Much of the original promise of gene therapy was its potential to treat inherited diseases. Inherited diseases, many of which have no current treatment, are ideal models for gene therapy treatment because they are usually caused by the deficiency of a single gene. Gene therapy would treat the disease by simply inserting a functional copy of the gene to correct the inherited deficiency.
The potential of gene therapy for the treatment of inherited diseases was recently shown in a clinical trial for severe combined immunodeficiency disease-X1 (SCID-X1). The authors isolated early hematopoietic progenitor cells from the bone marrow of 2 affected patients. They used a retroviral vector to insert a normal copy of the deficient gamma-c receptor gene into the cells during ex vivo culture and then returned the transduced cells to the patient. Now, more than a year later, both of the treated patients are still showing normal responses in immune function tests.1
Unfortunately, no commercial gene-therapy treatments for inherited disorders have thus far emerged. Phase 2 and 3 clinical trials, which would be required before a gene therapy product could become available, are extremely expensive and would require financial support by pharmaceutical or biotechnology companies. Because inherited diseases are rare, often affecting only a few thousand people worldwide, there is little potential for return on investments in expensive research and clinical trials.
Instead, the focus of most gene therapy research has shifted towards more common diseases such as cancer and the acquired immunodeficiency syndrome (AIDS). Of the 409 clinical gene therapy trials that have been submitted to the US National Institutes for Health, 249 have been for cancer, and 33 have been for AIDS. Only 50 have been for inherited diseases, and 20 of these have been for cystic fibrosis—the most common inherited disease among whites.2
Although common diseases may make attractive targets to pharmaceutical companies, they are also more complex models for treatment by gene therapy. Common diseases such as cancer or heart disease often involve many genes. Instead of merely inserting a functional copy of the defective gene as in inherited diseases, more innovative approaches are required. Before gene therapy becomes a standard treatment option, there are still 3 core technologies that must be improved.
First, the biggest obstacle to successful gene therapy seems to be an inability to introduce the therapeutic gene into a sufficient number of cells. The human body contains approximately 1014 cells, making it extremely difficult to treat all of them. However, most diseases affect only a single tissue. A gene therapy vector that could specifically target the affected organ would make it possible to treat a disease while introducing the gene into significantly fewer cells. Because of their improved efficiency, targeted vectors could improve the feasibility of gene transfer into a sufficient number of cells for the successful treatment of a disease.
Second, even when a therapeutic gene is successfully introduced into a target cell, the cell seems to be capable of recognizing it as foreign and turning it off through either methylation or other mechanisms.3 Gene therapy vectors that contain regulatory sequences more closely related to those actually used by human genes may be able to more effectively evade "gene silencing." Current gene therapy vectors also contain nonspecific promoters that drive high expression of the therapeutic gene in a wide variety of tissues. Many diseases, however, may require much more accurate temporal and spatial regulation of gene expression.4
Third, current technology for the production of most gene therapy vectors is based on the use of specialized cell lines called packaging cells. Although vectors produced in packaging cells have proven safe in the past when used on smaller scales, they may be less reliable on large commercial scales. Packaging cells, especially in large production conditions, are susceptible to infectious contaminants such as viruses, and they contain many elements that are not completely understood and cannot be easily controlled. Production of synthetic vectors by industrial techniques not dependent on cell lines would reduce this level of uncertainty.5
Although much remains to be learned about how to insert therapeutic genes into cells and how cells will respond to a new gene, recent successes indicate that the technical hurdles can be overcome. There is little doubt that successful gene-therapy treatments for more common diseases will be made available because of their economic potential. Unfortunately, because single-gene disorders are rare, there is little financial incentive to develop gene therapies for them. These diseases, however, are ideal targets for gene therapy, and patients who are diagnosed with them should not be denied treatment with this powerful new technology.
Ball BG, Anderson WF. Bringing Gene Therapy to the Clinic. JAMA. 2000;284(21):2788-2789. doi:10.1001/jama.284.21.2788-JMS1206-5-1