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Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy

Nature Medicine volume 24, pages 427–437 (2018)Cite this article

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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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Figure 1: AF2 modulation rescues degeneration in a fruit fly model of SBMA.
Figure 2: AR121Q-expressing mice recapitulate SBMA symptoms and pathology.
Figure 3: MEPB improves phenotypic outcomes and pathologic degeneration in a pilot preclinical trial in SBMA mice.
Figure 4: MEPB improves phenotypic outcomes and improves quality of life parameters in a preclinical trial in SBMA mice.
Figure 5: MEPB reduces degeneration in spinal cord and skeletal muscle of SBMA mice.
Figure 6: AF2 modulation does not inhibit AR functional activity.

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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

  1. Pradeep K Vuppala

    Present address: KinderPharm LLC, Exton, Pennsylvania, USA

  2. Emmanuelle R Quemin

    Present address: UBI, Département de Biologie Cellulaire et Infection and Centre d′Innovation et Recherche Technologique, Institut Pasteur, Paris, France

  3. Nam Chul Kim

    Present address: Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA

  4. Nisha M Badders and Ane Korff: These authors contributed equally to this work.

Authors and 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

  10. KinderPharm LLC, Exton, Pennsylvania, USA

    Emmanuelle R Quemin & Nam Chul Kim

  11. UBI, Département de Biologie Cellulaire et Infection and Centre d′Innovation et Recherche Technologique, Institut Pasteur, Paris, France

    Pradeep K Vuppala & Nam Chul Kim

  12. Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA

    Pradeep K Vuppala & Emmanuelle R Quemin

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  1. Nisha M Badders
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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.

Corresponding author

Correspondence to J Paul Taylor.

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The authors declare no competing financial interests.

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Badders, N., Korff, A., Miranda, H. et al. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nat Med 24, 427–437 (2018). https://doi.org/10.1038/nm.4500

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