sirolimus and Hearing-Loss--Sensorineural

Pendred syndrome (PDS)/DFNB 4 is a disorder with fluctuating and progressive hearing loss, vertigo, and thyroid goiter. We identified pathophysiology of a neurodegenerative disorder in PDS patient derived cochlear cells that were induced via induced pluripotent stem cells and found sirolimus, an mTOR inhibitor, as an inhibitor of cell death with the minimum effective concentration less than 1/10 of the approved dose for other diseases. Given that there is no rational standard therapy for PDS, we planned a study to examine effects of low dose oral administration of sirolimus for the fluctuating and progressive hearing loss, and the balance disorder of PDS by daily monitor of their audio-vestibular symptoms.. This is a phase I/IIa double blind parallel-group single institute trial in patient with PDS/DFNB4. Sixteen of outpatients with fluctuating hearing diagnosed as PDS in SLC26A4 genetic testing aged in between 7 and 50 years old at the time of consent are given either placebo or sirolimus tablet (NPC-12T). In NPC-12T placebo arm, placebo will be given for 36 weeks; in active substance arm, placebo will be given for 12 weeks and the NPC-12T for 24 weeks. Primary endpoints are safety and tolerability. The number of occurrences and types of adverse events and of side effects will be sorted by clinical symptoms and by abnormal change of clinical test results. A 2-sided 95% confidence interval of the incidence rate by respective dosing arms will be calculated using the Clopper-Pearson method. Clinical effects on audio-vestibular tests performed daily and precise physiological test at each visit will also be examined as secondary and expiratory endpoints.. JMA-IIA00361; Pre-results.

Topics: Adolescent; Adult; Audiometry; Child; Double-Blind Method; Female; Goiter, Nodular; Hearing Loss, Sensorineural; Humans; Male; Middle Aged; Sirolimus; Sulfate Transporters; Treatment Outcome; Vestibular Aqueduct; Vestibular Function Tests; Young Adult

The Food and Drug Administration–approved drug sirolimus, which inhibits mechanistic target of rapamycin (mTOR), is the leading candidate for targeting aging in rodents and humans. We previously demonstrated that sirolimus could treat ARHL in mice. In this study, we further demonstrate that sirolimus protects mice against cocaine-induced hearing loss. However, using efficacy and safety tests, we discovered that mice developed substantial hearing loss when administered high doses of sirolimus. Using pharmacological and genetic interventions in murine models, we demonstrate that the inactivation of mTORC2 is the major driver underlying hearing loss. Mechanistically, mTORC2 exerts its effects primarily through phosphorylating in the AKT/PKB signaling pathway, and ablation of P53 activity greatly attenuated the severity of the hearing phenotype in mTORC2-deficient mice. We also found that the selective activation of mTORC2 could protect mice from acoustic trauma and cisplatin-induced ototoxicity. Thus, in this study, we discover a function of mTORC2 and suggest that its therapeutic activation could represent a potentially effective and promising strategy to prevent sensorineural hearing loss. More importantly, we elucidate the side effects of sirolimus and provide an evaluation criterion for the rational use of this drug in a clinical setting.

Topics: Animals; Disease Models, Animal; Hearing Loss, Sensorineural; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; Rapamycin-Insensitive Companion of mTOR Protein; Signal Transduction; Sirolimus; Tumor Suppressor Protein p53

Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to "degenerative cochlear disease" and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.

Topics: Adolescent; Adult; Cell Line; Child; Child, Preschool; Cochlea; Female; Goiter, Nodular; Hearing Loss; Hearing Loss, Sensorineural; Human Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Infant, Newborn; Ion Exchange; Membrane Transport Proteins; Metformin; Phenotype; Protein Aggregates; Sirolimus; Sulfate Transporters; Vestibular Aqueduct

Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldwide. The detailed mechanism of cisplatin-induced ototoxicity is not completely understood. We investigated whether rapamycin could protect rats from cisplatin-induced ototoxicity.. Forty-eight male Wistar rats were randomly divided into six groups. Three groups were intraperitoneally (IP) infused with cisplatin at a dose of 16 mg/kg and immediately injected with either dimethylsulfoxide (DMSO), rapamycin, or chloroquine (CQ). The remaining three groups were treated with rapamycin, CQ, or saline alone. The auditory brainstem response (ABR) test was performed to detect the rats' hearing status. Serum was isolated to measure the level of the oxidative marker malondialdehyde (MDA), the basilar membrane was prepared to count the outer hair cell loss, and soft tissue samples extracted from the cochleae were lysed to analyze the microtubule-associated protein light chain 3 (LC3) and Beclin-1.. The rapamycin treatment significantly attenuated cisplatin-induced hearing loss, decreased oxidative stress, and alleviated the hair cell damage that was associated with the upregulation of the LC3-II/GAPDH ratio and increased Beclin-1 expression.. Our results demonstrated that rapamycin has an otoprotective effect; it attenuates cisplatin-induced ototoxicity, probably by attenuating oxidative damage and inducing autophagy.

Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cisplatin; Cochlea; Disease Models, Animal; Ear, Inner; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory, Outer; Hearing Loss, Sensorineural; Humans; Male; Malondialdehyde; Microtubule-Associated Proteins; Oxidative Stress; Rats; Rats, Wistar; Sirolimus