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Mol Ther. 2018 Mar 7;26(3):874-889. doi: 10.1016/j.ymthe.2018.01.009. Epub 2018 Jan 17.

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

Author information

1
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
2
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
3
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4
Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
5
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
6
Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA.
7
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, 1053 Buenos Aires, Argentina. Electronic address: ebongarz@uic.edu.

Abstract

We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function. Bone marrow transplantation, performed in this protocol without immunosuppressive preconditioning, added minimal benefits to the AAV9 gene therapy. Contrasting with other proposed pre-clinical therapies, these results demonstrate that achieving nearly complete correction of GALC's metabolic deficiencies across the entire nervous system via gene therapy can have a significant improvement to behavioral deficits, pathophysiological changes, and survival. These results are an important consideration for determining the safest and most effective manner for adapting gene therapy to treat this leukodystrophy in the clinic.

KEYWORDS:

AAV; Krabbe’s disease; demyelination; galactosylceramidase; gene therapy; leukodystrophy; microglia; myelin; oligodendrocytes; psychosine

PMID:
29433937
PMCID:
PMC5910889
DOI:
10.1016/j.ymthe.2018.01.009
[Indexed for MEDLINE]
Free PMC Article

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