I translated this from italian so the english is not perfect.
NEW STRATEGY OF GENE THERAPY FOR KRABBE'S DISEASE
Devised a new strategy of gene therapy to Krabbe disease, a severe genetic disorder that affects the nervous system: thanks to gene therapy with hematopoietic stem cells by an international team of researchers led by Luigi Naldini at the San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET) of Milan has succeeded for the first time to treat the disease in the animal model. The important result is shown in the pages of Science Translational Medicine *, the new magazine published by the prestigious international scientific journal dedicated to translational research, ie, strongly marked by the transfer 'from the laboratory bench to bedside'.
As explained by Alessandra Biffi, co-director of the study with Luigi Naldini, "Krabbe disease, also called cell leukodystrophy globoidi, is a lysosomal storage disease that strikes in childhood and has a course of rapidly progressive and always fatal. The disease is hereditary and is due to defects in the gene for galattocerebrosidasi (Galco), enzymes responsible for the disposal of some components of myelin, the insulating covering of nerves essential for the conduction of impulses in the central and peripheral nervous system. If the enzyme is defective, minus the natural turnover of these substances, which accumulate in the lysosomes as well (usually appointed facilities for waste disposal cell) and become toxic to myelin. The result is a progressive arrest of psychomotor development of affected children, who also lost motor skills and cognitive skills already acquired. "
Unfortunately to date there is no therapy capable of preventing or halting the progression of the disease, nor seek to restore lost functions. In some cases, can slow the progression of the disease by performing a transplant of hematopoietic stem cells (stem cells of all the elements of the blood) from a healthy donor before the onset of symptoms (ie within the first 4 months of life). Not always, however, is a compatible donor, also this type of transplant carries the risk of rejection by the body to the donor stem cells. Biffi continues: "Our experience in other similar diseases has shown that it can make treatment more effective and less risky genetically corrected hematopoietic stem cells of the patient. To do that you take advantage of specific viral vectors (lentiviral called) that will produce in the patient's cells than normal production of therapeutic gene (Galco in this case), in the absence of risks to the incompatibility between donor and transplant recipient. "
This approach, based on the possibility of using mature blood cells - derived hematopoietic stem cell transplantation - as a vehicle to transport the enzyme functioning in the nervous system affection, has already been successfully applied by researchers to model HSR pre-TIGET Preclinical other lysosomal storage diseases and is currently the subject of an ongoing clinical trial in patients with metachromatic leukodystrophy. So far, however, was not possible to apply it to Krabbe disease because, as explained by Naldini, "we came across an unexpected toxicity of the enzyme for Galco blood stem cells, something that did not occur in their differentiated progeny. We then devised a new strategy to regulate the expression of the therapeutic gene, which must be inserted in the stem cells to ensure its long-term maintenance, and transmit to all their offspring, but there has to express its product. For this we served of microRNAs, small regulatory elements of the expression of other genes. Each micro-RNA can "turn off" the expression of a battery of other genes that recognizes through a sort of 'bar code' imprinted on their message. "
Thanks to a new method developed by them to view the activity of miRNAs in single living cells, researchers have tried TIGET HSR-what were selectively expressed in the rare stem cells from bone marrow and not in their offspring during of differentiation. They found for the first time of microRNAs specific to hematopoietic stem cells and put the bar code recognized by one of these miRNAs in a lentiviral vector for gene therapy of Krabbe disease, which in this way is sensitive to silencing by microRNA. "Even if the vector is inserted into stem cells, the therapeutic gene can be expressed only in their mature progeny, after the microRNA has died" explains Naldini (see also figure below). "The transplantation of genetically corrected cells in animal model of Krabbe's disease, which presents a very human-like," has significantly improved the conditions of life and survival of treated animals. In particular, this therapy approach gene was more beneficial than the traditional transplanting healthy donor. In addition, our strategy is promising not only for the treatment of Krabbe disease, we intend to move to a clinical trial on patients as soon as we finished the other preclinical studies necessary - expected in 2 years - but also because it allows for more effective and safe gene therapy based on hematopoietic stem cells in many other genetic diseases. "
Sign their work as first authors Bernhard Gentner, a German researcher and medical Visigalli Ilaria, both in training at the Hsr-TIGET and University San Raffaele, University of Toronto and other collaborators. The study was conducted with funding provided by Telethon, the European Community, Cariplo Foundation (Project Nobel), National Tay Sachs and Allied Diseases Association and the European Leukodystrophy Association (ELA).
* B. Gentner, I. Visigalli, H. Hiramatsu, E. Lechman, S. Hungarians, A. Giustacchini, G. Schira, M. Amendola, A. Quattrini, S. Martin, A. Orlacchio, JE Dick, A. Biffi, L. Naldini, Hematopoietic Stem Cell-Identification of Specific Gene Therapy of miRNAs Enables Globoid Leukodystrophy. Sci Transl. Med 2, 58ra84 (2010).