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Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis
- Source :
- Molecular Genetics and Metabolism. 116:98-105
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- The neuronal ceroid lipofuscinoses (NCLs) are a group of related hereditary lysosomal storage disorders characterized by progressive loss of neurons in the central nervous system resulting in dementia, loss of motor skills, seizures and blindness. A characteristic intralysosomal accumulation of autofluorescent storage material occurs in the brain and other tissues. Three major forms and nearly a dozen minor forms of NCL are recognized. Infantile-onset NCL (CLN1 disease) is caused by severe deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1) and no therapy beyond supportive care is available. Homozygous Ppt1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death around 8 months. Direct delivery of lysosomal enzymes to the cerebrospinal fluid is an approach that has gained traction in small and large animal models of several other neuropathic lysosomal storage diseases, and has advanced to clinical trials. In the current study, Ppt1 knockout mice were treated with purified recombinant human PPT1 enzyme delivered to the lumbar intrathecal space on each of three consecutive days at 6 weeks of age. Untreated PPT1 knockout mice and wild-type mice served as additional controls. Four enzyme concentration levels (0, 2.6, 5.3 and 10.6 mg/ml of specific activity 20 U/mg) were administered in a volume of 80 μl infused over 8 min. Each group consisted of 16-20 mice. The treatment was well tolerated. Disease-specific survival was 233, 267, 272, and 284days for each of the four treatment groups, respectively, and the effect of treatment was highly significant (p
- Subjects :
- medicine.medical_specialty
Batten disease
Endocrinology, Diabetes and Metabolism
Central nervous system
Infantile neuronal ceroid lipofuscinosis
Biochemistry
Disease-Free Survival
Motion
Endocrinology
Neuronal Ceroid-Lipofuscinoses
Internal medicine
Genetics
medicine
Animals
Humans
Enzyme Replacement Therapy
Palmitoyl protein thioesterase
Molecular Biology
Injections, Spinal
Mice, Knockout
Dose-Response Relationship, Drug
Tripeptidyl-Peptidase 1
biology
Chemistry
Brain
Membrane Proteins
PPT1
Enzyme replacement therapy
medicine.disease
Spinal cord
Recombinant Proteins
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
biology.protein
Neuronal ceroid lipofuscinosis
Thiolester Hydrolases
Subjects
Details
- ISSN :
- 10967192
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Metabolism
- Accession number :
- edsair.doi.dedup.....10eda104dd7f6cc015eee9003e907439