神経変性疾患の治療の特性（アカデミアの立場から）

抄録

Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by an expanded trinucleotide CAG repeat, which encodes the polyglutamine tract, in the androgen receptor (AR) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons and intranuclear accumulations of mutant AR protein in the residual motor neurons. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. To elucidate the pathogenic mechanism and develop the therapeutics, we generated a model mouse with AR–97Q in androgen receptor gene. Androgen deprivation through castration or leuprorelin acetate administration improved the symptoms, histopathological findings, and nuclear accumulation of the pathogenic AR in the male AR–97Q mice. Androgen deprivation rescues neuronal dysfunction in animal models of SBMA associated with disappearance of nuclear pathogenic AR accumulation, suggesting that the molecular basis for motor neuron degeneration in this disorder is androgen–dependent nuclear accumulation of the mutant AR. We then performed an investigator–initiated clinical trial of leuprorelin for SBMA. Suppression of disease progression of the swallowing function, serum CK level and incidence of pneumonia by leuprorelin acetate has been demonstrated and leuprorelin was approved PMDA in Japan. Based on these clinical trials, we also demonstrated that disease–modifying therapy like the leuprorelin on SBMA takes a along term treatment up to 7 to 8 years long to assess the efficacy on the true endpoint like death or permanent respirator support.

Advances in basic and clinical researches on SBMA are providing the way for clinical application of molecular targeting therapeutics.