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1) Stem Cell Sources – Valeria Canto-Soler, PhD, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
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Short-Term Needs and Opportunities:
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a) Prioritize progress in human-induced pluripotent stem cell (hiPSC) technology, the most promising stem cell source to date:
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i) Improve methods for cell line manufacturing to reproducibly obtain cell lines with optimum differentiation efficiency and reproducibility. This includes a combination of the best primary cell source and the best reprogramming method.
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ii) Continue efforts to improve (and accelerate?) cell differentiation in vitro.
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iii) Continue efforts to establish cell line production pipelines compliant with current good manufacturing practices.
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iv) Continue efforts to establish banks for HLA-matched hiPSC universal donors.
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v) Develop methods to generate clinical grade, genetically corrected hiPSC for autologous transplantation.
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b) Establish appropriate platforms for evaluating non–cell-based therapeutic strategies. This includes appropriate disease models and drug screening platforms, for example.
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Long-Term Needs and Opportunities:
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c) Continue efforts to “unlock” the mechanisms of endogenous regeneration in the human adult retina as a potential regenerative strategy in the future.
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2) What Can We Learn from Retinal Development? – Sui Wang, PhD, Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States
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a)Dissect all genetic regulatory networks (GRNs) that regulate the genesis of rods and cones (different cone types) in different retinal progenitor cells (RPCs) and precursors.
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b) Understand how these GRNs transition between different developmental stages.
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c) Characterize RPC heterogeneity and label distinct RPCs.
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d) Discover the GRNs that control photoreceptor maturation (outer segments and synaptogenesis) and maintain photoreceptor function, and understand how these GRNs are dysregulated under disease conditions.
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3) Mimicking Retinal Development and Disease With Stem Cells – David Gamm, MD, PhD, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States
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a) Understanding and modulating the diversity of neural retinal cell types differentiated from human pluripotent stem cells over time.
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b) Maximizing retinal cell maturity and function.
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c) Achieving targeted photoreceptor enrichment, cone subtypes, and rods.
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d) Building more complex three-dimensional retinal model systems by adding RPE, vasculature, and so forth.
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e) Understanding and manipulating “aging” of cells/tissues in culture in relation to AMD, primary open-angle glaucoma, and so forth.
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f) Recapitulating relevant environmental influences in vitro, considering factors such as oxidation, light, high IOP, and so on.
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g) Understanding the role of epigenetics and gene modifiers in disease modeling.
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4) Strategies for Photoreceptor Cell Regeneration – Thomas Reh, PhD, Department of Biological Structure, University of Washington, Seattle, Washington, United States
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a) Transplantation of photoreceptors as dissociated cells or in small aggregates into the subretinal space of normal mice causes a small percentage of the transplanted cells to migrate into the host retina outer nuclear layer. Improve this percentage.
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b) Methods to purify rods and cones from stem cells will be important for translation of these results to humans.
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c) Improvements to the degree of integration between transplants of either retinal sheets or dissociated cells in late stages of retinal degeneration are needed.
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d) Most studies have been done in normal mice, more studies need to be carried out in late-stage retinal disease.
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e) Most transplant studies are done in mice; transplants in animals with larger eyes would be useful to predict how the cells will behave in human retinas.
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f) Only two studies have analyzed the effects of transplants on the survival of the remaining host cones. It is important to determine whether transplants early in the disease can affect the progression.
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g) The retina undergoes extensive remodeling after rods and cones have degenerated, with aberrant sprouting, glial hypertrophy, and disruptions in normal lamination of the inner retina. No study has yet tested whether this can be reversed, or even prevented, by a photoreceptor transplant.
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h) The degree to which the Muller glial hypertrophy and retinal reorganization that occurs after cone degeneration contributes to the very limited visual improvement observed in the human patients who have received transplants needs further evaluation.
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5) The Application of Stem Cells to Ocular Surface Diseases – Sheffer Tseng, MD, PhD, Ocular Surface Foundation, Miami, Florida, United States
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a) Recognize the causative relationship between inflammation and regeneration.
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b) Formulate a different and more effective strategy to control inflammation.
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i) Consider HC-HA/PTX3 as the novel matrix to target multiple aspects of inflammation mediated by different innate and adaptive immune cells.
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c) Reprogram into lineage-committed progenitors in lieu of iPSCs.
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i) Consider using HC-HA/PTX3 for such reprogramming.
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d) Investigate how the in vitro niche regulates limbal stem cell quiescence, self-renewal, and fate decision.
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i) Consider using in vitro niche to devise an effective ex vivo expansion protocol and other therapeutics.
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6) Stem Cell Uses in Glaucoma – Donald Zack, MD, PhD, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
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Short-Term Needs and Opportunities:
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a) Further explore the use of stem cell–derived trabecular meshwork cells as a complementary approach to reduce IOP.
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b) Identify small molecules and other factors to speed up and improve the generation of human stem cell–derived retinal ganglion cells (RGCs).
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c) Develop methods to generate and characterize stem cell–derived RGCs corresponding to the various subclasses of human RGCs.
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d) Human stem cell–derived RGCs used in combination with CRISPR/Cas9 genome editing offer an unprecedented opportunity to increase our understanding of the mechanisms of RGC injury in glaucoma and other forms of optic neuropathy.
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e) Expand the use of human stem cell–derived RGCs to identify and develop safe and effective neuroprotective drugs.
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Long-Term Needs and Opportunities:
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a) The holy grail of glaucoma stem cell research is to develop the ability of transplanted human RGCs to repopulate a damaged optic nerve and make appropriate synaptic connections so as to restore lost vision.
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b) Develop methods to achieve efficient integration of transplanted human stem cell–derived RGCs.
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c) Develop increased understanding of the identity and mechanisms of axonal guidance systems that are still active, or are reactivatable, in the adult retina and optic nerve (as most patients with optic nerve disease are adults, yet normal optic nerve formation takes place during development).
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d) Identify small molecules, optimize bioengineering-based scaffolds and fibers, and develop other methods to enhance the formation of synapses of RGCs to appropriate neurons in the lateral geniculate nucleus and other target tissues.
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7) The Use of Stem Cells in Treating Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusions – Susanna Park, MD, PhD, Department of Ophthalmology, University of California, Davis Eye Center, Sacramento, California, United States
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a) Stem cell therapy that can potentially regenerate both the damaged retinal vasculature and retinal neurons is desired.
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i) As such, adult stem cells with paracrine trophic effects on multiple cell types in the retina show promise.
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ii) Whether endothelial precursor cells or mesenchymal stem cells derived from cord blood or pluripotent sources are more pluripotent and therapeutic than adult cells remains to be determined but should be investigated.
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b) Adult stem cell therapies are in early clinical trial but efficacy and safety results are still pending.
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i) If these studies move forward to larger clinical studies, a more standardized approach to evaluating safety and efficacy of cell therapy for treatment of retinal vascular disorders will need to be developed.
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c) Understanding the interplay between various precursor cells is important to developing the ideal cell therapy for vascular regeneration.
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d) Host factors might affect the regenerative potential of stem cells for autologous cell therapy. Pharmacologic methods to overcome these potential host factors are being developed and these methods may enhance the regenerative potential of these stem cells.
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e) Understanding the molecular basis for the regenerative effect of stem cells in retinal vascular conditions should shed light on new pharmacologic approaches to treating retinal vascular disorders and new approaches to enhancing the therapeutic effects of currently available stem cell therapies.
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8) Stem Cell Therapy in the Treatment of Retinitis Pigmentosa – Michael Young, PhD, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
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Short-Term Needs and Opportunities:
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a) New photoreceptors can be generated from both fetal retinal and pluripotent stem cells. Better definition is needed.
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b) Transplantation of RPCs can replace lost photoreceptors in an analogous porcine allograft model. More work is needed on larger animal models.
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c) A clinical trial will examine the safety of human RPCs in treatment of advanced RP. More trials are needed for different diseases using different disease models.
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Long-Term Needs and Opportunities:
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a) The holy grail of retinal stem cells remains a combined RPE/cone composite grafts that restores high-acuity vision. Work should be focused to achieve this end.
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9) The Treatment of Rare Retinal Degenerative Diseases by Stem Cell Therapy – Anand Swaroop, PhD, Neurobiology, Neurodegeneration, and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
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a) Further investigate the importance of reporter pluripotent stem cell lines for studying retinal biology and disease.
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b) Further develop fluorescent reporters driven by specific promoters to help in the identification of cell types or developmental stages in three-dimensional retinal cultures.
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c) Purification and use of reporter-tagged cells for next-generation sequencing analyses or for transplantation in animal models.
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d) Use of three-dimensional retina derived from reporter stem cell lines for developing disease models and for designing targeted drug screens for retinal and macular diseases.
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e) To expedite scientific discovery by sharing of resources to avoid duplication of effort through the formation of a Retinal Stem Cell Consortium that can maximize the vast potential of stem cells in developing therapies for retinal and macular diseases.
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10) Stem Cell Use in AMD – Amir Kashani, MD, PhD, Department of Ophthalmology, USC School of Medicine, Los Angeles, California, United States
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a) There is a great need to develop novel, noninvasive diagnostic tests to assay RPE and retinal function at the molecular and cellular levels.
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b) Development of novel transplantation tools and surgical methods for optimal delivery of RPE to the subretinal space is needed.
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c) Expansion and advancement of stem cell science is important for the purpose of understanding host immune response in the subretinal space.
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d) Developing clinical grade methods to genetically modify stem cell–derived RPE is needed.
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11) Stem Cell Clinical Planning: Patients, Trials, and Expectations – Samuel Jacobson, MD, PhD, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States
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a) Develop a workup that will include the types of data (beyond the clinical examination) needed to decide whether a patient is or is not a future candidate for clinical trials of stem cell–based therapies. There should be specific workups for widespread retinal degenerations as well as maculopathies.
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b) Segmented optical coherence tomography images over a wide expanse of fundus should be part of all such workups, as well as appropriate perceptual testing to quantify the severity of visual loss.
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c) Develop robust outcome measures so that these future trials are not mired in controversy and without a definitive answer about efficacy as well as safety.
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d) Perform further noninvasive human research to understand the relationship between inner retinal abnormalities associated with photoreceptor loss and retinal remodeling so as to clarify if there will be any impediments to the goals of stem cell therapy or other forms of photoreceptor-based treatments before rather than after the trials are initiated.