الفهرس 
Genetic ToolsOnly 14 pages are availabe for public view
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Abstract
Genetic diseases of the eye and involving the eye continue as a leading cause of blindness in children and adults. Most genetic ocular disorders are considered untreatable and are without curative therapies because of our limited understanding of pathogenesis, and the need for well-designed and fully implemented animal model or human clinical trial testing of therapeutic methods. Advances in molecular genetics andgenetic testing techniques has helped in the identification of the causative genetic defects that led to the ocular disorders, introducing therapeutic possibilities that may give future hope including gene therapy and cell based therapy.
Many hereditary diseases are associated with changes of the visual system, some are isolated genetic diseases of the eye and others are associated with additional ocular or systemic disorders (syndrome). Diagnosis of such disorders is sometimes challenging, and requires the interaction between ophthalmologists and geneticists.
The eye acts as a window for some hereditary systemic diseases such as inborn errors of metabolism, where ocular manifestations are significant and can guide in the diagnosis of the disease, rendering diagnosis easier and helping in early treatment of the disease which can prevent the patients from severe complications if left untreated.
In the same time, genetic counselling and testing are very beneficial in the diagnosis of some eye diseases. Detecting the causative genetic defect and taking an accurate family history and pedigree can be extremely helpful to patients with inherited eye diseases, to be familiar with the inheritance pattern of the disease, recurrence risk assessment, identification of at-risk family members, and the possible management options.
Preventive measures could be done in some diseases with known genetic defect through preimplantation genetic diagnosis, prenatal diagnosis or newborn screening. An example is Retinoblastoma, where a procedure such as preimplantation genetic diagnosis or prenatal diagnosis in a high risk family with known RB1 mutation can save a child from losing an eye or from death. Genetic counseling also inform the patients and families with the most recent therapeutic options available and current clinical trials.
Gene-based therapies present the means to correct gene defects in inherited ocular disorders by gene replacement or silencing. Numerous studies in recent years have demonstrated proof-of-principle that gene-based therapies can mediate significant improvements in ocular morphology and visual function in experimental and preclinical models.
The retina is the primary target for gene therapy specially the retinal pigment epithelium and the photoreceptors. With the successful phase 1 and 2 trials on children and adults with RPE65 associated Leber congenital amaurosis, we expect further successes of gene therapy trials in the near future for the other retinal diseases such as retinitis pigmentosa, age related macular degeneration, X linked juvenile retinoschisis, choriodermia, usher syndrome and stargardt disease which are already being conducted with promising results on animal models, that renders gene therapy as a future therapy for humans. Trials of gene based therapies have been conducted in other disorders such as retinoblastoma, inborn errors of metabolism with ocular manifestations, mitochondrial disorders with ocular manifestations,
Recent advances in stem cell biology have led to the exploration of stem cell-based therapies to treat a wide range of human diseases. In the ophthalmic field, much hope has been placed on the potential use of these cells to restore sight, particularly in those conditions in which other established treatments have failed and in which visual function has been irreversibly damaged by disease or injury of retinal cells or corneal cells in heritable corneal dystrophies.
The retina however is the ideal-test bed for cell therapies., where cell replacement therapy using human embryonic stem cells has the potential to restore useful vision for these individuals especially after they have lost most or all of their light-sensing cells in the eye. Many cellular therapies are being developed for retinal degenerative diseases such as age related macular degeneration, stargardt disease, and retinitis pigmentosa. Stem cell therapy achieved a success in treatment of krabbe disease, a neurodegenerative disorder, preventing the development of optic atrophy when introduced as early as in the first month of life. Moreover, promising results have been achieved in animal models with MPSI, preventing visual impairment caused by severe corneal clouding and optic atrophy.
Basic concepts of genetics and their application to clinical ophthalmological practice are important
not only in making a precise diagnosis and appropriate referral, but
also in management and genetic counseling
.
With the successful phase 1 and 2 trials on children and adults with Leber congenital amaurosis caused by mutations of the RPE65 gene, we expect an explosion of gene therapy trials in the near future for diseases such as choroideremia, Usher syndrome, retinoschisis, and more.
Haematopoietic stem cell transplantation (HSCT) yields great improvement and is considered now a current treatment option in MPS I patients, preventing and treating severe visual impairment which occur due to severe progressive corneal clouding
Part of the difficulty is that the general ophthalmologist cannot possibly be expected to diagnose these rare disorders, keep up-to-date with the exploding genetic information, know how to solve complex genetic dilemmas or select appropriate testing (let alone interpret the results of those tests), or be able to identify appropriate treatment trials for the patients. Examining these patients and solving their mysteries takes hours of work, both during and after the clinical contact.
These programs offer the experience and knowledge to assist ophthalmologists in the diagnosis, testing, interpretation, support, and eventual treatment of patients with genetic eye disease. Ocular genetics represents a paradigm shift in ophthalmic patient care. No longer is it common to say, ”I’m sorry but I don’t know what you have” or ”I’m sorry, but there is nothing I can do; your child will be blind.” The rapid advances occurring every day in ocular genetics at Wills Eye Institute and elsewhere now allow us to give our patients hope, if not promise, for the future and the power of understanding and support that will give them strength today.