Science: Gene Therapy Technique Slows “Lorenzo’s Oil” Brain Disease

A strategy that combines gene therapy with blood stem cell therapy may be a useful tool for treating a fatal brain disease, researchers report in a new study in Science.

In a pilot study of two patients monitored for two years, the international team of researchers slowed the onset of the debilitating brain disease X-linked adrenoleukodystrophy (ALD), using a lentivirus delivery system to introduce a therapeutic gene into the patients’ blood cells.

Although studies with larger groups of patients are needed, these results suggest that gene therapy with lentiviral molecules, which are derived from disabled versions of human immunodeficiency virus (HIV), could become instrumental in treating a broad range of human disorders.

“This is the first time we were able to successfully use an HIV-derived lentivirus vector for gene therapy in humans, and also the first time that a very severe brain disease has been treated with efficacy by gene therapy,” said co-author Patrick Aubourg, professor of pediatrics at University Paris-Descartes and head of a research unit at Inserm-University Paris Descartes. “We’ve demonstrated that this HIV-derived lentivirus vector works as was hoped for so many years.”

The Science authors presented their findings to an audience of over 50 people, including reporters from French newspapers, magazines, wire services, and television, at a news briefing in Paris on 4 November.

Featured in the movie “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. People with ALD 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 as early as age 6, and death usually occurs before the patients reach adolescence.

Bone marrow transplants typically slow progression of the disease because the donor marrow includes cells that develop into myelin-producing cells. However, finding a matching bone marrow donor can be a challenging and lengthy process, and the procedure carries considerable risks. Genetically correcting the blood stem cells in the patients’ own bone marrow may prove to be a valuable alternative approach when no matching donors are available.

In the Science study, blood stem cells were removed from the patients and genetically corrected in the lab, using a lentiviral vector to introduce a working copy of the ALD gene into the cells. The modified cells were then infused back into the patients after they had received a treatment that destroyed their bone marrow. Two years later, healthy ALD proteins were still detectable in both patients’ blood cells. The two patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants.

Scientists have recently turned to gene therapy vectors based on the lentiviral family of retroviruses, which includes HIV. Lentiviral vectors can infect both dividing and nondividing cells, and are thought to provide long-term and stable expression of the therapeutic genes, unlike other retrovirus carriers.

Progeny of hematopoetic stem cells that were engineered to carry the correct version of a gene (through the integration of a lentiviral vector) distribute throughout the body. The Science authors show that some cells replaced diseased microglia in the brain and relieved lipid storage in patients suffering from ALD.

[Image courtesy of Y. Greenman/Science]

(l-r) Dr. Alain Fischer from the University Paris Descartes, Hospital Necker-Enfants Malades, and Inserm in Paris; Dr. Stella Hurtley from Science's Cambridge office; Dr. Christof von Kalle from NCT/DKFZ in Heidelberg, Germany; Dr. Nathalie Cartier, lead author of the study, from Inserm-University Paris Descartes; Dr. Salima Hacein-Bey-Abina from the Hospital Necker-Enfants Malades and Inserm-University Paris Descartes; Dr. Patrick Aubourg, team leader, from Inserm-University Paris Descartes and the Hospital Saint Vincent de Paul and Dr. Marina Cavazzana-Calvo from the University Paris Descartes, the Hospital Necker-Enfants Malades, and Inserm

[Photo by Natasha Pinol]

“The HIV-derived lentivirus vector allows expression of the therapeutic gene in principle for life, because the therapeutic gene is inserted in the chromosomes—the genome,” said Aubourg. “Therefore, cells that derive from the initially corrected cells, stem cells in particular, will continue to express the therapeutic gene forever.”

But the procedure is not without risks, said Paula Kiberstis, senior editor at Science. “In the 30 years since the concept was first introduced, the gene therapy field has reported several clinical successes but it has also experienced some widely publicized setbacks, the most recent being the development of leukemia in a subset of patients enrolled in a gene therapy trial for an immunodeficiency disorder,” Kiberstis said in written remarks read at the Paris briefing. “These setbacks have proved instructive and have led researchers to develop safer viral vectors for delivering therapeutic genes.”

In the worst-case scenario, the HIV-derived lentivirus vector could disturb the biology of patients’ cells, said Aubourg, but he noted that “the design of this vector makes patients less prone to this side effect.”

Aubourg said the lentiviral vector technique was able to correct 15% of the patients’ blood stem cells, just the right amount needed to slow brain disease in ALD. “Yet, this percentage of correction will not be sufficient for all diseases,” he warned. “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.”

Nadia Ramlagan

5 November 2009