Editing Retina (section)

==== Uncommon treatment modalities ====
'''Retinal gene therapy'''
{{Main|Adeno associated virus and gene therapy of the human retina}}

[[Gene therapy]] holds promise as a potential avenue to cure a wide range of retinal diseases. This involves using a non-infectious virus to shuttle a gene into a part of the retina. Recombinant [[adeno-associated virus]] (rAAV) vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner.<ref>{{cite journal |author1 = Dinculescu Astra |author2 = Glushakova Lyudmyla |author3 = Seok-Hong Min |author4 = Hauswirth William W |year = 2005 |title = Adeno-associated virus-vectored gene therapy for retinal disease |journal = Human Gene Therapy |volume = 16 |issue = 6 |pages = 649–663 |doi = 10.1089/hum.2005.16.649 |pmid = 15960597 }}</ref> rAAV vectors are increasingly utilized for their ability to mediate efficient transduction of [[retinal pigment epithelium]] (RPE), [[photoreceptor cells]] and [[retinal ganglion cells]]. Each cell type can be specifically targeted by choosing the appropriate combination of AAV [[serotype]], promoter, and intraocular injection site.

Several clinical trials have already reported positive results using rAAV to treat [[Leber's congenital amaurosis]], showing that the therapy was both safe and effective.<ref name="Cideciyan 2009">{{cite journal |author1 = Cideciyan A. V. |author2 = Hauswirth W. W. |author3 = Aleman T. S. |author4 = Kaushal S. |author5 = Schwartz S. B. |author6 = Boye S. L. |author7 = Windsor E. A. M. |year = 2009 |title = Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year |journal = Human Gene Therapy |volume = 20 |issue = 9 |pages = 999–1004 |doi = 10.1089/hum.2009.086 |pmid = 19583479 |pmc = 2829287 |display-authors = etal }}</ref><ref name="Simonelli 2010">{{cite journal |author1 = Simonelli F. |author2 = Maguire A. M. |author3 = Testa F. |author4 = Pierce E. A. |author5 = Mingozzi F. |author6 = Bennicelli J. L. |author7 = Rossi S. |year = 2010 |title = Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration |journal = Molecular Therapy |volume = 18 |issue = 3 |pages = 643–650 |doi = 10.1038/mt.2009.277 |pmid = 19953081 |pmc = 2839440 |display-authors = etal }}</ref> There were no serious adverse events, and patients in all three studies showed improvement in their visual function as measured by a number of methods. The methods used varied among the three trials, but included both functional methods such as visual acuity<ref name="Simonelli 2010" /><ref name="Maguire 2008">{{cite journal |author1 = Maguire A. M. |author2 = Simonelli F. |author3 = Pierce E. A. |author4 = Pugh E. N. |author5 = Mingozzi F. |author6 = Bennicelli J. |author7 = Banfi S. |year = 2008 |title = Safety and efficacy of gene transfer for Leber's congenital amaurosis |journal = [[The New England Journal of Medicine]] |volume = 358 |issue = 21 |pages = 2240–2248 |doi = 10.1056/NEJMoa0802315 |pmid = 18441370 |pmc = 2829748 |display-authors = etal }}</ref><ref name="Maguire 2009">{{cite journal |author1 = Maguire A. M. |author2 = High K. A. |author3 = Auricchio A. |author4 = Wright J. F. |author5 = Pierce E. A. |author6 = Testa F. |author7 = Mingozzi F. |year = 2009 |title = Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial |journal = Lancet |volume = 374 |issue = 9701 |pages = 1597–1605 |doi = 10.1016/S0140-6736(09)61836-5 |pmid = 19854499 |display-authors = etal |pmc = 4492302 }}</ref> and functional mobility<ref name="Maguire 2008" /><ref name="Maguire 2009" /><ref name="Bainbridge 2008">{{cite journal |author1 = Bainbridge J. W. B. |author2 = Smith A. J. |author3 = Barker S. S. |author4 = Robbie S. |author5 = Henderson R. |author6 = Balaggan K. |author7 = Viswanathan A. |year = 2008 |title = Effect of gene therapy on visual function in Leber's congenital amaurosis |url = http://cvrl.ioo.ucl.ac.uk/people/stockman/pubs/2008%20gene%20therapy%20b%20et%20al.pdf |journal = The New England Journal of Medicine |volume = 358 |issue = 21 |pages = 2231–2239 |doi = 10.1056/NEJMoa0802268 |pmid = 18441371 |hdl = 10261/271174 |display-authors = etal |url-status = live |archive-url = https://web.archive.org/web/20170811191322/http://cvrl.ioo.ucl.ac.uk/people/Stockman/pubs/2008%20Gene%20therapy%20B%20et%20al.pdf |archive-date = 11 August 2017 |citeseerx = 10.1.1.574.4003 }}</ref> as well as objective measures that are less susceptible to bias, such as the pupil's ability to respond to light<ref name="Cideciyan 2009" /><ref name="Hauswirth 2008">{{cite journal |author1 = Hauswirth W. W. |author2 = Aleman T. S. |author3 = Kaushal S. |author4 = Cideciyan A. V. |author5 = Schwartz S. B. |author6 = Wang L. |author7 = Conlon T. J. |year = 2008 |title = Treatment of Leber Congenital Amaurosis Due to RPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial |journal = Human Gene Therapy |volume = 19 |issue = 10 |pages = 979–990 |doi = 10.1089/hum.2008.107 |pmid = 18774912 |pmc = 2940541 |display-authors = etal }}</ref> and improvements on functional MRI.<ref name="Ashtari 2011">{{cite journal |author1 = Ashtari M. |author2 = Cyckowski L. L. |author3 = Monroe J. F. |author4 = Marshall K. A. |author5 = Chung D. C. |author6 = Auricchio A. |author7 = Simonelli F. |year = 2011 |title = The human visual cortex responds to gene therapy-mediated recovery of retinal function |journal = The Journal of Clinical Investigation |volume = 121 |issue = 6 |pages = 2160–2168 |doi = 10.1172/JCI57377 |pmid = 21606598 |pmc = 3104779 |display-authors = etal }}</ref> Improvements were sustained over the long-term, with patients continuing to do well after more than 1.5 years.<ref name="Cideciyan 2009" /><ref name="Simonelli 2010" />

The unique architecture of the retina and its relatively immune-privileged environment help this process.<ref>{{cite journal |author = Bennett J |year = 2003 |title = Immune response following intraocular delivery of recombinant viral vectors |journal = Gene Therapy |volume = 10 |issue = 11 |pages = 977–982 |doi = 10.1038/sj.gt.3302030 |pmid = 12756418 |doi-access = free }}</ref> [[Tight junction]]s that form the [[blood retinal barrier]] separate the subretinal space from the blood supply, thus protecting it from microbes and most immune-mediated damage, and enhancing its potential to respond to vector-mediated therapies. The highly compartmentalized anatomy of the eye facilitates accurate delivery of therapeutic vector suspensions to specific tissues under direct visualization using microsurgical techniques.<ref>{{cite journal |author1 = Curace Enrico M. |author2 = Auricchio Alberto |title = Versatility of AAV vectors for retinal gene transfer |doi = 10.1016/j.visres.2007.07.027 |pmid = 17923143 |date = 2008 |journal = Vision Research |volume = 48 |issue = 3 |pages = 353–359 |s2cid = 9926758 |doi-access = free }}</ref> In the sheltered environment of the retina, AAV vectors are able to maintain high levels of [[transgene]] expression in the retinal pigmented epithelium (RPE), photoreceptors, or ganglion cells for long periods of time after a single treatment. In addition, the eye and the visual system can be routinely and easily monitored for visual function and retinal structural changes after injections with noninvasive advanced technology, such as visual acuities, [[contrast sensitivity]], [[fundus (eye)|fundus]] auto-fluorescence (FAF), dark-adapted visual thresholds, vascular diameters, pupillometry, [[electroretinography]] (ERG), multifocal ERG and [[optical coherence tomography]] (OCT).<ref name="Hollander2008">{{Cite journal |last1 = den Hollander |first1 = Anneke I. |last2 = Roepman |first2 = Ronald |last3 = Koenekoop |first3 = Robert K. |last4 = Cremers |first4 = Frans P.M. |year = 2008 |title = Leber congenital amaurosis: Genes, proteins and disease mechanisms |journal = Progress in Retinal and Eye Research |volume = 27 |issue = 4 |pages = 391–419 |doi = 10.1016/j.preteyeres.2008.05.003 |pmid = 18632300 |s2cid = 30202286 }}</ref>

This strategy is effective against a number of retinal diseases that have been studied, including neovascular diseases that are features of [[age-related macular degeneration]], [[diabetic retinopathy]] and [[retinopathy of prematurity]]. Since the regulation of vascularization in the mature retina involves a balance between endogenous positive [[growth factors]], such as [[vascular endothelial growth factor]] (VEGF) and inhibitors of [[angiogenesis]], such as pigment epithelium-derived factor ([[PEDF]]), rAAV-mediated expression of PEDF, angiostatin, and the soluble VEGF receptor sFlt-1, which are all antiangiogenic proteins, have been shown to reduce aberrant vessel formation in animal models.<ref name="Rolling2004">{{Cite journal |last = Rolling |first = F. |date = 2004 |title = Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives |journal = Gene Therapy |volume = 11 |issue = S1 |pages = S26–S32 |doi = 10.1038/sj.gt.3302366 |issn = 0969-7128 |pmid = 15454954 |doi-access = free }}</ref> Since specific gene therapies cannot readily be used to treat a significant fraction of patients with retinal dystrophy, there is a major interest in developing a more generally applicable survival factor therapy. [[Neurotrophic factors]] have the ability to modulate neuronal growth during development to maintain existing cells and to allow recovery of injured neuronal populations in the eye. AAV encoding neurotrophic factors such as fibroblast growth factor (FGF) family members and GDNF either protected photoreceptors from apoptosis or slowed down cell death.<ref name="Rolling2004" />

'''Organ transplantation'''
[[Organ transplant|Transplantation]] of retinas has been attempted, but without much success. At [[Massachusetts Institute of Technology|MIT]], The University of Southern California, RWTH Aachen University, and the [[University of New South Wales]], an "artificial retina" is under development: an implant which will bypass the photoreceptors of the retina and stimulate the attached nerve cells directly, with signals from a digital camera.