Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy

Elizabeth Y. Qin, Jacqueline A. Hawkins-Salsbury, Xuntian Jiang, Adarsh S. Reddy, Nuri B. Farber, Daniel S. Ory, Mark S. Sands

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, oligodendrocytes. Currently, the only therapy for GLD is hematopoietic stem cell transplantation using bone marrow (BMT) or umbilical cord blood. However, this is only partially effective. Previous studies have shown that enzyme replacement therapy (ERT) provides some therapeutic benefit in the murine model of GLD, the Twitcher mouse. Experiments have also shown that two disparate therapies can produce synergistic effects when combined. The current study tests the hypothesis that BMT will increase the therapeutic effects of ERT when these two treatments are combined. Twitcher mice were treated with either ERT alone or both ERT and BMT during the first 2-4. days of life. Recombinant enzyme was delivered by intracerebroventricular (ICV) and intrathecal (IT) injections. Twitcher mice receiving ERT had supraphysiological levels of GALC activity in the brain 24. h after injection. At 36. days of age, ERT-treated Twitcher mice had reduced psychosine levels, reduced neuroinflammation, improved motor function, and increased lifespan. Twitcher mice receiving both ERT and BMT had significantly increased lifespan, improved motor function, reduced psychosine levels, and reduced neuroinflammation in certain areas of the brain compared to untreated or ERT-treated Twitcher mice. Together, these results indicate that BMT enhances the efficacy of ERT in GLD.

Original languageEnglish
Pages (from-to)186-196
Number of pages11
JournalMolecular genetics and metabolism
Volume107
Issue number1-2
DOIs
StatePublished - Sep 1 2012

Keywords

  • Bone marrow transplantation
  • Enzyme replacement therapy
  • Globoid cell leukodystrophy
  • Lysosomal storage disease
  • Neurodegenerative disease
  • Twitcher mouse

Fingerprint Dive into the research topics of 'Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy'. Together they form a unique fingerprint.

  • Cite this