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Scerri T.S.,Walter and Eliza Hall Institute of Medical Research | Scerri T.S.,University of Melbourne | Quaglieri A.,Walter and Eliza Hall Institute of Medical Research | Quaglieri A.,University of Melbourne | And 16 more authors.
Nature Genetics | Year: 2017

Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10-8) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10 -17; rs715 at 2q34, P = 9.97 × 10 -14; rs477992 at 1p12, P = 2.60 × 10 -12) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1,134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences in blood serum levels of glycine (P = 4.04 × 10 -6) and serine (P = 2.48 × 10 -4) between MacTel cases and controls.


News Article | February 27, 2017
Site: www.eurekalert.org

Australian scientists have discovered the first evidence of genes that cause Macular Telangiectasia type 2 (MacTel), a degenerative eye disease which leads to blindness and is currently incurable and untreatable Australian scientists have discovered the first evidence of genes that cause Macular Telangiectasia type 2 (MacTel), a degenerative eye disease which leads to blindness and is currently incurable and untreatable. The team's findings established five key regions -- or loci -- in the genome most likely to influence a person's risk of developing MacTel. The finding will enable researchers to better understand the disease and look for ways to prevent or stop its progression. The study, published today in Nature Genetics, was an international collaboration led by bioinformaticians Professor Melanie Bahlo and Dr Thomas Scerri at Melbourne's Walter and Eliza Hall Institute of Medical Research. MacTel is a rare and complex disease that mainly affects people from the age of 40 onwards. The disease causes abnormal growth of blood vessels in the macula -- located in the middle of the retina. Patients experience a loss of central vision crucial for tasks requiring focus, such as driving or reading, with no treatment available to stop progression of the disease. Professor Bahlo said the study involved detailed genetic analysis of MacTel patients from around the world, including Australia, using genome wide association studies (GWAS). "We analysed more than six million genetic markers and identified five regions, called loci, across the genome that had similar patterns in people with the disease, but not the healthy individuals," Professor Bahlo said. "These five genetic risk loci are our treasure map, telling us where to 'keep digging' in order to discover the specific genes implicated in MacTel," she said. Professor Bahlo said the team worked with collaborators in London and New York to analyse the genetic data from 476 people with MacTel and 1733 controls (people without the disease). "We were thrilled when our results were corroborated by two further independent validation studies," she said. The analysis also revealed that people with the MacTel genetic risk loci identified in the study had changes in their metabolism, specifically in their glycine and serine levels. Professor Bahlo said this meant there could be a significant relationship between the level of glycine and serine in the body, and onset of the disease. "Though the exact link between the disease and glycine and serine is yet to be confirmed, the connection is an exciting clue to help us further explore metabolic abnormalities in people with MacTel," Professor Bahlo said. Dr Scerri said the team's work highlighted crucial points of interest that, with further investigation, could help researchers find a way to prevent the progression of the disease. "We are continuing to explore the genetic data to try to identify the specific genes involved, and the precise genetic variations that are leading to the disease," Dr Scerri said. President of the Lowy Medical Research Institute that sponsored the research Professor Martin Friedlander said the work represented a significant advancement in efforts to understand the cause of MacTel. "We are working to develop treatments effective in preserving vision in patients with this disease," he said. The research was supported by the Lowy Medical Research Institute, The Genomics Core Facility at the University of Utah School of Medicine, participants of the MacTel Project, the National Eye Institute, the Wellcome Trust, the British Heart Foundation, Diabetes UK, the National Institute for Health Research, Moorfields Biomedical Research Centre, Victorian State Government Operational Infrastructure and Support Scheme, and the National Health and Medical Research Council.


PubMed | STEMCELL Technologies, Lowy Medical Research Institute and Scripps Research Institute
Type: Journal Article | Journal: JCI insight | Year: 2017

Vascular abnormalities are a common component of eye diseases that often lead to vision loss. Vaso-obliteration is associated with inherited retinal degenerations, since photoreceptor atrophy lowers local metabolic demands and vascular support to those regions is no longer required. Given the degree of neurovascular crosstalk in the retina, it may be possible to use one cell type to rescue another cell type in the face of severe stress, such as hypoxia or genetically encoded cell-specific degenerations. Here, we show that intravitreally injected human endothelial colony-forming cells (ECFCs) that can be isolated and differentiated from cord blood in xeno-free media collect in the vitreous cavity and rescue vaso-obliteration and neurodegeneration in animal models of retinal disease. Furthermore, we determined that a subset of the ECFCs was more effective at anatomically and functionally preventing retinopathy; these cells expressed high levels of CD44, the hyaluronic acid receptor, and IGFBPs (insulin-like growth factor-binding proteins). Injection of cultured media from ECFCs or only recombinant human IGFBPs also rescued the ischemia phenotype. These results help us to understand the mechanism of ECFC-based therapies for ischemic insults and retinal neurodegenerative diseases.


Westenskow P.,Scripps Research Institute | Westenskow P.,Lowy Medical Research Institute | Sedillo Z.,Scripps Research Institute | Sedillo Z.,Lowy Medical Research Institute | And 3 more authors.
Journal of Visualized Experiments | Year: 2015

No cure has been discovered for age-related macular degeneration (AMD), the leading cause of vision loss in people over the age of 55. AMD is complex multifactorial disease with an unknown etiology, although it is largely thought to occur due to death or dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells that underlies the retina and provides critical support for photoreceptors. RPE cell replacement strategies may hold great promise for providing therapeutic relief for a large subset of AMD patients, and RPE cells that strongly resemble primary human cells (hRPE) have been generated in multiple independent labs, including our own. In addition, the uses for iPS-RPE are not limited to cell-based therapies, but also have been used to model RPE diseases. These types of studies may not only elucidate the molecular bases of the diseases, but also serve as invaluable tools for developing and testing novel drugs. We present here an optimized protocol for directed differentiation of RPE from stem cells. Adding nicotinamide and either Activin A or IDE-1, a small molecule that mimics its effects, at specific time points, greatly enhances the yield of RPE cells. Using this technique we can derive large numbers of low passage RPE in as early as three months. © 2015 Journal of Visualized Experiments.


Westenskow P.D.,Scripps Research Institute | Westenskow P.D.,Lowy Medical Research Institute | Kurihara T.,Scripps Research Institute | Bravo S.,Scripps Research Institute | And 5 more authors.
Journal of Visualized Experiments | Year: 2015

The conversion of light into electrical impulses occurs in the outer retina and is accomplished largely by rod and cone photoreceptors and retinal pigment epithelium (RPE) cells. RPE provide critical support for photoreceptors and death or dysfunction of RPE cells is characteristic of age-related macular degeneration (AMD), the leading cause of permanent vision loss in people age 55 and older. While no cure for AMD has been identified, implantation of healthy RPE in diseased eyes may prove to be an effective treatment, and large numbers of RPE cells can be readily generated from pluripotent stem cells. Several interesting questions regarding the safety and efficacy of RPE cell delivery can still be examined in animal models, and well-accepted protocols used to inject RPE have been developed. The technique described here has been used by multiple groups in various studies and involves first creating a hole in the eye with a sharp needle. Then a syringe with a blunt needle loaded with cells is inserted through the hole and passed through the vitreous until it gently touches the RPE. Using this injection method, which is relatively simple and requires minimal equipment, we achieve consistent and efficient integration of stem cell-derived RPE cells in between the host RPE that prevents significant amount of photoreceptor degeneration in animal models. While not part of the actual protocol, we also describe how to determine the extent of the trauma induced by the injection, and how to verify that the cells were injected into the subretinal space using in vivo imaging modalities. Finally, the use of this protocol is not limited to RPE cells; it may be used to inject any compound or cell into the subretinal space. © JoVE 2006-2015. All Rights Reserved.


Westenskow P.D.,Scripps Research Institute | Westenskow P.D.,Lowy Medical Research Institute | Bucher F.,Scripps Research Institute | Bravo S.,Scripps Research Institute | And 6 more authors.
Stem Cells International | Year: 2016

Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 2 1/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes. © 2016 Peter D. Westenskow et al.


Usui Y.,Scripps Research Institute | Westenskow P.D.,Scripps Research Institute | Westenskow P.D.,Lowy Medical Research Institute | Kurihara T.,Scripps Research Institute | And 9 more authors.
Journal of Clinical Investigation | Year: 2015

Functional interactions between neurons, vasculature, and glia within neurovascular units are critical for maintenance of the retina and other CNS tissues. For example, the architecture of the neurosensory retina is a highly organized structure with alternating layers of neurons and blood vessels that match the metabolic demand of neuronal activity with an appropriate supply of oxygen within perfused blood. Here, using murine genetic models and cell ablation strategies, we have demonstrated that a subset of retinal interneurons, the amacrine and horizontal cells, form neurovascular units with capillaries in 2 of the 3 retinal vascular plexuses. Moreover, we determined that these cells are required for generating and maintaining the intraretinal vasculature through precise regulation of hypoxia-inducible and proangiogenic factors, and that amacrine and horizontal cell dysfunction induces alterations to the intraretinal vasculature and substantial visual deficits. These findings demonstrate that specific retinal interneurons and the intraretinal vasculature are highly interdependent, and loss of either or both elicits profound effects on photoreceptor survival and function.


PubMed | Lowy Medical Research Institute and Scripps Research Institute
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2015

The conversion of light into electrical impulses occurs in the outer retina and is accomplished largely by rod and cone photoreceptors and retinal pigment epithelium (RPE) cells. RPE provide critical support for photoreceptors and death or dysfunction of RPE cells is characteristic of age-related macular degeneration (AMD), the leading cause of permanent vision loss in people age 55 and older. While no cure for AMD has been identified, implantation of healthy RPE in diseased eyes may prove to be an effective treatment, and large numbers of RPE cells can be readily generated from pluripotent stem cells. Several interesting questions regarding the safety and efficacy of RPE cell delivery can still be examined in animal models, and well-accepted protocols used to inject RPE have been developed. The technique described here has been used by multiple groups in various studies and involves first creating a hole in the eye with a sharp needle. Then a syringe with a blunt needle loaded with cells is inserted through the hole and passed through the vitreous until it gently touches the RPE. Using this injection method, which is relatively simple and requires minimal equipment, we achieve consistent and efficient integration of stem cell-derived RPE cells in between the host RPE that prevents significant amount of photoreceptor degeneration in animal models. While not part of the actual protocol, we also describe how to determine the extent of the trauma induced by the injection, and how to verify that the cells were injected into the subretinal space using in vivo imaging modalities. Finally, the use of this protocol is not limited to RPE cells; it may be used to inject any compound or cell into the subretinal space.


PubMed | Lowy Medical Research Institute and Scripps Research Institute
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2015

No cure has been discovered for age-related macular degeneration (AMD), the leading cause of vision loss in people over the age of 55. AMD is complex multifactorial disease with an unknown etiology, although it is largely thought to occur due to death or dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells that underlies the retina and provides critical support for photoreceptors. RPE cell replacement strategies may hold great promise for providing therapeutic relief for a large subset of AMD patients, and RPE cells that strongly resemble primary human cells (hRPE) have been generated in multiple independent labs, including our own. In addition, the uses for iPS-RPE are not limited to cell-based therapies, but also have been used to model RPE diseases. These types of studies may not only elucidate the molecular bases of the diseases, but also serve as invaluable tools for developing and testing novel drugs. We present here an optimized protocol for directed differentiation of RPE from stem cells. Adding nicotinamide and either Activin A or IDE-1, a small molecule that mimics its effects, at specific time points, greatly enhances the yield of RPE cells. Using this technique we can derive large numbers of low passage RPE in as early as three months.

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