Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum

被引:115
作者
Cressant, A
Desmaris, N
Verot, L
Bréjot, T
Froissart, R
Vanier, MT
Maire, I
Heard, JM
机构
[1] Inst Pasteur, Unite Retrovirus & Transfert Genet, Dept Neurosci, INSERM,U622, F-75015 Paris, France
[2] Fac Med Lyon Sud, INSERM, U189, F-69921 Oullins, France
[3] Hop Debrousse, Serv Biochim Pediat, F-69322 Lyon, France
关键词
lysosomal storage disease; alpha-N-acetylglucosaminidase; adeno-associated virus vectors; gangliosides; hyperactivity; elevated plus-maze;
D O I
10.1523/JNEUROSCI.3558-04.2004
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Sanfilippo syndrome is a mucopolysaccharidosis ( MPS) caused by a lysosomal enzyme defect interrupting the degradation pathway of heparan sulfates. Affected children develop hyperactivity, aggressiveness, delayed development, and severe neuropathology. We observed relevant behaviors in the mouse model of Sanfilippo syndrome type B ( MPSIIIB), in which the gene coding for alpha-N-acetylglucosaminidase ( NaGlu) is invalidated. We addressed the feasibility of gene therapy in these animals. Vectors derived from adeno-associated virus serotype 2 ( AAV2) or 5 ( AAV5) coding for NaGlu were injected at a single site in the putamen of 45 6-week-old MPSIIIB mice. Normal behavior was observed in treated mice. High NaGlu activity, far above physiological levels, was measured in the brain and persisted at 38 weeks of age. NaGlu immunoreactivity was detected in neuron intracellular organelles, including lysosomes. Enzyme activity spread beyond vector diffusion areas. Delivery to the entire brain was reproducibly obtained with both vector types. NaGlu activity was higher and distribution was broader with AAV5-NaGlu than with AAV2-NaGlu vectors. The compensatory increase in the activity of various lysosomal enzymes was improved. The accumulation of gangliosides GM2 and GM3 present before treatment and possibly participating in neuropathology was reversed. Characteristic vacuolations in microglia, perivascular cells, and neurons, which were prominent before the age of treatment, disappeared in areas in which NaGlu was present. However, improvement was only partial in some animals, in contrast to high NaGlu activity. These results indicate that NaGlu delivery from intracerebral sources has the capacity to alleviate most disease manifestations in the MPSIIIB mouse model.
引用
收藏
页码:10229 / 10239
页数:11
相关论文
共 52 条
[11]   Targeted disruption of the mouse sphingolipid activator protein gene: A complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids [J].
Fujita, N ;
Suzuki, K ;
Vanier, MT ;
Popko, B ;
Maeda, N ;
Klein, A ;
Henseler, M ;
Sandhoff, K ;
Nakayasu, H ;
Suzuki, K .
HUMAN MOLECULAR GENETICS, 1996, 5 (06) :711-725
[12]  
GEHLER J, 1974, HUMANGENETIK, V23, P149
[13]   Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent [J].
Gondré-Lewis, MC ;
McGlynn, R ;
Walkley, SU .
CURRENT BIOLOGY, 2003, 13 (15) :1324-1329
[14]  
GOODWIN EC, 1992, J BIOL CHEM, V267, P16330
[15]   ROLE OF THE AMYGDALA AND PERIAQUEDUCTAL GRAY IN ANXIETY AND PANIC [J].
GRAEFF, FG ;
SILVEIRA, MCL ;
NOGUEIRA, RL ;
AUDI, EA ;
OLIVEIRA, RMW .
BEHAVIOURAL BRAIN RESEARCH, 1993, 58 (1-2) :123-131
[16]   Novel tools for production and purification of recombinant adenoassociated virus vectors [J].
Grimm, D ;
Kern, A ;
Rittner, K ;
Kleinschmidt, JA .
HUMAN GENE THERAPY, 1998, 9 (18) :2745-2760
[17]   ULTRASTRUCTURAL AND BIOCHEMICAL ASPECTS OF THE SANFILIPPO SYNDROME, TYPE-III GENETIC MUCOPOLYSACCHARIDOSIS [J].
HAUST, MD ;
GORDON, BA .
CONNECTIVE TISSUE RESEARCH, 1986, 15 (1-2) :57-64
[18]   A review of the validity and variability of the elevated plus-maze as an animal model of anxiety [J].
Hogg, S .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1996, 54 (01) :21-30
[19]   Apoptotic cell death in mouse models of G(M2) gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases [J].
Huang, JQ ;
Trasler, JM ;
Igdoura, S ;
Michaud, J ;
Hanai, N ;
Gravel, RA .
HUMAN MOLECULAR GENETICS, 1997, 6 (11) :1879-1885
[20]   HEXOSAMINIDASE A ACTIVITY IN SKIN FIBROBLASTS FROM VARIOUS TYPES OF GM2 GANGLIOSIDOSIS USING A FLUOROGENIC SULFATED SUBSTRATE [J].
INUI, K ;
YUTAKA, T ;
OKADA, S ;
YABUUCHI, H ;
WENGER, DA ;
DESNICK, RJ .
JOURNAL OF INHERITED METABOLIC DISEASE, 1985, 8 (03) :149-150