Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy

Banno, Haruhiko; Katsuno, Masahisa; Suzuki, Keisuke; Takeuchi, Yu; Kawashima, Motoshi; Suga, Noriaki; Takamori, Motoko; Ito, Mizuki; Nakamura, Tomohiko; Matsuo, Koji; Yamada, Shin‐ichi; Oki, Yuichi; Adachi, Hiroaki; Minamiyama, Makoto; Waza, Masahiro; Atsuta, Naoki; Watanabe, Haruo; Fujimoto, Yasushi; Nakashima, Tsutomu; Tanaka, Fumiaki; Doyu, Manabu; Sobue, Gen

doi:10.1002/ana.21540

Cited by 143 publications

(107 citation statements)

References 53 publications

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“…Previous studies showed that the pathogenic AR containing an expanded polyglutamine tract accumulates in the nuclei of motor neurons in a testosterone-dependent manner, and that inhibition of testosterone production prevents this accumulation (Katsuno et al, 2002;Takeyama et al, 2002). Furthermore, testosterone reduction, by castration or medication, mitigates neurodegeneration in SBMA mice and patients ChevalierLarsen et al, 2004;Banno et al, 2009). We thus examined whether castration restores the TGF-␤-Smad2/3 signal pathway in male AR-97Q mice.…”

Section: Expression Of T␤rii Is Decreased In Sbmamentioning

confidence: 98%

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Katsuno¹,

Adachi²,

Minamiyama³

et al. 2010

J. Neurosci.

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Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-␤ signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-␤ signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-␤ receptor type II (T␤RII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of T␤RII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-␤ due to the transcriptional dysregulation of T␤RII is associated with polyglutamine-induced motor neuron damage in SBMA.

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Section: Expression Of T␤rii Is Decreased In Sbmamentioning

confidence: 98%

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Katsuno¹,

Adachi²,

Minamiyama³

et al. 2010

J. Neurosci.

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“…Testosterone reduction by castration in SBMA transgenic mice restored motor function [91,92], and testosterone administration to female transgenic mice induced an SBMA phenotype [91]. Consistent with the testosterone-dependent toxicity of the mutant AR in SBMA, treatment of transgenic mice with the antiandrogen leuprorelin extended survival and rescued behavioral deficits [93], and gave promising results in phase 2 clinical trial [94]. Leuprorelin is a lutenizing hormone-releasing hormone agonist, which decreases serum testosterone levels and thus is a potential therapy for SBMA.…”

Section: Sbmamentioning

confidence: 73%

Therapeutic Prospects for Polyglutamine Disease

Pennuto

Fischbeck

2010

Protein Misfolding Diseases

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“…5 Although no medical treatment can delay or reverse the progression of SBMA, 24 some promising results have been shown using anti-androgen therapy in a small clinical trial. 25 Only 2 studies 10,26 report on postoperative complications in patients with SBMA. One study 26 reports on a single case in which epidural anesthesia was used for an internal urethrotomy.…”

Section: Discussionmentioning

confidence: 99%

Complications After Cardiovascular Surgery in a Case of Undiagnosed Spinal-Bulbar Muscular Atrophy (Kennedy Disease)

Skoretz

Yee

Martino

2012

American Journal of Critical Care

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Neurodegenerative diseases are often associated with life-threatening declines in respiratory and swallowing mechanisms. We report the case of a 70-year-old man who had postoperative dysphagia and respiratory failure that required reintubation after coronary artery bypass surgery. Impairment of the patient's speech, swallowing, and respiratory mechanisms identified during postoperative clinical and instrumental examinations was suggestive of a neurodegenerative disease. Genetic testing confirmed a diagnosis of spinal-bulbar muscular atrophy (Kennedy disease). This case report aims to highlight increased morbidity in patients with undiagnosed neuromuscular disorders in the critical care setting and the benefits of vigilant postoperative monitoring and multidisciplinary involvement throughout the care of complex patients.

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Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy

Cited by 143 publications

References 53 publications

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Therapeutic Prospects for Polyglutamine Disease

Complications After Cardiovascular Surgery in a Case of Undiagnosed Spinal-Bulbar Muscular Atrophy (Kennedy Disease)

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