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Krabbe disease successfully treated via monotherapy of intrathecal gene therapy

Journal of Clinical Investigation, ISSN: 1558-8238, Vol: 130, Issue: 9, Page: 4906-4920
2020
  • 48
    Citations
  • 176
    Usage
  • 70
    Captures
  • 7
    Mentions
  • 64
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    48
  • Usage
    176
  • Captures
    70
  • Mentions
    7
    • News Mentions
      6
      • News
        6
    • References
      1
      • Wikipedia
        1
  • Social Media
    64
    • Shares, Likes & Comments
      64
      • Facebook
        64

Most Recent News

University of Pennsylvania School of Veterinary Medicine: Progress Toward a Treatment for Krabbe Disease

The University of Pennsylvania School of Veterinary Medicine issued the following news release: In one out of 100,000 infants, a mutation in the GALC gene

Article Description

Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically. Copyright:

Bibliographic Details

Bradbury, Allison M; Bagel, Jessica H; Nguyen, Duc; Lykken, Erik A; Pesayco Salvador, Jill; Jiang, Xuntian; Swain, Gary P; Assenmacher, Charles A; Hendricks, Ian J; Miyadera, Keiko; Hess, Rebecka S; Ostrager, Arielle; ODonnell, Patricia; Sands, Mark S; Ory, Daniel S; Shelton, G Diane; Bongarzone, Ernesto R; Gray, Steven J; Vite, Charles H

American Society for Clinical Investigation

Medicine

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