Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow.

2.50
Hdl Handle:
http://hdl.handle.net/10541/95890
Title:
Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow.
Authors:
Fairbairn, Leslie J; Lashford, Linda S; Spooncer, Elaine; McDermott, R H; Lebens, G; Arrand, Jane E; Arrand, John R; Bellantuono, Ilaria; Holt, R; Hatton, C E; Cooper, A; Besley, G T; Wraith, J Ed; Anson, D S; Hopwood, J J; Dexter, T Michael
Abstract:
Allogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. Various gene-transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols, we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, by using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of hemopoietic colonies as 25-56%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. The enzyme is secreted into the medium and functional localization has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This work suggests that retroviral gene transfer into human bone marrow may offer the prospect for gene therapy of Hurler syndrome in young patients without a matched sibling donor.
Affiliation:
Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester, United Kingdom.
Citation:
Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow. 1996, 93 (5):2025-30 Proc. Natl. Acad. Sci. U.S.A.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
5-Mar-1996
URI:
http://hdl.handle.net/10541/95890
PubMed ID:
8700879
Type:
Article
Language:
en
ISSN:
0027-8424
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorFairbairn, Leslie Jen
dc.contributor.authorLashford, Linda Sen
dc.contributor.authorSpooncer, Elaineen
dc.contributor.authorMcDermott, R Hen
dc.contributor.authorLebens, Gen
dc.contributor.authorArrand, Jane Een
dc.contributor.authorArrand, John Ren
dc.contributor.authorBellantuono, Ilariaen
dc.contributor.authorHolt, Ren
dc.contributor.authorHatton, C Een
dc.contributor.authorCooper, Aen
dc.contributor.authorBesley, G Ten
dc.contributor.authorWraith, J Eden
dc.contributor.authorAnson, D Sen
dc.contributor.authorHopwood, J Jen
dc.contributor.authorDexter, T Michaelen
dc.date.accessioned2010-04-07T14:27:23Z-
dc.date.available2010-04-07T14:27:23Z-
dc.date.issued1996-03-05-
dc.identifier.citationLong-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow. 1996, 93 (5):2025-30 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn0027-8424-
dc.identifier.pmid8700879-
dc.identifier.urihttp://hdl.handle.net/10541/95890-
dc.description.abstractAllogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. Various gene-transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols, we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, by using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of hemopoietic colonies as 25-56%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. The enzyme is secreted into the medium and functional localization has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This work suggests that retroviral gene transfer into human bone marrow may offer the prospect for gene therapy of Hurler syndrome in young patients without a matched sibling donor.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshAntigens, CD34-
dc.subject.meshBase Sequence-
dc.subject.meshBone Marrow-
dc.subject.meshCells, Cultured-
dc.subject.meshDNA Primers-
dc.subject.meshGene Expression-
dc.subject.meshGene Therapy-
dc.subject.meshGenetic Vectors-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHumans-
dc.subject.meshIduronidase-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMucopolysaccharidosis I-
dc.subject.meshPhenotype-
dc.subject.meshTime Factors-
dc.titleLong-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow.en
dc.typeArticleen
dc.contributor.departmentDepartment of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester, United Kingdom.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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