Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease
Xin Chen, … , Joseph R. Mazzulli, Steven J. Gray
Xin Chen, … , Joseph R. Mazzulli, Steven J. Gray
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e146286. https://doi.org/10.1172/JCI146286.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 8

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease

  • Text
  • PDF
Abstract

Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8– /– mice at P7–P10 or P120 with high or low dose led to clear age- and dose-dependent effects. A high dose of AAV9/MFSD8 at P7–P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.

Authors

Xin Chen, Thomas Dong, Yuhui Hu, Frances C. Shaffo, Nandkishore R. Belur, Joseph R. Mazzulli, Steven J. Gray

×

Figure 3

AAV9/MFSD8 GT dose dependently induces hMFSD8opt mRNA expression in the CNS of KO mice.

Options: View larger image (or click on image) Download as PowerPoint
AAV9/MFSD8 GT dose dependently induces hMFSD8opt mRNA expression in the ...
High (5 × 1011 vg/mouse) or low (1.25 × 1011 vg/mouse) dose of AAV9/MFSD8 vector was administered i.t. to equal numbers of male and female mice at P7–P10. At 4.5 months old, mouse brain and spinal cord were harvested for RNAscope staining to detect hMFSD8opt mRNA (A). Histology images with 1 section/animal were digitized with a ScanScope slide scanner and analyzed using custom analysis settings in HALO Image Analysis Platform. Results are presented as percentage of area staining positive for hMFSD8opt mRNA by tissue region (B). A ROUT test was used first to remove any outlier. Each data point represents a measurement from an individual animal (n = 5–6), with lines representing the mean measurement ± SEM. Data sets that passed tests for normality or homogeneity of variance were analyzed using 1-way ANOVA with α set at 0.05 and Dunnett’s correction for relevant pairwise comparisons. Data sets that did not pass tests for normality or homogeneity of variance were analyzed using the Kruskal-Wallis test with α set at 0.05 and Dunn’s correction for relevant pairwise comparisons. *P < 0.05; **P < 0.01, compared with KO-Veh. Scale bars: 500 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 3 X users
Referenced in 2 patents
On 1 Facebook pages
53 readers on Mendeley
See more details