In:
eLife, eLife Sciences Publications, Ltd, Vol. 2 ( 2013-08-27)
Abstract:
Retinitis pigmentosa is an inherited disorder in which the gradual degeneration of light-sensitive cells in the outer retina, known as photoreceptors, causes a progressive loss of sight. Retinitis pigmentosa can also occur as part of a wider syndrome: patients with Usher syndrome, for example, suffer from early-onset deafness and then develop retinitis pigmentosa later in life. Usher syndrome is caused by mutations in any of more than ten genes, but the most commonly affected is USH2A, which encodes a protein called usherin. Mutations in USH2A can also cause retinitis pigmentosa on its own. Clinical trials are underway to determine whether it is possible to treat various forms of inherited retinal degeneration using gene therapy. This involves inserting a functional copy of the gene associated with the disease into an inactivated virus, which is then injected into the eye. The virus carries the target gene to the light-sensitive photoreceptor cells where it can replace the faulty gene. This could be particularly useful for conditions such as Usher syndrome, in which the early-onset deafness makes it possible to diagnose retinitis pigmentosa before substantial numbers of photoreceptor cells have been lost. For gene therapy to become a widely used strategy for the treatment of retinal degenerative disease, identification and functional interrogation of the disease-causing gene/mutations will be critical. This is especially true for large highly polymorphic genes such as USH2A that often have mutations that are difficult to identify by standard sequencing techniques. Likewise, viruses that can carry large amounts of genetic material, or endogenous genome editing approaches, will need to be developed and validated in an efficient patient-specific model system. Tucker et al. might have found a way to address these problems. In their study, they used skin cells from a retinitis pigmentosa patient with mutations in USH2A to produce induced pluripotent stem cells. These are cells that can be made to develop into a wide variety of mature cell types, depending on the exact conditions in which they are cultured. Tucker et al. used these stem cells to generate photoreceptor precursor cells, which they transplanted into the retinas of immune-suppressed mice. The cells developed into normal-looking photoreceptor cells that expressed photoreceptor-specific proteins. These results have several implications. First, they support the idea that stem cell-derived retinal photoreceptor cells, generated from patients with unknown mutations, can be used to identify disease-causing genes and to interrogate disease pathophysiology. This will allow for a more rapid development of gene therapy strategies. Second, they demonstrate that USH2A mutations cause retinitis pigmentosa by affecting photoreceptors later in life rather than by altering their development. This suggests that it should, via early intervention, be possible to treat retinitis pigmentosa in adult patients with this form of the disease. Third, the technique could be used to generate animal models in which to study the effects of specific disease-causing mutations on cellular development and function. Finally, this study suggests that skin cells from adults with retinitis pigmentosa could be used to generate immunologically matched photoreceptor cells that can be transplanted back into the same patients to restore their sight. Many questions remain to be answered before this technique can be moved into clinical trials but, in the meantime, it will provide a new tool for research into this major cause of blindness.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.00824.001
DOI:
10.7554/eLife.00824.002
DOI:
10.7554/eLife.00824.003
DOI:
10.7554/eLife.00824.004
DOI:
10.7554/eLife.00824.005
DOI:
10.7554/eLife.00824.006
DOI:
10.7554/eLife.00824.007
DOI:
10.7554/eLife.00824.008
DOI:
10.7554/eLife.00824.009
DOI:
10.7554/eLife.00824.010
DOI:
10.7554/eLife.00824.011
DOI:
10.7554/eLife.00824.012
DOI:
10.7554/eLife.00824.013
DOI:
10.7554/eLife.00824.014
DOI:
10.7554/eLife.00824.015
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2013
detail.hit.zdb_id:
2687154-3
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