Hematopoietic stem cell gene therapy for the treatment of metachromatic leukodystrophy

Published on September 3, 2014   37 min

Other Talks in the Therapeutic Area: Haematology

0:00
I'm Alessandra Biffi, MD. I'm working at the San Raffaele Telethon Institute for Gene Therapy in Milano, Italy. And my talk is going to be dedicated to the presentation of our recent results in the development of hematopoietic stem cell gene therapy for the treatment of metachromatic leukodystrophy.
0:25
Metachromatic leukodystrophy is a demyelinating lysosomal storage disorder. It is due to the deficiency of the activity of the arylsulfatase A enzyme, which is a lysosomal enzyme that plays a key role in the maintenance of myelin sheaths in the center and peripheral nervous system. Arylsulfatase A indeed is critical for the metabolize of sulfatides that are major components of myelin, again, both present in the central and peripheral nervous system. It is a disease that is inherited in an autosomal recessive fashion. It's a rare disorder, with an overall frequency of one affected children over 40,000 live births, and it is characterized by quite variable clinical presentations. In particular, we recognize four different variants of the disease that are distinguished according to the age at onset of the first symptoms of the disease and include the late infantile variant, with symptom onset before two years of age; the early juvenile MLD variant, in which the disease manifests in between two and six years of age; late juvenile MLD, in which symptom onset occurs between six age and puberty; and the adult variant, in which the onset of symptom occurs from puberty on. All of these disease variants are characterized by clinical manifestations related to the myelin damage occurring in the nervous system, and so they basically present with signs of dysfunction of the central and peripheral nervous system that, in children, are manifest in the form of developmental delay, so delay in the acquisition of motor and cognitive milestones and early loss of previously acquired motor and cognitive skills. Whereas in adults, mostly manifests in the form of deterioration of cognitive abilities and, later on, motor abilities, and the psychiatric manifestations. Whatever the disease variant, the MLD is characterized by a very severe prognosis and is fatal, basically, in all of the patients within a few years from disease onset. At the moment, that are few therapeutic options available for MLD. In particular, we do have the opportunity of hematopoietic stem cell transplantation, which is available for a minority of patients and which has been shown to stabilize disease evolution mostly in late-onset MLD variants and when the transplant is performed very early in the course of the disease. Then we have some experimental treatments under testing which include gene therapy and enzyme replacement therapy. Enzyme replacement therapy, which consists in the administration of the recombinant arylsulfatase A to the patients, failed to exert a benefit when administered systemically whereas is under phase one clinical testing upon administration into the thecal space-- so within the cerebrospinal fluid. Gene therapy is under testing with two different approaches, the first one being an in vivo gene therapy approach, namely administration of gene therapy vectors within the brain parenchyma, and the other one being hematopoietic stem cell gene therapy, so the approach we are going to discuss during this presentation.
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Hematopoietic stem cell gene therapy for the treatment of metachromatic leukodystrophy

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