Abstract
Primary mitochondrial disorders occur at a prevalence of one in 10 000; ∼50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease.
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Acknowledgements
We would like to thank the staff of the Bioresources Unit, Trinity College Dublin, for technical assistance, Rustam Rakhmatullin for technical assistance with MEMRI and Dr Michael Wride for helpful discussion and critical reading of this manuscript. We would also like to thank Don Zack for his gift of the eGFP transgenic mice. This research was funded by Fighting Blindness Ireland, the Health Research Board of Ireland (HRB) and Science Foundation Ireland (SFI).
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Professor Farrar and Dr Kenna are directors of Genable Technologies; Dr Chadderton is a consultant for Genable Technologies, Dr Mansergh and Dr Gobbo declare no conflict of interest.
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Mansergh, F., Chadderton, N., Kenna, P. et al. Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy. Eur J Hum Genet 22, 1314–1320 (2014). https://doi.org/10.1038/ejhg.2014.26
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DOI: https://doi.org/10.1038/ejhg.2014.26
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