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


METHODS
Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen.


RESULTS
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.


CONCLUSIONS
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.
Ciron
Carine
C
Institut National de la Sante et de la Recherche Médicale U649, CHU Hôtel Dieu, Nantes, France.
Desmaris
Nathalie
N
Colle
Marie-Anne
MA
Raoul
Sylvie
S
Joussemet
Béatrice
B
Vérot
Lucie
L
Ausseil
Jérôme
J
Froissart
Roseline
R
Roux
Françoise
F
Chérel
Yan
Y
Ferry
Nicolas
N
Lajat
Yaouen
Y
Schwartz
Bertrand
B
Vanier
Marie-Thérèse
MT
Maire
Irène
I
Tardieu
Marc
M
Moullier
Philippe
P
Heard
Jean-Michel
JM
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000473:pathology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001835:Body Weight; D001921:Brain / Q000473:pathology*; D004285:Dogs; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006025:Glycosaminoglycans / Q000378:metabolism; D007068:Iduronidase / Q000276:immunology; D008297:Male; D008059:Mucopolysaccharidosis I / Q000473:pathology* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013238:Stereotaxic Techniques
D001323:Autoantibodies; D005732:Gangliosides; D006025:Glycosaminoglycans; D007068:Iduronidase