Preliminary results reporting the safety and effectiveness of gene therapy in patients with metachromatic leukodystrophy published in The Lancet

The gene therapy developed in the laboratories of the San Raffaele Telethon Institute for Gene Therapy in Milan (SR-Tiget) remains effective as a potential early treatment of metachromatic leukodystrophy (MLD), a rare neurodegenerative disease caused by the alteration of a gene called arylsulfatase A (ARSA), which leads to progressive loss of cognitive and motor skills of children who are affected.

Ana Carolina

The results published in the scientific journal The Lancet describe the first nine patients in an ongoing phase I-II clinical study of twenty patients which started in 2010 and was coordinated by Alessandra Biffi at the San Raffaele Telethon Institute for Gene Therapy in Milan. The nine patients in the study are affected by late infantile or early juvenile MLD, the most severe early-onset forms of the disease and were treated either before the onset of the disease or during the early stage of disease, thanks to early detection facilitated by family history (i.e. the presence of an older sibling suffering from the same disease). The patients received an infusion of hematopoietic stem cells obtained from the patient’s own bone marrow and corrected in the laboratory through the use of "carriers" or "shuttles" to carry the therapeutic gene ARSA.

The publication reports that the first nine children treated with the investigational gene therapy. are alive and eight of them are in good health, with an average of three years follow-up (range, 1.5-4.5 years).
«Metachromatic leukodystrophy is a disease with no effective treatment today for those with the late infantile form of the disease and with treatments of variable efficacy for those with the early juvenile form of disease. Our study shows that gene therapy can potentially provide a therapeutic benefit to patients with early onset of the disease, when treated pre-symptomatically or during the earliest manifestations of disease» commented Alessandra Biffi, who coordinated the work at the Institute San Raffaele Telethon for gene therapy of Milan.

«This disease in early-onset forms has a fatal outcome and the young patients, after a normal psychomotor development, at an early age gradually lose all motor and cognitive skills previously acquired, as well as speech and vision. This happened to the older untreated siblings of many of the children treated. For children treated with this investigational gene therapy, most cases have thus far shown normal growth, with the development of motor and cognitive skills appropriate to their age».

Luigi Naldini, Director of the San Raffaele Telethon Institute for Gene Therapy in Milan, said: «Apart from the obvious benefit that early onset patients have had so far from treatment, these encouraging results demonstrate the potential that gene therapy has to develop new therapeutic strategies. In fact, in early onset metachromatic leukodystrophy transplantation of stem cells from healthy donor is weak. With gene therapy we have engineered the stem cells of the patient so that they could deliver to the nervous system greater levels of therapeutic enzyme than could be achieved by the cells of a healthy donor. We therefore not only corrected an enzyme deficiency, but also intend to make the patient's cells more effective in preventing the damage of the disease than would be achieved by the cells of a healthy donor. The follow-up of the first nine patients treated with gene therapy encourages us now to apply a similar strategy also to other neurodegenerative storage diseases where transplantation has non-satisfactory results».

Gene therapy procedure
The treatment involves taking bone marrow from the patients themselves, isolating hematopoietic stem cells (ie intended to generate all blood elements) and using a viral vector derived from HIV to introduce a correct version of the gene that is defective and responsible for the disease into the stem cells. The potential of using a HIV derived vector for gene therapy was first suggested by Luigi Naldini, Director of the San Raffaele Telethon Institute for Gene Therapy. Due to the efficiency of these vectors, the stem cells corrected in the laboratory are able, once reintroduced into the body, to generate other cells capable of producing the missing protein in quantities exceeding those of the cells of a healthy donor and to have thus a therapeutic effect.

The treatment involved the infusion of hematopoietic stem cells derived from patients’ own bone marrow in which a functional ARSA gene had been introduced previously through the use of vectors, following exposure to a chemotherapy regimen. A fraction of gene modified stem cells and their progeny engraft in the bone marrow and migrated to the central and peripheral nervous system, restoring in these tissues the ARSA activity.

The study's findings and the next steps
The first preliminary evidence of the potential effectiveness of this investigational gene therapy in the first three pre-symptomatic late infantile MLD patients were published by the SR-Tiget researchers in Science 2013.
The Lancet 2016 publication describes the medium term preliminary data for the first nine patients with early-onset metachromatic leukodystrophy treated with gene therapy. In eight patients, most of whom have been treated in the pre-symptomatic phase of the disease, a clear benefit was demonstrated by preventing disease or arresting its progression. The treatment has proved able to prevent the loss of myelin (the insulating coating of the nervous system) in the brain of children and to improve in some patients the defects present in peripheral nerves with signs of reconstruction of myelin at both locations. Moreover, in sharp contrast with the natural course of the disease, these eight children showed not only the maintenance, but also the acquisition of new motor and cognitive skills in line with their age.

At the time of the data presentation in the Lancet publication, the childrenwere between the ages of 5 and 10 years old and came from different countries of the world. In the coming years they will continue to be monitored through periodic checks at the clinical area of the San Raffaele Telethon Institute for Gene Therapy. Results of this study will be published when all 20 patients have achieved 3 years follow-up.

Metachromatic leukodystrophy
Metachromatic leukodystrophy (MLD) is a severe neurodegenerative disease of genetic origin due to deficiency of ARSA, responsible for the disposal of particular substances, the sulfatides, that in the absence of ARSA accumulate in the nervous system and progressively and irreversibly damage the myelin, the insulating covering of nerves. Clinically this results in the gradual loss of cognitive and motor skills acquired so far: born apparently healthy, these children gradually stop moving, eating independently, speaking and communicate in the terminal phase only through the eyes, the smile, the tears. In the most severe forms (late infantile and early juvenile MLD, collectively referred to as early onset MLD) symptoms begin to occur early, within two years in the first case and by the age of 6 in the second, with the death that occurs within a few years of diagnosis. At the moment there is no treatment that can invariably stop the degenerative process. The general prevalence of MLD varies from 1:40,000 to 1:100,000 (~60% LI, 20-30% juvenile and 10-20% adult). [Von Figura 2001]

The collaboration GSK / Telethon / OSR
Gene therapy for treatment of metachromatic leukodystrophy developed in Milan at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) has been exclusively licensed to GSK, a global healthcare company. In order to transform research results into therapies for patients, in fact, the Telethon Foundation has partnered since 2004 with GSK for their research and development capabilities and expertise. In 2010, this partnership has become a strategic alliance between the Telethon Foundation, San Raffaele Hospital and GSK itself to fight seven rare genetic diseases such as MLD. Thanks to this agreement, a gene therapy for another rare genetic disorder, adenosine deaminase-severe combined immunodeficiency syndrome (ADA-SCID), obtained authorization from the European Commission in May 2016 to be marketed under the name Strimvelis. The production of carriers for therapeutic use and handling of stem cells of patients for clinical trials thus far developed from this collaboration, including metachromatic leukodystrophy, were made by MolMed. This work was possible thanks to funding from the Telethon Foundation, San Raffaele Hospital in Milan and GSK.

The Lancet, 8 June 2016
Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial

M. Sessa1,2,*,#, L. Lorioli1,3,4,5,*, F. Fumagalli1,2, S. Acquati1, D. Redaelli1, C. Baldoli6, S. Canale1, I.D. Lopez2, F. Morena7, A. Calabria1, R. Fiori8, P. Silvani8, P.M.V. Rancoita5, M. Gabaldo1, F. Benedicenti1, G. Antonioli3,4, A. Assanelli3,4, M.P. Cicalese3,4, U. del Carro2, M. G. Natali Sora2, S. Martino7, A. Quattrini2, E. Montini1, C. Di Serio5, F. Ciceri4, M.G. Roncarolo1,5, A. Aiuti1,3,4,5, L. Naldini1,5, A. Biffi1,3,4,5,§
(1) San Raffaele Telethon Institute for Gene Therapy (TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy;
(2) Neurology Unit;
(3) Pediatric Immunohematology Unit;
(4) Bone Marrow Transplantation Program;
(6) Neuroradiology Unit;
(8) Departement of Anesthesia and Critical Care; at IRCCS San Raffaele Scientific Institute, Milano, Italy.
(5) Vita Salute San Raffaele University, Milano, Italy.
(7) Department of Chemistry, Biology and Biotechnologies, University of Perugia, Perugia, Italy.(*) Equal contribution.

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