1,721,320 research outputs found
Genetically-modified hematopoietic stem cells and their progeny for widespread and efficient protein delivery to diseased sites: The case of lysosomal storage disorders
No full textEfficient therapeutic protein delivery is a challenging task in several disease contexts and particularly when the CNS is concerned. Different approaches for brain-directed delivery have been thus far investigated, including direct injection of molecules or of their coding information carried by dedicated vector systems within the brain parenchyma or in the ventricular space, intravenous systemic administration of molecules/vectors modified to target and cross the blood-brainbarrier, and exploitation of allogeneic and/or autologous and genetically modified cells as vehicles for the therapeutic of interest. Among these, we here review one of the most promising approaches based on hematopoietic stem cells, taking advantage of lysosomal storage disorders as representative disease setting. © 2012 Bentham Science Publishers
Hematopoietic stem cell gene therapy for metachromatic leukodystrophy and other lysosomal storage diseases
No full textBeyond remote working, the paradigm of "smart" work. Designing interdependencies
No full textIndicazione della progettazione organizzativa dello smart working basata sulla impostazione delle interdipendenz
Novel candidate disease for gene therapy: Metachromatic leukodystrophy
No full textMetachromatic leukodystrophy (MLD) is a rare, fatal, inherited, autosomal recessive, lysosomal storage disorder, characterized by severe and progressive demyelination affecting the central and peripheral nervous systems. Despite some initial expectations in hematopoietic stem cell transplantation, and despite the ameliorated supportive therapy, MLD remains a life-threatening disease, with an extremely poor quality of life and a severe prognosis for all affected patients. Prospectively, in children affected by MLD, who have no other therapeutic option and an extremely poor prognosis, the potential risks associated with the use of a novel technology, such as gene therapy, might be well balanced by the potential benefit of a positive outcome. Thus, MLD might be considered an optimal candidate disease for testing innovative and potentially efficacious therapeutic approaches. Some of the gene therapy approaches discussed here, such as hematopoietic stem cells gene therapy, are likely to enter clinical testing in the near future. © 2007 Informa UK Ltd
Gene therapy for leukodystrophies
No full textLeukodystrophies (LDs) refer to a group on inherited diseases in which molecular abnormalities of glial cells are responsible for exclusive or predominant defects in myelin formation and/or maintenance within the central and, sometimes, the peripheral nervous system. For three of them [X-linked adrenoleukodystrophy (X-ALD), metachromatic (MLD) and globoid cell LDs], a gene therapy strategy aiming at transferring the disease gene into autologous hematopoietic stem cells (HSCs) using lentiviral vectors has been developed and has already entered into the clinics for X-ALD and MLD. Long-term follow-up has shown that HSCs gene therapy can arrest the devastating progression of X-ALD. Brain gene therapy relying upon intracerebral injections of adeno-associated vectors is also envisaged for MLD. The development of new gene therapy viral vectors allowing targeting of the disease gene into oligodendrocytes or astrocytes should soon benefit other forms of LDs. © The Author 2011. Published by Oxford University Press. All rights reserved
Hematopoietic stem cell transplantation for metachromatic leukodystrophy
No full textMetachromatic leukodystrophy (MLD) is a rare, fatal, inherited lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA). The enzymatic defect results in the accumulation of the ARSA substrate, mainly in myelin forming cells, leading to progressive demyelination and dysfunction in the CNS and peripheral nervous system. The severity of the disease and the absence of approved treatments stimulate testing innovative therapeutic strategies.Areas covered: Among diverse experimental approaches, hematopoietic stem cell (HSC) transplantation (HSCT) from healthy compatible donors, and very recently, gene therapy based on transplantation of autologous HSCs transduced with a lentiviral vector encoding for the ARSA cDNA have been applied to MLD patients. State of the development of these HSC-based strategies is here analyzed, based on a review of the scientific literature, focusing on the outcomes of allogeneic HSCT, and on its potential clinical benefit and limitations.Expert opinion: HSC-based approaches would require the evaluation of long-term follow-up on neurological and transplant-related outcomes of larger cohorts of patients, in order to rationally define indication to treatment for MLD patients
Human hematopoietic stem cells in gene therapy: Pre-clinical and clinical issues
No full textHematopoietic stem and progenitor cells (HSC) have been widely used in allogeneic transplant procedures, therefore their intrinsic characteristics, the biology of their niche in the bone marrow, and the mobilization and homing processes have been extensively investigated. With the development of gene therapy strategies, new therapeutic options based on autologous HSC have become available which may reduce the morbidity and mortality associated to allogeneic transplantation, but require an ex vivo manipulation of the cells to be corrected before re-infusion. For the success of these approaches it is necessary to optimize culture conditions in order to achieve efficient cell transduction while preserving the biological properties of the stem cells. We review here the factors critical for achieving efficient HSC transduction and maintenance of HSC stemness and homing capacity upon ex vivo culture. When HSC gene therapy is used in genetic disorders, permanent integration of therapeutic genes into the chromosomes of affected cells is needed. Indeed, by use of integrating vectors, such as retroviruses, gene therapy has met significant success in immunodeficiency syndromes characterized by a selective advantage of the transduced cells. However, retroviral integration can take place in stem cells at a variety of chromosomal sites, and examples have been reported of integration of therapeutic vectors causing cancer in patients. The clinical benefit arising from the long-term correction of the genetic defect, due to vector integration into the HSC genome, and the adverse consequences of these events are also here discussed, together with the new and challenging perspectives of HSC gene therapy. © 2008 Bentham Science Publishers Ltd
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