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Transgenic rescue of Krabbe disease in the twitcher mouse

Gene Therapy volume 11, pages 1188–1194 (2004)Cite this article

Abstract

The twitcher mouse is a natural model of Krabbe disease caused by galactocerebrosidase (GALC) deficiency. Previous attempts at rescuing the twitcher mouse by bone marrow transplantion, viral transduction, or transgenesis were only partially successful. Here, we report the transgenic (tg) rescue of the twitcher mouse with a BAC clone harboring the entire GALC. The twi/twi/hGALC tg mice exhibited growth, motor function, and fertility similar to those of nonaffected animals. These animals had normal levels of GALC activity in brain and were free of the typical twitcher demyelinating pathology. Surprisingly, GALC expression in twi/twi hGALC tg kidneys was low and galactocerebroside storage was only partially cleared. Nonetheless, these mice have been maintained for over 1 year without any sign of disease. Since pathological damage associated with GALC deficiency is confined to the nervous system, our work represents the first successful rescue of the twitcher mouse and opens the possibility of developing novel therapeutic approaches.

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Acknowledgements

The support of the Microscopy Shared Research Facility of the Mount Sinai School of Medicine is greatly appreciated. Supported in part by grants from the Hunter's Hope Foundation and the National Multiple Sclerosis Society (PP072) to MAGS.

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Authors and Affiliations

  1. Department of Psychiatry, Mount Sinai School of Medicine of New York University, New York, NY, USA

    R De Gasperi, G M Perez, E Senturk, P H Wen, G A Elder & M A Gama Sosa

  2. Department of Neurobiology, Mount Sinai School of Medicine of New York University, New York, NY, USA

    V L Friedrich

  3. Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine of New York University, New York, NY, USA

    K Kelley

  4. Mouse Genetics Shared Research Facility, Mount Sinai School of Medicine of New York University, New York, NY, USA

    K Kelley

  5. Psychiatry Research, Bronx Veterans Administration Medical Center, Bronx, NY, USA

    R De Gasperi, G M Perez, E Senturk, P H Wen, G A Elder & M A Gama Sosa

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  1. R De Gasperi
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  8. M A Gama Sosa
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Dedicated with respect and appreciation to Professor Robert A Lazzarini, our teacher and mentor, who made all this research possible

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De Gasperi, R., Friedrich, V., Perez, G. et al. Transgenic rescue of Krabbe disease in the twitcher mouse. Gene Ther 11, 1188–1194 (2004). https://doi.org/10.1038/sj.gt.3302282

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