Ciron, C et al.. Gene therapy of the brain in the dog model of Hurler's syndrome. Ann Neurol 60: 204-213

Institut National de la Sante et de la Recherche Médicale U649, CHU Hôtel Dieu, Nantes, France.
Annals of Neurology (Impact Factor: 9.98). 08/2006; 60(2):204-13. DOI: 10.1002/ana.20870
Source: PubMed


A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno-associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme-deficient dogs.
Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen.
Treatment was tolerated well. We observed broad dispersion of vector genomes in the brain of efficiently immunosuppressed dogs. The delivery of IDUA to large areas, which could encompass the entire brain, prevented glycosaminoglycan and secondary ganglioside accumulations. This condition was associated with drastic reduction of neuropathology throughout the encephalon. In contrast, vector injection combined with partial immunosuppression was associated with subacute encephalitis, production of antibodies against IDUA in brain tissues, and elimination of genetically modified cells.
Gene therapy directed to the entire brain is feasible and may be beneficial to children with Hurler's syndrome. The possibility of subacute encephalitis emphasizes the importance of preventing immune response against IDUA, a problem that needs to be considered in similar therapies for other genetic defects.

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    • "Dogs have proven to be very good model animals for human Alzheimer's disease and aging [27] [28] [29]. There are also dog models for more rare diseases such as Hurler's syndrome, Sanfilippo syndromes and Duchenne muscular dystrophy [30] [31] [32]. "
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    ABSTRACT: As the number of fully sequenced animal genomes and the performance of advanced mass spectrometry-based proteomics techniques are continuously improving, there is now a great opportunity to increase the knowledge of various animal proteomes. This research area is further stimulated by a growing interest from veterinary medicine and the pharmaceutical industry. Cerebrospinal fluid (CSF) is a good source for better understanding of diseases related to the central nervous system, both in humans and other animals.
    Full-text · Article · Jul 2015
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    • "Unfortunately, these depletion kits have been tested for only a limited number of donor species (usually human beings and rodents). On the other hand, there is increasing interest in the development of dog models for diseases, such as the Hurler syndrome [12], the Sanfilippo syndrome [13] or Duchenne muscular dystrophy [14]. This interest, together with the first proteomic studies directed at the identification of CSF biomarkers for canine diseases [15,16], prompted us to investigate the applicability of commercial depletion kits for dog CSF. "
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    ABSTRACT: Background Highly abundant proteins in biological fluids such as serum or cerebrospinal fluid (CSF) can hinder the detection of proteins in lower abundance, e.g., potential biomarkers. Commercial products are available for the depletion of albumin and immunoglobulins (Igs), although most of these kits have not been validated for dog samples. The present study therefore examines the use of different types of depletion kits for dog CSF. Findings Three kits, with different mechanisms for the depletion of albumin and Igs, were tested with dog CSF specimens. One product significantly decreased the amount of albumin; with all kits, IgG was less efficiently removed than albumin. Mass spectrometry of the fractions eluted from the depletion columns revealed considerable co-depletion of other CSF proteins. Conclusions A commercially available depletion kit was identified which depletes albumin and (to a lower extent) immunoglobulins from dog CSF. However, the limited efficacy and the concomitant loss of other proteins from the sample should be taken into account when using this product.
    Full-text · Article · Jun 2014 · Fluids and Barriers of the CNS
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    • "This could provide sustained therapy if a sufficient level of enzyme was secreted in the brain. We and others have demonstrated the potential of different vectors in correcting neuronal pathologies in MPS II (Cardone et al., 2006), MPS IIIA and B (Cressant et al., 2004; Langford- Smith et al., 2012), and MPS VII mice (Bosch et al., 2000a,b; Liu et al., 2007) as well as in larger animal models for the disease (Ciron et al., 2006; Ellinwood et al., 2011). However, clinically relevant gene therapy using common human pathogens as vectors may be complicated by the high incidence of preexisting humoral and cellular immunity (Chirmule et al., 1999; Perreau et al., 2007a). "
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    ABSTRACT: Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders due to their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing ß-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in ß-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. Following intracranial administration of HD-RIGIE, we show long-term expression of ß-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for a brain therapy in patients with lysosomal storage disease.
    Full-text · Article · Dec 2013 · Human gene therapy
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