title: Partial correction of the CNS lysosomal storage defect in a mouse model of juvenile neuronal ceroid lipofuscinosis by neonatal CNS administration of an adeno-associated virus serotype rh.10 vector expressing the human CLN3 gene.
abstract: Juvenile neuronal ceroid lipofuscinosis (JNCL or CLN3 disease) is an autosomal recessive lysosomal storage disease resulting from mutations in the CLN3 gene that encodes a lysosomal membrane protein. The disease primarily affects the brain with widespread intralysosomal accumulation of autofluorescent material and fibrillary gliosis, as well as the loss of specific neuronal populations. As an experimental treatment for the CNS manifestations of JNCL, we have developed a serotype rh.10 adeno-associated virus vector expressing the human CLN3 cDNA (AAVrh.10hCLN3). We hypothesized that administration of AAVrh.10hCLN3 to the Cln3(Δex7/8) knock-in mouse model of JNCL would reverse the lysosomal storage defect, as well as have a therapeutic effect on gliosis and neuron loss. Newborn Cln3(Δex7/8) mice were administered 3 × 10(10) genome copies of AAVrh.10hCLN3 to the brain, with control groups including untreated Cln3(Δex7/8) mice and wild-type littermate mice. After 18 months, CLN3 transgene expression was detected in various locations throughout the brain, particularly in the hippocampus and deep anterior cortical regions. Changes in the CNS neuronal lysosomal accumulation of storage material were assessed by immunodetection of subunit C of ATP synthase, luxol fast blue staining, and periodic acid-Schiff staining. For all parameters, Cln3(Δex7/8) mice exhibited abnormal lysosomal accumulation, but AAVrh.10hCLN3 administration resulted in significant reductions in storage material burden. There was also a significant decrease in gliosis in AAVrh.10hCLN3-treated Cln3(Δex7/8) mice, and a trend toward improved neuron counts, compared with their untreated counterparts. These data demonstrate that AAVrh.10 delivery of a wild-type cDNA to the CNS is not harmful and instead provides a partial correction of the neurological lysosomal storage defect of a disease caused by a lysosomal membrane protein, indicating that this may be an effective therapeutic strategy for JNCL and other diseases in this category.
authors.affiliation: 1 Department of Genetic Medicine, Weill Medical College, Cornell University , New York, NY 10065.
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.forename: Emma C
authors.initials: EC
authors.lastname: Scott
authors.forename: Alvin
authors.initials: A
authors.lastname: Chen
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Andrew M S
authors.initials: AM
authors.lastname: Wong
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kubiak
authors.forename: Hemanth R
authors.initials: HR
authors.lastname: Nelvagal
authors.forename: Yewande
authors.initials: Y
authors.lastname: Pearse
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cotman
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections; D007395:Interneurons / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000628:therapy*; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D012333:RNA, Messenger