Abstract

Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.

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Acknowledgements

We thank N. Nedelsky for editorial assistance. We thank the transgenic core facility at St. Jude for production of AR121Q transgenic mice and ARC Technical Services at St. Jude for surgical and animal care assistance. We also thank W. Denney for guidance in use of the 'PKNCA' R package. This work was supported by the Howard Hughes Medical Institute (J.P.T.), the American-Lebanese-Syrian Associated Charities (J.P.T., H.T.), NIH R01 NS053825 (J.P.T.), NIH R01 NS100023 (A.R.L.), the Muscular Dystrophy Association (A.R.L.) and the Kennedy's Disease Association (H.C.M.).

Author information

Author notes

    • Pradeep K Vuppala
    • , Emmanuelle R Quemin
    •  & Nam Chul Kim

    Present address: KinderPharm LLC, Exton, Pennsylvania, USA (P.K.V.), UBI, Département de Biologie Cellulaire et Infection and Centre d′Innovation et Recherche Technologique, Institut Pasteur, Paris, France (E.R.Q.), and Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA (N.C.K.).

    • Nisha M Badders
    •  & Ane Korff

    These authors contributed equally to this work.

Affiliations

  1. Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Nisha M Badders
    • , Ane Korff
    • , Rebecca B Smith
    • , Brett J Winborn
    • , Emmanuelle R Quemin
    • , Jennifer Dearman
    • , James Messing
    • , Nam Chul Kim
    • , Jennifer Moore
    • , Brian D Freibaum
    • , Anderson P Kanagaraj
    • , Baochang Fan
    • , Hong Joo Kim
    •  & J Paul Taylor
  2. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Ane Korff
    • , James Messing
    •  & J Paul Taylor
  3. Department of Pediatrics, University of California at San Diego, La Jolla, California, USA.

    • Helen C Miranda
    •  & Albert R La Spada
  4. Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Pradeep K Vuppala
    • , Yingzhe Wang
    •  & Burgess B Freeman III
  5. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • Bryce L Sopher
  6. Departments of Neurology, Neurobiology and Cell Biology, and the Duke Center for Neurodegeneration & Neurotherapeutics, Durham, North Carolina, USA.

    • Albert R La Spada
  7. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Heather Tillman
  8. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Ping-Chung Chen
  9. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Yimei Li

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Contributions

N.M.B., A.K., H.J.K., A.R.L. and J.P.T. designed the fruit fly, mouse and cell-based experiments. N.M.B., A.K. and H.C.M. performed the experiments and data analyses. P.K.V., Y.W. and B.B.F. performed the pharmacokinetics analyses. R.B.S., E.R.Q. and N.C.K. provided assistance in the fruit fly experiments. J.D., J. Messing, B.D.F. and P.-C.C. provided assistance in the mouse experiments. B.J.W. performed in silico docking of TA into the AR LBD and generated the structural depictions of the AR LBD. B.L.S. and A.P.K. performed the cloning and preparation of the constructs used to generate AR121Q transgenic mice. J. Moore and B.F. provided assistance in cell-based experiments for digital PCR. J. Moore provided assistance in mouse tissue and plasma collection for pharmacokinetics analysis. H.T. performed histopathologic analysis of AR121Q transgenic mice. Y.L. performed the sample size estimation (power analysis) and statistical QOL analysis. N.M.B., A.K., H.J.K. and J.P.T. wrote the manuscript. All of the authors provided scientific input and read and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to J Paul Taylor.

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https://doi.org/10.1038/nm.4500