Dataset Information

Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain.

ABSTRACT: Severe deficiency in lysosomal ?-glucuronidase (?-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in ?-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the first study attempting the correction of the >200-fold larger and challenging canine MPS VII brain. Here, the efficacy of a helper-dependent (HD) canine adenovirus (CAV-2) vector harboring a human GUSB expression cassette (HD-RIGIE) in the MPS VII dog brain was tested. Vector genomes, ?-glu activity, GAG content, lysosome morphology and neuropathology were analyzed and quantified. Our data demonstrated that CAV-2 vectors preferentially transduced neurons and axonal retrograde transport from the injection site to efferent regions was efficient. HD-RIGIE injections, associated with mild and transient immunosuppression, corrected neuropathology in injected and noninjected structures throughout the cerebrum. These data support the clinical evaluation of HD CAV-2 vectors to treat the neurological defects associated with MPS VII and possibly other neuropathic lysosomal storage diseases.

SUBMITTER: Cubizolle A

PROVIDER: S-EPMC3983960 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain.

Cubizolle Aurelie A Serratrice Nicolas N Skander Nadia N Colle Marie-Anne MA Ibanes Sandy S Gennetier Aurelie A Bayo-Puxan Neus N Mazouni Khalil K Mennechet Franck F Joussemet Beatrice B Cherel Yan Y Lajat Yaouen Y Vite Charles C Bernex Florence F Kalatzis Vasiliki V Haskins Mark E ME Kremer Eric J EJ

Molecular therapy : the journal of the American Society of Gene Therapy 20131217 4

Severe deficiency in lysosomal β-glucuronidase (β-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in β-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammatio ...[more]

PMID: 24343103

Similar Datasets

Project description:Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of incompletely degraded heparan, dermatan and chondroitin sulfate glycosaminoglycans (GAGs). Patients with MPS VII exhibit progressive skeletal deformity including kyphoscoliosis and joint dysplasia, which decrease quality of life and increase mortality. Previously, using the naturally-occurring canine model, we demonstrated that one of the earliest skeletal abnormalities to manifest in MPS VII is failed initiation of secondary ossification in vertebrae and long bones at the requisite postnatal developmental stage. The objective of this study was to obtain global insights into the molecular mechanisms underlying this failed initiation of secondary ossification using whole transcriptome sequencing (RNA-Seq). Epiphyseal tissue was isolated from the vertebrae of control and MPS VII affected dogs at 9 and 14 days-of-age (n=5 for each group). Differences in global gene expression across this developmental window for both cohorts were established using RNA-Seq. A targeted analysis focused on signaling pathways important in the regulation of endochondral ossification, and a subset of gene expression changes were validated using qPCR. Principal Component Analysis revealed clustering of samples from each group, indicating clear effects of both age and disease state. At 9 days-of-age, 1375 genes were significantly differentially expression between MPS VII and control, and by 14 days-of-age, this increased to 4719 genes. Osteoactivin (GPNMB) was the top upregulated gene in MPS VII at both ages. Targeted analysis revealed temporal changes in gene expression from 9 to 14 days-of-age in control samples consistent with chondrocyte maturation, cartilage resorption, and osteogenesis. In MPS VII samples, however, elements of key osteogenic pathways such as Wnt/β-catenin and BMP signaling were dysregulated. In conclusion, this study represents the first step towards identifying druggable therapeutic targets and putative biomarkers for bone disease in MPS VII patients during postnatal growth.

Project description:ObjectiveThis study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy.MethodsHeight, weight, and body mass index (BMI) measurements and Z-scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively.ResultsAmong 20 enrolled patients with MPS VII, height Z-scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight Z-score. BMI Z-scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight Z-scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight Z-scores in female patients.ConclusionsIn patients with MPS VII, declines in height Z-score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height Z-score with age than did patients without a history of NIHF.Clinical trial registration: This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results.

Dataset Information

Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain.

Publications

Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets