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

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.).

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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.

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Correspondence to J Paul Taylor.

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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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