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AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse

Gene Therapy volume 20, pages 785–796 (2013)Cite this article

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Abstract

Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus (AAV)-expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates, and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however, there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however, nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.

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Acknowledgements

We thank Waldemar Ladno for assistance with CT imaging of mice and Daniela Markovic for assistance with the statistical evaluation, and both the Semel Institute for Neuroscience and the Intellectual and Developmental Disabilities Research Center at UCLA for their support. The authors declare no financial or other conflict of interest. This work was supported by grants from the NIH (5K08HD057555-05 and 1R01NS071076-02A1).

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Authors and Affiliations

  1. Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA

    E K Lee, C Hu, R Bhargava, H Park, S Novicoff & G S Lipshutz

  2. Department of Psychology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    R Ponnusamy

  3. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    N Rozengurt & W W Grody

  4. Laboratory of Neurochemistry and Behavior, University of Antwerp and Institute Born Bunge, Antwerp, Belgium

    B Marescau & P De Deyn

  5. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    D Stout

  6. Biochemical Genetics Laboratory, University of Colorado, Denver, CO, USA

    L Schlichting

  7. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    W W Grody & S D Cederbaum

  8. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA, CA

    W W Grody & S D Cederbaum

  9. Department of Psychiatry (Intellectual and Development Disabilities Research Center at UCLA), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    S D Cederbaum & G S Lipshutz

  10. The Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    S D Cederbaum & G S Lipshutz

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  1. E K Lee
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Correspondence to G S Lipshutz.

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Lee, E., Hu, C., Bhargava, R. et al. AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse. Gene Ther 20, 785–796 (2013). https://doi.org/10.1038/gt.2012.99

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