Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector.
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency in human arylsulfatase A (hASA). We recently reported that ependymal cells and the choroid plexus are selectively transduced by intracerebroventricular (ICV) injection of adeno-associated virus serotype 1 (AAV1) vector and serve as a biological reservoir for the secretion of lysosomal enzymes into the cerebrospinal fluid (CSF). In the present study, we examined the feasibility of this AAV-mediated gene therapy to treat MLD model mice. Preliminary experiments showed that the hASA level in the CSF after ICV injection of self-complementary (sc) AAV1 was much higher than in mice injected with single-stranded AAV1 or scAAV9. However, when 18-week-old MLD mice were treated with ICV injection of scAAV1, the concentration of hASA in the CSF gradually decreased and was not detectable at 12 weeks after injection, probably due to the development of anti-hASA antibodies. As a result, the sulfatide levels in brain tissues of treated MLD mice were only slightly reduced compared with those of untreated MLD mice. These results suggest that this approach is potentially promising for treating MLD, but that controlling the immune response appears to be crucial for long-term expression of therapeutic proteins in the CSF.
1] Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan [2] Department of Neurological Surgery; Nippon Medical School, Tokyo, 113-8603, Japan.
Kohei
K
Hironaka
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Yoshiyuki
Y
Yamazaki
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Yukihiko
Y
Hirai
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Motoko
M
Yamamoto
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Noriko
N
Miyake
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Koichi
K
Miyake
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Takashi
T
Okada
Department of Neurological Surgery; Nippon Medical School, Tokyo, 113-8603, Japan.
Akio
A
Morita
Department of Biochemistry and Molecular Biology; Division of Gene Therapy, Research Center for Advanced Medical Technology; Nippon Medical School, Tokyo, 113-8603, Japan.
Takashi
T
Shimada
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002553:Cerebroside-Sulfatase / Q000008:administration & dosage* / Q000235:genetics; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D056947:Enzyme Replacement Therapy / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007276:Injections, Intraventricular; D007966:Leukodystrophy, Metachromatic / Q000134:cerebrospinal fluid / Q000201:enzymology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D016896:Treatment Outcome
D002553:Cerebroside-Sulfatase