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

Dolan Sondhi, Emma C. Scott, Alvin Chen, Neil R. Hackett, Andrew M.S. Wong, Agnieszka Kubiak, Hemanth R. Nelvagal, Yewande Pearse, Susan L. Cotman, Jonathan D. Cooper, Ronald Crystal

Research output: Contribution to journalArticle

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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 Cln3Δex7/8 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 Cln3Δex7/8 mice were administered 3×1010 genome copies of AAVrh.10hCLN3 to the brain, with control groups including untreated Cln3Δex7/8 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, Cln3Δex7/8 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 Cln3Δex7/8 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.

Original languageEnglish
Pages (from-to)223-239
Number of pages17
JournalHuman Gene Therapy
Volume25
Issue number3
DOIs
Publication statusPublished - 1 Mar 2014
Externally publishedYes

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Neuronal Ceroid-Lipofuscinoses
Dependovirus
Gliosis
Lysosome-Associated Membrane Glycoproteins
Genes
Brain
Complementary DNA
Staining and Labeling
Lysosomal Storage Diseases
Neurons
Periodic Acid
Therapeutic Uses
Transgenes
Serogroup
Hippocampus
Adenosine Triphosphate
Genome
Control Groups
Mutation
Population

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

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. / Sondhi, Dolan; Scott, Emma C.; Chen, Alvin; Hackett, Neil R.; Wong, Andrew M.S.; Kubiak, Agnieszka; Nelvagal, Hemanth R.; Pearse, Yewande; Cotman, Susan L.; Cooper, Jonathan D.; Crystal, Ronald.

In: Human Gene Therapy, Vol. 25, No. 3, 01.03.2014, p. 223-239.

Research output: Contribution to journalArticle

Sondhi, Dolan ; Scott, Emma C. ; Chen, Alvin ; Hackett, Neil R. ; Wong, Andrew M.S. ; Kubiak, Agnieszka ; Nelvagal, Hemanth R. ; Pearse, Yewande ; Cotman, Susan L. ; Cooper, Jonathan D. ; Crystal, Ronald. / 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. In: Human Gene Therapy. 2014 ; Vol. 25, No. 3. pp. 223-239.
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