Vesicular stomatitis virus glycoprotein- and Venezuelan equine encephalitis virus-derived glycoprotein-pseudotyped lentivirus vectors differentially transduce corneal endothelium, trabecular meshwork, and human photoreceptors.

The ability to deliver a large transgene efficiently to photoreceptors using viral vectors remains problematic and yet is critical for the future therapy of inherited retinal diseases such as Stargardt's and Usher's 1B. Herein, we examine the ocular tropism of a HIV-1-based lentivirus vector pseudotyped with Venezuelan equine encephalitis virus-derived glycoprotein (VEEV-G) after intraocular delivery to the posterior and anterior chambers of C57BL/6 wild-type mice. Reporter gene (EGFP) expression was evaluated using in vivo fluorescence imaging followed by postmortem immunohistochemistry and retinal function assessed by electroretinography. Intracameral administration of VEEV-G and vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped vectors resulted in robust transgene expression in the corneal endothelium and trabecular meshwork. After subretinal administration, onset of transgene expression was observed in the retinal pigment epithelium (RPE) 1 day postinjection with both VEEV-G and control VSV-G pseudotypes, but no significant photoreceptor transduction was apparent. Substantial degeneration of the outer nuclear layer was observed with VEEV-G-pseudotyped vector, which corresponded to ablation of retinal function. Subretinal administration of VSV-G was observed to result in significant suppression of electrophysiological function compared with buffer-injected and uninjected control eyes. Suppression of the c-wave amplitude, in addition to reduced RPE65 expression, indicated potential RPE dysfunction. Ex vivo tropism of VSV-G was assessed using organotypic culture of explanted retina harvested from wild-type mice and human patients undergoing retinal detachment surgery to examine the prevention of transduction by physical barriers and species differences in tropism.

Treatment in vitro of retinal cells with IL-4 increases the survival of retinal ganglion cells: the involvement of BDNF.

Interleukin 4 (IL-4) is a pleiotropic cytokine involved in many functions during the development as well as in adult life. Previous work from our group demonstrated, in vitro, that this interleukin is able to prevent rat retinal ganglion cells death after axotomy. The aim of the present study was to investigate the signaling pathways involved in this trophic effect, particularly the cAMP pathway and also to demonstrate the expression of IL-4 in retinas at different stages of post natal development. Our results show that the trophic effect of IL-4 on rat retinal ganglion cells is dependent on the activation of Janus Kinase 3, Protein Kinase A, c-Jun N-terminal Kinase and Tropomyosin related Kinase receptors, on the increase in intracellular calcium levels, on polypeptide release and on the endogenous Brain Derived Neurotrophic Factor (BDNF). We also observed that treatment with IL-4 enhances c-AMP response element binding and Mitogen Activated Protein Kinase phosphorylation and increases the expression of BDNF. Concerning the IL-4 expression our data show an increase in IL-4 levels during post natal development. Taken together our results demonstrate that the trophic effect of IL-4 on retinal ganglion cells of newborn rats is mediated by cAMP pathway and BDNF release.

Trasplante de tejido retiniano y de células progenitoras retinianas: una promesa terapéutica para pacientes con enfermedad de la retina / Retinal tissue transplantation and retinal progenitor cells: a therapeutic promise for patients with retinal disease

La retinopatía diabética, la degeneración macular relacionada con la edad y la retinitis pigmentosason las enfermedades retinianas más frecuentes en todo el mundo. A pesar de no contar consuficientes estudios que demuestren resultados funcionales positivos en cuanto a recuperar lafunción visual, el uso de células madre y células progenitoras retinianas y el trasplante de retinafetal parecen bastante promisorios. Hasta el momento no se han podido obtener resultadospositivos sobre la funcionalidad de las células trasplantadas, pero sí se ha demostrado que elprocedimiento para transferir el tejido retiniano es seguro y confiable. Aún no se ha intentadoen seres humanos el trasplante de células progenitoras retinianas, pero dicho trasplante ha dadoresultados satisfactorios en modelos múridos. Los estudios con células progenitoras retinianashan logrado demostrar en modelos múridos que se activan y expresan los fotorreceptores. Existenalgunas barreras de disponibilidad para el uso de células progenitoras retinianas, que se debensuperar con el fin de adelantar estudios que permitan aumentar las posibilidades de integracióny diferenciación de dichas células hacia fotorreceptores.

Retinal tissue transplantation and retinal progenitor cells: A therapeutic promise for patients with retinal diseaseWorldwide, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosahave the highest incidence rate among retinal diseases. Despite the lack of enough trialsdemonstrating positive functional results on eyesight recovery, the use of stem cells, retinalprogenitor cells, and fetal retinal tissue transplantation seem very promising. So far positiveresults on the functionality of the transplanted cells have not been obtained. However, the safetyand reliability of the procedure to transfer retinal tissue have been demonstrated. Transplantationof retinal progenitor cells has not been tried on human beings, but there have been satisfactory results with it in murine models. Trials with retinalprogenitor cells have demonstrated activation andexpression of photoreceptors in murine models. Somebarriers of availability exist for the use of retinalprogenitor cells that must be overcome in order tocarry out studies to increase the possibility of theirintegration and differentiation towards photoreceptors.

Strategies to promote optic nerve regeneration

Damage to the adult mammalian optic nerve (ON) usually results in the degeneration of the ON and death of retinal ganglion cells (RGCs), leading to permanent loss of visual functions. New strategies, especially the transplantation of a peripheral nerve (PN) to the retina or transected ON, have been created to promote the neuronal survival and axonal regeneration of axotomized RGCs. In this review, we focus on how a PN and other factors are used to overcome the unfavorable extrinsic CNS environment and the lack of trophic factors, and upregulate the intrinsic growth potential of the axotomized neurons since recent studies suggest that the lack of intrinsic growth potential in the CNS neurons is also an important factor contributing to the failure of CNS regeneration.

Conditions for optic axon outgrowth.

A series of studies is described which show that retinal axon outgrowth can be stimulated by the close proximity of an appropriate target region. The suggestion is offered that, in normal development, optic axons first follow cues available at the surface of the brainstem, but once they reach a target region, ramify there in response to the presence of a target-derived factor.