[Development of disease-modifying therapy for neurodegenerative diseases].
ABSTRACT Although recent advancements in molecular biology have provided increasing insights into the pathophysiology of neurodegenerative diseases, there is almost no disease-modifying therapy for which the efficacy has been verified in clinical trials. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat in the androgen receptor (AR) gene. SBMA exclusively affects males, whereas does not manifest in the females homozygous for the AR mutation. The ligand-dependent nuclear accumulation of pathogenic AR protein is central to the pathogenesis, although additional steps such as inter- and intra-molecular interaction are also required for toxicity. Leuprorelin, a luteinizing hormone-releasing hormone (LHRH) analogue that suppresses testosterone production from testis, inhibits toxic accumulation of pathogenic AR, thereby mitigating histopathological and behavioral impairments in a mouse model of SBMA. Although a randomized placebo-controlled multi-centric clinical trial showed no definite effect of the drug on motor functions, there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. These results indicate a need to elucidate the entire disease mechanism, clarify the natural history, initiate therapeutic intervention at an early stage, and develop sensitive outcome measures to evaluate drug effect.