulator gene to the lung epithelium.

Despite these successes, we have a lot to learn about developing methods for gene transfer. We also face problems in developing both viral and nonviral gene delivery methods. With viral vectors, toxicity is a major problem, and with nonviral vectors, inefficient gene transduction and limited gene expression are stumbling blocks.

But serious adverse events pose the biggest problem in our field. The number of these has been limited, considering the number of patients who have been treated. However, a recent incident in which two children participating in an X-SCID gene therapy trial developed leukemia highlights the need to proceed cautiously. In that trial, which tested the use of a retroviral vector to treat patients with X-SCID, immune function was restored in most patients.

Unfortunately, adverse events are part of the research process in this field, as in others. And additional risks may emerge as we treat patients who are less sick.

Further challenges include manufacturing and toxicology. For large-scale production of gene therapies, we will need to devise a system of reference strains and vectors, agree on a dosing standard unit, and refine techniques for obtaining highly purified vectors for preclinical studies. To improve our understanding of the toxicology of these new therapies, we will need to select appropriate animal models, standardize toxicology procedures, perform preclinical studies with toxicology in mind, improve risk-benefit analysis, and implement the mandate for 15-year follow-ups in gene therapy trials.

In terms of the future, it has become obvious that one or two vectors will not meet all needs. We have an opportunity to better match vectors with diseases. This is particularly true of the evolving use of gene transfer to bone marrow stem cells, which has reached a high level of sophistication. Other types of adult stem cells also have exciting potential as vectors.

We will probably see gene therapy start to blend into standard medical practice, becoming part of a multimodal approach for treating cancer and other diseases. And there is much interest in using gene transfer tools for vaccines.

As we pioneer a new wave of genetic medicine, progress will not come without setbacks. The path will require faith, innovation, stamina, and reason. The marriage of technology development and clinical research has proved itself in the past, and I am confident that gene therapy will be no exception.

JOSEPH C. GLORIOSO III, PH.D., is president of the American Society of Gene Therapy and professor and chairman of the molecular genetics and biochemistry department at the University of Pittsburgh.

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