Therapeutic Target and Drug for Spinal and Bulbar Muscular Atrophy (SBMA)

Inhibitors against a new therapeutic target molecule improved the body weight, grip power, performance on the rotarod task and lifespan of SBMA mouse model.

Core Benefits

  • This therapy could be the novel specific treatment for SBMA.
  • It could be also applied to other types of neuromuscular diseases.
  • Some of these inhibitors are under clinical development for another indication.

Background & Technology

SBMA is a X-linked neurodegenerative disorder resulting in muscle cramps and progressive weakness caused by CAG expansion of the androgen receptor gene. This condition affects fewer than 1 in 150,000 males and there is only one therapeutic: androgen deprivation therapy using leuprorelin, a luteinizing hormone-releasing hormone agonist. However, it is sometimes hard to prescribe leuprorelin especially for young patients due to its side effect of sexual dysfunction.
Our previous studies revealed that testosterone-dependent intra-neuronal accumulation of the pathogenic AR protein plays a crucial role in SBMA (1). Recently, we identified molecular changes that commonly emerge in both motor neurons and skeletal muscles of a mouse model of SBMA (AR-97Q mice), such as mitochondrial dysfunction and NFκB signal activation (2). Here, we further performed a comprehensive analysis of signal pathways in the mouse model and identified another important signaling pathway and its target molecule which activation has the strongest impact on the pathophysiology of SBMA. In addition, we also confirmed that existing blood-brain barrier-crossing inhibitors of the target molecule improved cell-viability of SBMA model cells and survival rate of SBMA mice.

Data & Publication

This study

無題1 無題2


Reference

  1. Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Sang C, Kobayashi Y, Doyu M, Sobue G. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron. 35: 843-854, 2002.
  2. Iida M, Katsuno M, Nakatsuji H, Adachi H, Kondo N, Miyazaki Y, Tohnai G, Ikenaka K, Watanabe H, Yamamoto M, Kishida K, Sobue G. Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors. Hum Mol Genet. 24: 314-329, 2015.

Patent

Patent pending (unpublished)

Researcher

Dr. Masahisa Katsuno (Nagoya University Department of Neurology)

Product No: TP-00747

 

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