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      Genetic Basis of Inherited Macular Dystrophies and Implications for Stem Cell Therapy

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          Untreatable hereditary macular dystrophy (HMD) presents a major burden to society in terms of the resulting patient disability and the cost to the healthcare provision system. HMD results in central vision loss in humans sufficiently severe for blind registration, and key issues in the development of therapeutic strategies to target these conditions are greater understanding of the causes of photoreceptor loss and the development of restorative procedures. More effective and precise analytical techniques coupled to the development of transgenic models of disease have led to a prolific growth in the identification and our understanding of the genetic mutations that underly HMD. Recent successes in driving differentiation of pluripotent cells towards specific somatic lineages have led to the development of more efficient protocols that can yield enriched populations of a desired phenotype. Retinal pigmented epithelial cells and photoreceptors derived from these are some of the most promising cells that may soon be used in the treatment of specific HMD, especially since rapid developments in the field of induced pluripotency have now set the stage for the production of patient-derived stem cells that overcome the ethical and methodological issues surrounding the use of embryonic derivatives. In this review we highlight a selection of HMD which appear suitable candidates for combinatorial restorative therapy, focusing specifically on where those photoreceptor loss occurs. This technology, along with increased genetic screening, opens up an entirely new pathway to restore vision in patients affected by HMD.

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          Generation of induced pluripotent stem cells using recombinant proteins.

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            Induced pluripotent stem cells from a spinal muscular atrophy patient.

            Spinal muscular atrophy is one of the most common inherited forms of neurological disease leading to infant mortality. Patients have selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Although patient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies.
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              Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

              Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.

                Author and article information

                Stem Cells
                Stem Cells (Dayton, Ohio)
                Wiley Subscription Services, Inc., A Wiley Company
                November 2009
                23 June 2009
                : 27
                : 11
                : 2833-2845
                [a ]Institute of Human Genetics andInternational Centre for Life Newcastle Upon Tyne, United Kingdom
                [b ]North East Stem Cell Institute, Newcastle University, International Centre for Life Newcastle Upon Tyne, United Kingdom
                [c ]Sunderland Eye Infirmary Queen Alexandra Road, Sunderland, Tyne and Wear, United Kingdom
                Author notes
                Correspondence: Majlinda Lako, Ph.D., Newcastle Newcastle University, Institute of Human Genetics and NESCI, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ. Telephone: 0-191-241-8688; Fax: 0-191-241-8666; e-mail: majlinda.lako@ 123456ncl.ac.uk

                Author contributions: C.B.M.: Manuscript writing; D.H.W.S.: Manuscript writing and fund raising; M.L.: Manuscript writing and fund raising.

                Disclosure of potential conflicts of interest is found at the end of this article.

                Copyright © 2009 AlphaMed Press

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Translational and Clinical Research


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