PerspectiveGene Therapy

The Best of Times, the Worst of Times

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Science  28 Apr 2000:
Vol. 288, Issue 5466, pp. 627-629
DOI: 10.1126/science.288.5466.627

According to recent press coverage, gene therapy has fallen on hard times. If one were to believe the news media, gene therapy is both a scientific failure and unsafe. Is this gloomy picture true? Fortunately, no. The paper by Cavazzana-Calvo et al. (1) on page 669 of this issue provides an example of the exciting results that are starting to be obtained in human gene therapy clinical trials. The authors have successfully treated with gene therapy (for at least up to 10 months) two infants suffering from inherited severe combined immunodeficiency (SCID).

Mutations in several different genes of immune cells can result in SCID. The first gene therapy trial almost 10 years ago treated two girls suffering from a type of SCID caused by a deficiency in the enzyme adenosine deaminase (ADA). In the new study, Cavazzana-Calvo et al. treat patients with an X-linked form of SCID (SCID-X1) caused by a mutation in the gene encoding the γc subunit, a component of certain cytokine receptors. After several years of preclinical studies, these investigators have carried out a clinical trial with two SCID-X1 patients, ages 11 and 8 months. They took hematopoietic stem cells (which expressed the surface marker CD34 and were capable of differentiating into all types of blood cells) from the infants' bone marrow and incubated the cells ex vivo with a retroviral vector carrying the γc cDNA. The transduced stem cells were then transfused back into the SCID-X1 patients. The authors present data from 10 months of follow-up and the results are very encouraging. Ten months after receiving transduced stem cells, the numbers of T, B, and natural killer (NK) cells of the immune system were normal, as were a number of measures of immune function (such as specific responses to antigen). Clinically, the two patients improved considerably and were able to leave protective isolation in the hospital after 3 months and have been at home ever since. Clearly, longer follow-up is necessary and more patients need to be treated, but the initial data strongly suggest that SCID-X1 can be successfully treated by retroviral-mediated gene therapy.

Why are the results of Cavazzana-Calvo et al. more encouraging than those from the earlier gene therapy experiments that treated ADA-deficient SCID patients (26)? In the first clinical protocol, the investigators inserted a normal copy of the gene encoding ADA (carried in a retroviral vector) into mature T lymphocytes (2). Later protocols attempted to transfer the same gene into bone marrow stem cells (35), which would differentiate into T lymphocytes capable of responding to new antigens. Cavazzana-Calvo and co-workers used a Moloney-derived retroviral vector (MFG) to deliver the therapeutic gene to the SCID-X1 infants. MFG is an improvement over the earliest retroviral vectors and may be more effective for expressing genes in T cells, but the vector itself could not be the major reason for success; MFG has been used in a number of trials without significant efficacy. Certainly, the transduction conditions of the new study are far superior to those of the early 1990s. Of most significance, perhaps, is the inclusion of Flt3 (a factor that greatly enhances stem cell growth in culture) along with other growth factors in the medium for culturing bone marrow stem cells, and the use of fibronectin-coated culture vessels. The levels of gene transduction obtained by Cavazzana-Calvo et al. are, consequently, much higher than those obtained in earlier studies.

Unlike the earlier gene therapy trials that treated ADA-deficient SCID patients, Cavazzana-Calvo and colleagues did not have to administer PEG-ADA—a polyethylene glycol-conjugated ADA enzyme preparation that reduces the levels of the toxic molecule deoxyadenosine in ADA-deficient patients—to the SCID-X1 infants. The concomitant administration of PEG-ADA is believed to lessen the potential growth advantage of ADA gene-corrected cells (7). Finally, SCID-X1 can result in a more profound deficiency in T cells than ADA-deficient SCID; therefore, the positive selection for gene-corrected T cells may have been more vigorous in the SCID-X1 patients.

The majority of ADA-deficient SCID patients treated with gene-corrected stem cells have not been significantly helped. But the very first ADA-deficient SCID patient, a 4-year-old girl who received only gene-corrected mature T cells, and not stem cells, has thrived (2, 8, 9) (see the figure). She received 11 infusions from September 1990 to August 1992 and has maintained a circulating level of 20 to 25% gene-corrected T cells and a normal life-style with amelioration of her disease symptoms. Her partial response to PEG-ADA treatment before gene therapy had not provided her with an adequate immune system; nonetheless, we have felt it wise to continue treating her with PEG-ADA as a safety-net.

Ashanti de Silva.

Now 13, Ashanti was the first patient to be treated with gene therapy. She received infusions of T cells that had been transduced with a gene for ADA (an enzyme that she lacks), resulting in an amelioration of the symptoms of her severe combined immunodeficiency.


Careful monitoring indicates that the vigor of her immune response has gradually diminished over the past several years, but it still remains in the normal range, albeit at the low end. But, as she only received mature gene-corrected T cells that, unlike stem cells, cannot be educated to respond to new antigens, how has she been able to generate an immune response to the new antigens that she encounters constantly? One explanation is provided by the data obtained in the first 6 months of treatment [see figure 1A of (2)]. When only a small number of gene-corrected T cells were infused (less than 1% of the total T cell population), the total number of T cells tripled from 500 to 1500 per microliter of blood. When several infusions were missed because of technical problems, the T cell number plummeted back to 500. When infusions of gene-corrected T cells were resumed, the total T cell number again rose rapidly, this time to over 2000. One could speculate that it requires only a threshold level of “normal” (that is, gene-corrected) T cells in the lymphoid tissues to provide a microenvironment that allows the noncorrected (both immature and mature) T cells to function normally. Thus, her immature T cells may be able to differentiate in lymphoid tissue, and thereby provide her with immune protection against new antigens, as long as the “normal” mature T cells are maintained above a critical level.

The successful treatment of the first gene therapy patient suggests that the positive results of Cavazzana-Calvo et al. may continue over the long term. The gene-corrected stem cells of the two SCID-X1 infants should continue to experience a positive selection in the patients so that even if some cells have their γc gene silenced over time, others will expand to maintain the immune status of the patients.

In addition to the success achieved with gene therapy for the treatment of SCID, recent publications suggest progress in the treatment of hemophilia (10) and in the growth of new blood vessels to treat cardiovascular disease (11). Furthermore, early data demonstrate headway in the development of gene-based vaccines for treating several chronic infectious diseases and some types of cancer.

The field of gene therapy has been criticized for promising too much and providing too little during its first 10 years of existence. But gene therapy, like every other major new technology, takes time to develop. Antibiotics, monoclonal antibodies, organ transplants, to name just a few areas of medicine, have taken many years to mature. Major new technologies in every field, such as the manned rocket to the moon, had failures and disappointments. Early hopes are always frustrated by the many incremental steps necessary to produce “success.” Gene therapy will succeed with time. And it is important that it does succeed, because no other area of medicine holds as much promise for providing cures for the many devastating diseases that now ravage humankind.


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