Abstract
Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydroxylase alpha-l-iduronidase (IDUA). The resulting accumulation of dermatan and heparan sulfate induces intellectual disabilities and pre-mature death, and only a few treatment options are available. In a previous study, we demonstrated the feasibility, safety, and efficacy of gene therapy by injecting recombinant adeno-associated viral vector serotype (AAV)2/5-IDUA into the brain of a canine model of MPS I. We report on a quantitative proteomic analysis of control dogs and untreated dogs with MPS I cerebrospinal fluid (CSF) that had been collected throughout the study in the MPS I dogs. Mass spectrometry (MS) analysis identified numerous proteins present at altered levels in MPS I CSF samples. Quantitative immunoblotting, performed on CSF from healthy controls, untreated MPS I dogs, and MPS I dogs early treated and late treated by gene therapy, confirmed the MS data for a subset of proteins with higher abundance (neuronal pentraxin 1, chitinase 3-like 1, monocyte differentiation antigen CD14, and insulin-like growth factor-binding protein 2). Scoring of the results shows that the expression levels of these proteins are close to those of the control group for dogs that underwent gene therapy early in life but not for older treated animals. Our results disclose four novel predictive biomarker candidates that might be valuable in monitoring the course of the neurological disease in MPS patients at diagnosis, during clinical follow-up, and after treatment.
Highlights
In the field of neurological and neurodegenerative diseases, there is an increasing need for reliable, objective cerebrospinal fluid (CSF) biomarkers of disease severity, disease progression/regression, and response to treatment
The primary objective of the present study was to identify individual proteins or specific combinations thereof in the CSF, the presence or concentration of which would reflect the Mucopolysaccharidosis type I (MPS I) disease stage. We addressed this goal by analyzing CSF samples that had been collected throughout the study in the MPS I dogs
We first assayed IDUA activity in the CSF samples, in order to determine whether the disease correction observed in the brain of treated MPS I dogs was reflected by changes in the cerebrospinal compartment
Summary
In the field of neurological and neurodegenerative diseases, there is an increasing need for reliable, objective cerebrospinal fluid (CSF) biomarkers of disease severity, disease progression/regression, and response to treatment. CSF Biomarkers in MPS I (LSDs) result in intellectual disabilities and pre-mature death [1]. The mucopolysaccharidoses (MPSs) are a family of hereditary LSDs caused by deficiencies of the lysosomal enzymes required for the degradation of glycosaminoglycans. Mucopolysaccharidosis type 1 (MPS I, referred to as Hurler syndrome; OMIM #607014) is caused by deficiency of the lysosomal hydrolase alpha-L-iduronidase (IDUA, EC3.2.1.76), which leads to the accumulation of dermatan sulfate and heparan sulfate. The most severely affected children show profound intellectual disabilities before the age of 10, and the progression of MPS I results in multiple disabilities. The cloning of all genes implicated in the various types of MPS enabled the production of recombinant enzymes for administration as intravenous enzyme replacement therapy in MPS patients with peripheral lesions. We observed that late gene therapy was less efficacious than gene therapy immediately after weaning—confirming that the window for treating these diseases is narrow
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