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Tackling Loss of Hearing with Mutation Correction of Patient Specific Stem Cells

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Review of “Genetic Correction of iPSCs From a Deaf Patient with MYO7A Mutation Results in Morphologic and Functional Recovery of the Derived Hair Cell-Like Cells” from Stem Cells Translational Medicine by Stuart P. Atkinson

The differentiation of genetically corrected human induced pluripotent stem cells (hiPSCs) aims to provide a source of patient-specific cells for therapeutic purposes. A new study from the group of Jin-Fu Wang (Zhejiang University, People’s Republic of China), aimed to create, correct, and differentiate hiPSCs from a patient with hereditary deafness associated with mutations in the MYO7A gene [1, 2] in the hope that they could generate functional, healthy into inner ear hair cell-like cells [3, 4]. This new study, published in Stem Cells Translational Medicine, confirms the importance of the MYO7A gene to proper auditory function and may represent the first step to cell-based treatments for deafness [5].

Using retroviral infection of Oct4, Sox2, c-Myc, and Klf4, the authors first produced iPSCs from the urinary cells of three patients – a deaf patient with compound heterozygous double MYO7A mutations (P-iPSCs), the patient’s asymptomatic father with a single MYO7A mutation (CF-iPSCs), and a healthy donor with normal MYO7A (C-iPSCs).

Using a previously described differentiation protocol [3], the iPSCs formed two distinct cells types - otic epithelial progenitors (OEPs) and otic neural progenitors (ONP). OEPs from all iPSC lines had the ability to further differentiate into hair cell-like cells using specific culture conditions [3]. However, cells carrying the compound heterozygous MYO7A mutations displayed an abnormal morphology, related to the disruption of stereocilia-like protrusion structures characteristic of normal inner ear hair cells (See Figure), and abnormal electrophysiological function, related to proper mechanotransduction required to transmit sound in the ear.

In an attempt to reverse these abnormalities, the authors then corrected one mutation in the P-iPSCs via application of CRISPR/Cas9 gene-editing technology (to generate CP-iPSCs). Correction occurred without detectable off-target effects or loss in pluripotency, and directed differentiation succeeded in producing hair cell-like cells with normal stereocilia-like protrusion structure (See Figure) and normal electrophysiological function, indicative of the recovery of inner ear hair cell-like cell function.

Not only does this study emphasize the potential for mutation correction of patient-specific iPSCs in the treatment of genetic diseases, it also confirms the relative importance of MYO7A in the proper assembly of stereocilia and the ability to hear properly. The dynamic duo of iPSCs and CRISPR reign supreme again!

References

  1. Liu XZ, Walsh J, Tamagawa Y, et al. Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene. Nat Genet 1997;17:268-269.
  2. Weil D, Kussel P, Blanchard S, et al. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat Genet 1997;16:191-193.
  3. Chen W, Jongkamonwiwat N, Abbas L, et al. Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 2012;490:278-282.
  4. Ronaghi M, Nasr M, Ealy M, et al. Inner ear hair cell-like cells from human embryonic stem cells. Stem Cells Dev 2014;23:1275-1284.
  5. Tang Z-H, Chen J-R, Zheng J, et al. Genetic Correction of Induced Pluripotent Stem Cells From a Deaf Patient With MYO7A Mutation Results in Morphologic and Functional Recovery of the Derived Hair Cell-Like Cells. Stem Cells Translational Medicine 2016;5:561-571.