Therapies For Retinal Degenerative Diseases Research Articles

Earthquakes, volcanoes and Nordic Congress of Ophthalmology

Those of you who remember the Nordic Congress of Ophthalmology in Reykjavik in 2000 will recall the 6.8 Richter scale earthquake on the first day of the congress and the 6.5 earthquake at the end of the Gala dinner. At the time the organizing committee apologized for only being able to arrange earthquakes and promised to do better the next time around. Now we have. A volcanic eruption has started in Eyjafjallajokull, a beautiful glacier on the south coast of Iceland. This is about 90 min by car from Reykjavik and I can tell you from personal experience that the view is spectacular and the experience breath-taking. Molten lava is spewing at least 150 meters into the air piling up a new pitch-black mountain and melting away the white snow and ice all around. The last time Eyjafjallajokull erupted in 1821 the eruption lasted for 2 years and we are optimistic that the eruption will be going full force throughout the summer and can be included in the social program of the Nordic Ophthalmology Meeting. There is even a possibility for Katla, a huge volcano in neighbouring Myrdalsjokull to become active. This enormous volcano has been known to follow Eyjafallajokull at least for the last thousand years. The volcanic eruption is more than hundred kilometres away from Reykjavik and presents no danger to the population or visitors. The preliminary program for the Nordic Meeting is available on http://www.NOK2010.is. It is a powerful program with speakers from the Nordic countries, Great Britain, Japan and United States. It includes cutting edge science such as the keynote lecture by Robert MacLaren in Oxfold on gene therapy and stem cells for retinal disease and the keynote lecture by Gerald Chader, USA, on emerging therapies for retinal degenerative diseases. Dr. Chader will also talk about retinal electronic prosthesis in a retinitis pigmentosa symposium. All subspecialties in ophthalmology will be presented. Bill Aylward from Moorfields Eye Hospital will discuss controversies in retinal detachment surgery in a key note lecture, and Paul Lichter from the United States will discuss clinical trials in glaucoma in another key note lecture. Charlotta Zetterström will give a key note on cataract surgery in the third world. The Acta Ophthalmologica honourary lecture will be given by Professor Anders Heijl and we presume he will discuss important issues in glaucoma. Experts in all of the Nordic Countries have organized symposia with outstanding Nordic and international speakers in all fields of ophthalmology including vitreoretinal surgery, dislocated lenses, strabismus, exfoliation glaucoma, tumours in the lacrimal system, age-related macular degeneration, retinal imaging, corneal cross linking, glaucoma surgery, retinopathy of prematurity, optic neuritis, cataract surgery, paediatric uveitis, ocular oncology, neovascular AMD, glaucoma physiology, keratoconus, congenital cataracts, lens opacities, uveitis, imaging in glaucoma and clinical physiological examinations, eye banking and corneal bio-engineering, orbital diseases, glaucoma perimetry, retinitis pigmentosa, glaucoma management, oxygen physiology, corneal grafting, diabetic retinopathy and rehabilitation after stroke. The preliminary program is seen on the next page. It is not only the volcanic eruptions and the scientific program that should encourage you to come to Reykjavik this summer. As you may recall from 2000, even strong earthquakes do not cause any collapses in Iceland. Our houses are strongly built and do not collapse even in strong earthquakes. The same cannot be said for our banks, which indeed have collapsed and along with it the value of the Icelandic Krona. This means that you get more than twice as much for your Danish, Swedish or Norwegian Krona or Euro compared to last time which means that prices in Iceland have gone from being ridiculously expensive to being quite reasonable or even cheap. At the same time it must be stated that there is no collapse in Icelandic society. The economy is humming along nicely, all services are in place and indeed tourism is thriving better than ever. We look forward to seeing you in Reykjavik on August 4–7, 2010. Some of you may want to stay for the ARVO summer meeting on diabetic retinopathy a week later and I hope many of you will use the opportunity to bring your families and enjoy a wonderful summer in Iceland and a spectacular volcanic eruption. Happy summer.

Potential for neural regeneration after neurotoxic injury in the adult mammalian retina.

It has long been believed that the retina of mature mammals is incapable of regeneration. In this study, using the N-methyl-D-aspartate neurotoxicity model of adult rat retina, we observed that some Müller glial cells were stimulated to proliferate in response to a toxic injury and produce bipolar cells and rod photoreceptors. Although these newly produced neurons were limited in number, retinoic acid treatment promoted the number of regenerated bipolar cells. Moreover, misexpression of basic helix-loop-helix and homeobox genes promoted the induction of amacrine, horizontal, and rod photoreceptor specific phenotypes. These findings demonstrated that retinal neurons regenerated even in adult mammalian retina after toxic injury. Furthermore, we could partially control the fate of the regenerated neurons with extrinsic factors or intrinsic genes. The Müller glial cells constitute a potential source for the regeneration of adult mammalian retina and can be a target for drug delivery and gene therapy in retinal degenerative diseases.

Delivery of genes to the eye using lentiviral vectors.

The primary aim of gene transfer into the retinal cells has been to investigate the developmental mechanisms of the retinal cells or to reverse retinal diseases. Retroviruses have been used to investigate the differentiation of retinal cells, to study the embryonic retina in vivo or explant organ culture, and to trace the fate of the cells that were dividing at the time of gene transfer. Using adenovirus, Bennett et al. showed the possibility of using gene therapy to correct degenerative diseases of the central nervous system (CNS) (6). However, owing to the short duration of the gene expression, adenovirus is not suitable for correcting chronic diseases. Currently, lentivirus (7-9) and adenoassociated virus vectors (10-14) are being used for studying and correcting gene therapy of retinal degenerative diseases. Using an HIV vector carrying the green fluorescent protein (GFP) gene expressed from the cytomegalovirus (CMV) promoter, we showed that efficient and long-lasting gene expression could be obtained in the retina (7,8). Moreover, gene expression was restricted to the photoreceptor cells and was more efficient with the rhodopsin promoter. Similar results were reported using adeno-associated virus (AAV) vector. Using a lentivirus vector carrying the phosphodiesterase beta subunit (PDEbeta) gene, the mutation of which causes retinal degeneration called retinitis pigmentosa in rd mice, photoreceptor cells were rescued from degeneration in rd mice for at least 6 mo by PDEbeta transduction using HIV-based lentivirus vector (9).

Chapter 23 Preservation and restoration of vision following transplantation

The use of retinal transplantation as a possible therapy for retinal degenerative diseases appears to be progressing rapidly to the human study stage. This chapter discusses number of findings critical to the progress of this field. The current retinal transplantation work encompasses a number of different strands of research that have developed independently, as well as with reference to each other, and have recently begun to integrate. The broad areas of research are sub-retinal transplants, which initially focused on reconstruction of retinal structure, but have subsequently examined functional recovery; and peripheral nerve grafts, which have studied the ability of inner retinal cells—specifically retinal ganglion cell—to regenerate functional connections with central visual structures. However, a limitation to grafting as a routine therapy lies in sourcing of cells. Freshly harvested cells present logistic problems, not only in supply of suitable donor retinae, but also in screening the cells sufficiently for infective agents.

Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina.

Recombinant adeno-associated virus (rAAV) is a promising vector for therapy of retinal degenerative diseases. We evaluated the efficiency, cellular specificity, and safety of retinal cell transduction in nonhuman primates after subretinal delivery of an rAAV carrying a cDNA encoding green fluorescent protein (EGFP), rAAV. CMV.EGFP. The treatment results in efficient and stable EGFP expression lasting >1 year. Transgene expression in the neural retina is limited exclusively to rod photoreceptors. There is neither electroretinographic nor histologic evidence of photoreceptor toxicity. Despite significant serum antibody responses to the vector, subretinal readministration results in additional transduction events. The findings further characterize the retinal cell tropism of rAAV. They also support the development of studies aimed ultimately at treating inherited retinal degeneration by using rAAV-mediated gene therapy.

Adenovirus-mediated delivery of rhodopsin-promoted bcl-2 results in a delay in photoreceptor cell death in the rd/rd mouse.

Gene transfer to retinal cells may provide a means to retard photoreceptor cell death and thus prevent blindness in diseases such as retinitis pigmentosa. We tested the possibility of interfering with apoptotic photoreceptor cell death in the rd mouse through subretinal delivery of a recombinant replication-defective adenovirus containing the human cDNA for bcl-2, Ad.2.5HRPbcl-2. Photoreceptor-specific transgene expression was accomplished through incorporation of the 2.5 kb human rhodopsin upstream fragment (HRP). Ad.2.5HRPbcl-2 was injected alone or in combination with Ad.CMVPDE beta. Ad.CMVPDE beta contains a cDNA encoding the beta subunit of cGMP phosphodiesterase (PDE beta). Recombinant viruses containing lacZ (driven either by the cytomegalovirus (CMV) promoter/enhancer or HRP) and of Ad.CMVPDE beta and vehicle alone were injected in contralateral eyes as control. Injection of Ad.2.5HRPbcl-2 in the rd mouse resulted in histologically detectable rescue lasting 6 weeks after birth. Extent of rescue was not as large as after delivery of wildtype PDE beta, the gene defective in the rd mouse. However, delivery of genes which prevent apoptotic cell death may have broad application to gene therapy of retinal degenerative diseases.