Gene therapy – the substituting of inherited defective genes with good ones – does not have an outstanding success record but now is getting off the ground. As pointed out in an editorial in the Nov 6 2009 issue of Science magazine, “Gene therapy has recently had some important successes in treating severe inherited diseases after years of skepticism from the scientific community and neglect by the pharmaceutical industry. On page 818 in this issue, Cartier et al. (4) report another major advance—the successful first clinical testing of an HIV-derived vector in hematopoietic stem cell (HSC)–based gene therapy. The procedure was used to treat a severe neurodegenerative disease, X-linked adrenoleukodystrophy (ALD), and the results indicate stable expression of a therapeutic gene in a substantial fraction of patients’ hematopoietic cells, as well as clinical benefits.”
ALD is a rare disease that typically affects boys between the ages of six and 10. Featured in the Hollywood film Lorenzo’s Oil, “ALD is a severe hereditary condition caused by a deficiency of a protein called ALD that is involved in fatty acid degradation. Sufferers steadily lose their myelin sheath, the protective layer that coats nerve fibers in the brain. Without myelin the nerves lose function, leading to increasing physical and mental disability in patients. X-linked ALD, the most common form of the disease, affects boys starting at age 6-8 years of age and death usually occurs before the patients reach adolescence(ref).”
The November 6 2009 research article Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy was reported widely in the press and describes successful treatment by a French team of two patients with ALD. “X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate–binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.”
“The healthy ALD protein was expressed in about 15 percent of blood cells, yet surprisingly this low level was sufficient to slow brain disease in ALD. This percentage of correction will not be sufficient for all diseases,” warns Aubourg (Patrick Aubourg, co-author of the study). “There is a lot of work to be done to make this gene therapy vector more powerful, less complicated, and less expensive. This is only the beginning,” he said(ref).”
What is particularly interesting in the study is use of a defanged version of the HIV virus as a delivery vector for getting the corrected genes into the hematopoietic stem cells extracted from the patients. “In most gene therapy studies, a working gene is inserted into the genome to replace a dysfunctional, disease-causing gene. A carrier molecule called a vector is used to deliver the therapeutic gene into the patient’s cells. Vectors are typically the backbones of viruses that have been genetically altered to carry normal human DNA. Scientists have recently turned to vectors based on the lentivirus genus of retroviruses, which includes HIV. Lentiviral vectors are a type of retrovirus that can infect both dividing and nondividing cells, and are thought to provide long-term and stable gene expression, unlike other retroviruses(ref).”
“Although studies with larger cohorts of patients are needed, these results suggest that gene therapy with lentiviral vectors, which are derived from disabled versions of human immunodeficiency virus (HIV), could potentially become instrumental in treating a broad range of human disorders(ref).” A concern has been that the lentiviral DNA could integrate itself into the stem cells and their descendents and in time create mischief. “Gene therapy is not without serious risks. Like other retrovirus vectors, the HIV-derived lentivirus vector is tasked with inserting the therapeutic gene in the chromosomes of the patients’ cells. In a worst case scenario, this action could disturb the biology of the cells and patients could end up with leukemia; this outcome has occurred in past gene therapy trials. “The HIV-derived lentivirus vector basically has this same risk, although the design of the vector makes patients less prone to this side effect,” said Aubourg(ref).” It seems like the two boys are doing fine so far.