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      Advances in Gene Therapy for Diseases of the Eye

      review-article
      Author(s): 1 , 1, , 2 , 1, , 2, , *
      Publication date (Electronic):
      Journal: Human Gene Therapy
      Publisher: Mary Ann Liebert, Inc.

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          Abstract

          Over the last few years, huge progress has been made with regard to the understanding of molecular mechanisms underlying the pathogenesis of neurodegenerative diseases of the eye. Such knowledge has led to the development of gene therapy approaches to treat these devastating disorders. Challenges regarding the efficacy and efficiency of therapeutic gene delivery have driven the development of novel therapeutic approaches, which continue to evolve the field of ocular gene therapy. In this review article, we will discuss the evolution of preclinical and clinical strategies that have improved gene therapy in the eye, showing that treatment of vision loss has a bright future.

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          Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration.

          Anding Bi, Jinjuan Cui, Yu-Ping Ma … (2006)
          The death of photoreceptor cells caused by retinal degenerative diseases often results in a complete loss of retinal responses to light. We explore the feasibility of converting inner retinal neurons to photosensitive cells as a possible strategy for imparting light sensitivity to retinas lacking rods and cones. Using delivery by an adeno-associated viral vector, here, we show that long-term expression of a microbial-type rhodopsin, channelrhodopsin-2 (ChR2), can be achieved in rodent inner retinal neurons in vivo. Furthermore, we demonstrate that expression of ChR2 in surviving inner retinal neurons of a mouse with photoreceptor degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex. Thus, expression of microbial-type channelrhodopsins, such as ChR2, in surviving inner retinal neurons is a potential strategy for the restoration of vision after rod and cone degeneration.
          Article 0 comments Cited 210 times – based on 0 reviews     Review now
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            Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa.

            Volker Busskamp, Jens Duebel, David Balya … (2010)
            Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.
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              Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene.

              Thomas R. Hurd, Ron Stewart, Heather Boyd … (2007)
              We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Hum Gene Ther
                Journal ID (iso-abbrev): Hum. Gene Ther
                Journal ID (publisher-id): hum
                Title: Human Gene Therapy
                Publisher: Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                ISSN (Print): 1043-0342
                ISSN (Electronic): 1557-7422
                Publication date (Print): 01 August 2016
                Publication date (Electronic): 01 August 2016
                Publication date PMC-release: 01 August 2016
                Volume: 27
                Issue: 8
                Pages: 563-579
                Affiliations
                [ 1 ]Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
                [ 2 ]Department of Neurobiology, University of Massachusetts Medical School , Worcester, Massachusetts.
                Author notes
                [*] [ * ] Correspondence: Dr. Claudio Punzo, Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, 386 Plantation Street, Worcester, MA 01605. E-mail: claudio.punzo@ 123456umassmed.edu
                Article
                Publisher ID: 10.1089/hum.2016.040
                DOI: 10.1089/hum.2016.040
                PMC ID: 4991575
                PubMed ID: 27178388
                SO-VID: 5c1e7c64-cab4-47ad-9b38-0d9d7055b33c
                Copyright © © Lolita Petit et al., 2016; Published by Mary Ann Liebert, Inc.
                License:

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Date received : 28 March 2016
                Date accepted : 10 May 2016
                Page count
                Figures: 1, References: 198, Pages: 17
                Categories
                Subject: Review

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