Gene therapy of the brain in the dog model of Hurler's syndrome

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

ABSTRACT 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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    • "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.
    Fluids and Barriers of the CNS 06/2014; 11:14. DOI:10.1186/2045-8118-11-14
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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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    Human gene therapy 12/2013; 25(3). DOI:10.1089/hum.2013.152 · 3.76 Impact Factor
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    • "Thus we aim to test the efficacy of Ad-hsFlt3L and Ad-TK in dog patients bearing spontaneous GBM. To this end we and others have previously demonstrated the feasibility of delivering therapeutic transgenes to dog GBM cells in vitro and dog brain cells in vivo upon intracranial injection of gene therapy vectors, such as type 5 adenoviral vectors [21]–[23] and adeno-associated viral vectors [24]. Also, we have shown that TK expression exerts a powerful cytotoxic effect on dog GBM cells [21], [22]. "
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