leuprolide and Bulbo-Spinal-Atrophy--X-Linked

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (

Topics: 5-alpha Reductase Inhibitors; Adipose Tissue; Adrenergic beta-Agonists; Autophagy; Biomarkers; Bulbo-Spinal Atrophy, X-Linked; Clenbuterol; Creatinine; Dutasteride; Glycolysis; Humans; Insulin-Like Growth Factor I; Leuprolide; Magnetic Resonance Imaging; Mitochondria; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Oligonucleotides, Antisense; Oxidation-Reduction; Receptors, Androgen; RNAi Therapeutics; Trinucleotide Repeat Expansion

Neurodegenerative diseases have long been construed as incurable disorders. However, therapeutic developments for these diseases are now facing a turning point, that is, analyses of cellular and animal models have provided insights into the pathogenesis of neurodegenerative diseases and have indicated rational therapeutic approaches. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. This disease is caused by the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. The results of animal studies suggest that testosterone-dependent nuclear accumulation of the pathogenic AR protein is a fundamental step in the neurodegenerative process. Androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue suppresses the toxicity of the mutant AR in animal models of SBMA. In a phase 3 trial, 48 weeks of treatment with leuprorelin acetate, an LHRH analogue, tended to improve swallowing function in a subgroup of SBMA patients with disease duration less than 10 years but did not significantly affect the total population. Disease duration might influence the efficacy of leuprorelin acetate, and therefore, a further clinical trial that involves sensitive outcome measures is in progress. Advances in basic and clinical research on SBMA are now paving the way for the clinical application of pathogenesis-targeting therapies. To optimize translational research related to the process of testing candidate therapies in humans, it is important to identify biomarkers that can be used as surrogate endpoints in clinical trials for neurodegenerative diseases.

Topics: Animals; Bulbo-Spinal Atrophy, X-Linked; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Mice; Receptors, Androgen; Translational Research, Biomedical

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The histopathological finding in SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. There is no established disease-modifying therapy for SBMA. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the ubiquitin-proteasome system and transcriptional regulation are also potential targets for development of therapy for SBMA. Among these therapeutic approaches, the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents nuclear translocation of aberrant AR proteins, resulting in a significant improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical trial of leuprorelin, the patients treated with this drug exhibited decreased mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the possibility that leuprorelin treatment is associated with improved swallowing function particularly in patients with a disease duration less than 10 years. These observations suggest that pharmacological inhibition of the toxic accumulation of mutant AR is a potential therapy for SBMA.

Topics: Animals; Bulbo-Spinal Atrophy, X-Linked; Clinical Trials as Topic; Humans; Leuprolide; Molecular Targeted Therapy

Neurodegenerative diseases have been construed as incurable disorders. However, therapeutic development for these diseases is now facing a turning point: analyses of cellular and animal models have provided insights into pathogenesis of neurodegenerative diseases, and have indicated rational therapeutic approaches to them. Therefore, how to realize molecular targeted therapy for neurodegenerative diseases is becoming one of the most challenging issues in the clinical neurology. Primarily, pathophysiological understanding of the disease from basic science is the first step. For the successful clinical trials, effective trial design, sufficient economic and social support, and education are indispensable. The development of androgen deprivation therapy for spinal and bulbar muscular atrophy (SBMA) is a representative study in this field. SBMA is a hereditary neurodegenerative disease caused by expansion of a trinucleotide CAG repeat in the first exon of the androgen receptor (AR) gene. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into phase 2, and then phase 3, clinical trials.

Topics: Androgen Antagonists; Animals; Bulbo-Spinal Atrophy, X-Linked; Clinical Trials as Topic; Exons; Humans; Leuprolide; Mice; Neurodegenerative Diseases; Receptors, Androgen; Testosterone; Translational Research, Biomedical; Trinucleotide Repeat Expansion

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated lower motor neuron disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, which is followed by several molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondria dysfunction. Androgen deprivation suppresses the toxicity of the mutant AR in animal models of SBMA, and these insights have been translated to clinic. Animal studies have also suggested that activation of protein quality control systems are potential therapies for SBMA. To optimize "proof of concept", the process for testing candidate therapies in humans, it is of importance to identify responders to each therapy, to initiate interventions in early stages of the disease, and to establish biomarkers which can be used for evaluating the efficacy of treatment.

Topics: Adult; Animals; Biomarkers; Bulbo-Spinal Atrophy, X-Linked; Clinical Trials, Phase II as Topic; Humans; Leuprolide; Male; Motor Neurons; Mutation; Peptides; Receptors, Androgen; Testosterone; Trinucleotide Repeat Expansion

This study aimed to investigate the effect of androgen suppression therapy using leuprorelin focused on the bulbar function of patients with spinal and bulbar muscular atrophy (SBMA).. Genetically confirmed SBMA patients who consented to participate in this observational study were enrolled. Leuprorelin was subcutaneously injected every 12 weeks. Videofluoroscopic swallowing study was performed at baseline and after androgen suppression therapy for 1 year. The primary outcome measures were the changes in the vallecular residue and pyriform sinus residue. The videofluoroscopic swallowing study data were analyzed and interpreted by two experienced physiatrists.. A total of 40 patients with SBMA were analyzed in this study. The inter-rater reliability testing showed good agreement for the pharyngeal residue (ICC = 0.84) and videofluoroscopic dysphagia scale (ICC = 0.75). The vallecular residue and pyriform sinus residue after swallowing 9 mL yogurt were significantly reduced (26.8 ± 22.6 to 14.6 ± 14.5, p < 0.001, 14.9 ± 16.9 to 7.6 ± 9.9, p < 0.001, respectively). The swallowing subscore of amyotrophic lateral sclerosis functional rating scale-revised improved after androgen suppression therapy (3.3 ± 0.5 to 3.5 ± 0.6, p = 0.041).. Leuprorelin significantly reduced the pharyngeal residue in patients with SBMA after 1 year of treatment without any serious adverse events and longitudinal studies are needed to confirm these results.

Topics: Bulbo-Spinal Atrophy, X-Linked; Deglutition; Deglutition Disorders; Humans; Leuprolide; Muscular Atrophy, Spinal; Reproducibility of Results

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied.. Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began.. The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, - 4.12% (95% CI, - 8.40-0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups.. The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Bulbo-Spinal Atrophy, X-Linked; Double-Blind Method; Female; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Testosterone; Treatment Outcome

Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. A 41-year-old man with SBMA received the androgen deprivation agent leuprorelin acetate for 7 years in clinical trials and underwent castration following the trial. Suppression of testosterone levels for 14 years resulted in a slower disease progression, as measured prospectively with quantitative measurements, than the historical control data reported in previous studies. This suggests that long-term androgen deprivation delays disease progression in SBMA.

Topics: Adult; Androgen Antagonists; Animals; Bulbo-Spinal Atrophy, X-Linked; Disease Progression; Follow-Up Studies; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms

Topics: Bulbo-Spinal Atrophy, X-Linked; Humans; Leuprolide; Long-Term Care; Muscular Atrophy, Spinal; Spine