期刊
SCIENCE
卷 341, 期 6148, 页码 864-U58出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1233158
关键词
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资金
- Fondazione Telethon (TIGET) [B2, F3, D2, D1]
- European Union (EU) [F2-2010-241622, GA 222878 PERSIST]
- European Leukodystrophy Foundation [ELA 2007-00515]
- Italian Ministry of Health [Progetto Giovani Ricercatori GR-2008-57, Progetto Giovani Ricercatori GR-2007-684057]
- European Research Council (ERC) [249845]
- Italian Ministry of Health
- Association for International Cancer Research [AICR 09-0784]
- Italian Higher Institute of Health
- European Research Council (ERC) [249845] Funding Source: European Research Council (ERC)
- Worldwide Cancer Research [09-0784] Funding Source: researchfish
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
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