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Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
- Source :
- Science
- Publication Year :
- 2013
-
Abstract
- 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. 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. "\"\\\"\\\\\\\"\\\\\\\\\\\\\\\"\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\"\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\"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.\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\"\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\"\\\\\\\\\\\\\\\"\\\\\\\"\\\"\""
- Subjects :
- Arylsulfatase A
medicine.medical_treatment
Genetic enhancement
Virus Integration
Genetic Vectors
lysosomal enzymes
Hematopoietic stem cell transplantation
lipid storage restoration
Biology
03 medical and health sciences
Transduction
0302 clinical medicine
Genetic
Transduction, Genetic
Lysosomal storage disease
medicine
Humans
Cerebroside-Sulfatase
030304 developmental biology
0303 health sciences
Multidisciplinary
arylsulfatase A activity in CSF
Leukodystrophy
Lentivirus
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell
Brain
Genetic Therapy
Leukodystrophy, Metachromatic
Metachromatic
medicine.disease
Hematopoietic Stem Cells
Magnetic Resonance Imaging
3. Good health
Metachromatic leukodystrophy
Transplantation
medicine.anatomical_structure
Treatment Outcome
Immunology
Genetic Engineering
030217 neurology & neurosurgery
DNA Damage
Follow-Up Studies
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Science
- Accession number :
- edsair.doi.dedup.....e0b73b79dcb6a546b5d5cd3f2ef922c5