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Regen Ther. 2018 Dec 17;10:54-63. doi: 10.1016/j.reth.2018.11.001. eCollection 2019 Jun.

Estimating the concentration of therapeutic range using disease-specific iPS cells: Low-dose rapamycin therapy for Pendred syndrome.

Author information

1
Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
2
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
3
The Laboratory of Auditory Disorders and Division of Hearing and Balance Research, National Institute of Sensory Organs, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.
4
Medical Genetics Center, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.

Abstract

Introduction:

Pendred syndrome is an autosomal-recessive disease characterized by congenital hearing loss and thyroid goiter. Previously, cell stress susceptibilities were shown to increase in patient-derived cells with intracellular aggregation using an in vitro acute cochlear cell model derived from patient-specific pluripotent stem (iPS) cells. Moreover, we showed that rapamycin can relieve cell death. However, studies regarding long-term cell survival without cell stressors that mimic the natural course of disease or the rational minimum concentration of rapamycin that prevents cell death are missing.

Methods:

In this report, we first investigated the rational minimum concentration of rapamycin using patient-specific iPS cells derived-cochlear cells with three different conditions of acute stress. We next confirmed the effects of rapamycin in long-term cell survival and phenotypes by using cochlear cells derived from three different patient-derived iPS cells.

Results:

We found that inner ear cells derived from Pendred syndrome patients are more vulnerable than those from healthy individuals during long-term culturing; however, this susceptibility was relieved via treatment with low-dose rapamycin. The slow progression of hearing loss in patients may be explained, in part, by the vulnerability observed in patient cells during long-term culturing. We successfully evaluated the rational minimum concentration of rapamycin for treatment of Pendred syndrome.

Conclusion:

Our results suggest that low-dose rapamycin not only decreases acute symptoms but may prevent progression of hearing loss in Pendred syndrome patients.

KEYWORDS:

Hereditary hearing loss; Induced pluripotent stem cell; PDS, Pendred syndrome; Pendred syndrome; SLC26A4, Solute carrier family 26 member 4; iPS, Induced pluripotent stem cell; mTOR, Mammalian target of rapamycin

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