Age-related macular degeneration (AMD) is a leading cause of
legal blindness in developed countries. Even with the recent advent of several treatment options, treatment of exudative AMD, characterized by
choroidal neovascularization (CNV), remains difficult. Thus, in this review article, we report on the investigation of novel approaches for the management of AMD, antiangiogenic
therapy for CNV, and
retinal regenerative
therapy. Polyion complex(PIC)
micelles have a range in size of several
tens of nanometers formed through an electrostatic interaction, and accumulate in solid
tumors through an enhanced permeability and retention(EPR) effect. In this study, we examined the distribution of the PIC
micelles which encapsulate
fluorescein isothiocyanate-labeled poly-
L-lysine{
FITC-P(Lys)} in experimental CNV in rats, to investigate whether PIC
micelles can be used for the treatment of CNV. We demonstrated that PIC
micelles accumulate in the CNV lesions and are retained in the lesions for as long as 168 hours after
intravenous administration. These results raise the possibility that PIC
micelles can be used for achieving an effective drug delivery system against CNV. Although
photodynamic therapy (
PDT) is a very promising treatment for AMD, most patients require repeated treatments. For effective
PDT against AMD, the selective delivery of a
photosensitizer to the CNV lesions and an effective photochemical reaction at the CNV site are necessary. The characteristic dendritic structure of the
photosensitizer prevents aggregation of its core sensitizer, thereby inducing a highly effective photochemical reaction. We present an effective
PDT for AMD employing a supramolecular nanomedical device, i.e., a novel dendritic
photosensitizer encapsulated in a polymeric
micelle formulation. With its highly selective accumulation in CNV lesions, this treatment resulted in a remarkably efficacious CNV occlusion with minimal unfavorable
phototoxicity. Our results will provide a basis for an effective approach to
PDT for AMD. Spatial control of gene transfection in the body is a core issue in the gene therapy for ocular diseases including AMD. Photochemical internalization (PCI) is a technology that effects light-induced delivery of
DNA directly inside cells. PCI usually requires that a
photosensitizer be added to the drug-delivery system to photochemically destabilize the endosomal membrane. We have developed a ternary complex composed of a core containing
DNA packaged with cationic
peptides and enveloped in the anionic
dendrimer,
phthalocyanine, which provides the photosensitizing action. Subconjunctival injection of the ternary complex followed by
laser irradiation resulted in transgene expression only in the
laser-irradiated site in rats. This PCI-mediated gene delivery system is potentially useful in gene therapy for ophthalmic diseases. Accumulation of
lipofuscin is related to an increased risk of AMD. We report that a major
lipofuscin component, A2E(N-retinyledin-N-retinylethanolamin), activates the
retinoic acid receptor (RAR). In vivo experiments suggest that A2E accumulation results in the pro-angiogenic conversion of
retinal pigment epithelial(RPE) cell phenotype. This physiological consequence of A2E accumulation may be related to a novel potential therapeutic target for CNV. To recover visual function damaged by AMD,
retinal regenerative
therapy is essential. We investigated whether subretinal
transplantation of bone marrow mesenchymal stem cells(MSCs) promotes photoreceptor survival in a rat model of
retinal degeneration. Morphological and functional studies in vivo, including histological analysis and electrophysiological studies, indicate that the subretinal
transplantation of MSCs delays
retinal degeneration and preserves
retinal function. These results suggest that MSC is a useful cell source for
cell-transplantation therapy for
retinal degeneration. In order to elucidate the molecular mechanisms of development of the fovea, which is composed mainly of cone photoreceptors and is susceptible to injury from AMD, we performed a comparative gene expression analysis between the central and peripheral regions of the monkey retina using monkey (rhesus macaque) genome microarray chips. We then selected the clones which were expressed at significantly higher levels in the central region and confirmed their expression in the monkey retina by section in situ hybridization. This study sheds light on the mechanisms of foveal development and may lead to the development of regenerative medicine for cone photoreceptors.