Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A

M S Alexander; M J Gasperini; P T Tsai; D E Gibbs; J M Spinazzola; J L Marshall; M J Feyder; M T Pletcher; E L P Chekler; C A Morris; M Sahin; J F Harms; C J Schmidt; R J Kleiman; L M Kunkel

doi:10.1038/tp.2016.174

Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A

Transl Psychiatry. 2016 Sep 27;6(9):e901. doi: 10.1038/tp.2016.174.

Authors

M S Alexander^{1

2

3}, M J Gasperini¹, P T Tsai⁴, D E Gibbs¹, J M Spinazzola^{1

2}, J L Marshall¹, M J Feyder¹, M T Pletcher⁵, E L P Chekler⁵, C A Morris⁵, M Sahin⁴, J F Harms⁶, C J Schmidt⁶, R J Kleiman⁴, L M Kunkel^{1

2

3

7

8}

Affiliations

¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
² Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.
³ The Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
⁴ The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Rare Disease Research Unit, Pfizer, Cambridge, MA, USA.
⁶ Neuroscience Research Unit, Pfizer Global Research and Development, Cambridge, MA, USA.
⁷ The Manton Center for Orphan Diseases, Boston, MA, USA.
⁸ Harvard Stem Cell Institute, Cambridge, MA, USA.

Abstract

Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.

Abstract

Grants and funding