How this treatment paradigm could change ocular cell therapy
Nanoscale extracellular vesicles (EVs) that include exomers, exosomes and microvesicles/ectosomes are thought to have a future in treatment of degenerative retinal diseases,1 according to a team of European researchers led by Federico Manai, MD, Department of Biology and Biotechnology “L. Spallanzani,” University of Pavia, Pavia, Italy.
The researchers explained that EVs, which are lipid bilayer-delimited particles that almost all cells release, have a number of functions, that is, they are involved in transferring lipids, nucleic acids and proteins from donor to recipient cells or distant organs and regulating cell-cell communication and signaling. These activities make EVs important in intercellular communication that includes mediating the crosstalk between different cell types even over long distances.
In addition, the investigators explained that the EVs are crucial in cellular homeostasis and disease pathogenesis, and because the content of the EVs reflect the donor cell status, the EVs can provide valuable information about complex biologic processes.
“Recent advances in isolation and analytical methods have led to substantial improvements in both characterising and engineering EVs, leading to their use either as novel biomarkers for disease diagnosis/prognosis or even as novel therapies. Due to their capacity to carry biomolecules, various EV-based therapeutic applications have been devised for several pathological conditions including eye diseases,” the authors said.
Regarding the eye, EVs have been found in the retina, aqueous humor, vitreous body, and tears. Experiences with other forms of intraocular drug applications have opened new ways to use EVs to treat retinal diseases. The researchers reviewed the extensive research into EVs in age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, retinitis pigmentosa (RP), and other retinopathies and enumerated the extensive published results. They described in detail the physiological and pathological role of EVs in the cellular communication in the eye and the roles of EVs in those retinal pathological processes and diseases.
The bottom line is that the EVs may have potential beneficial properties as therapeutic agents in in retinal pathologies. Dr Manai and colleagues noted that in ophthalmology, among the first evidence that this may be the case was from the use of an αB-crystallin-derived peptide engineered into a polymer nanoparticle to rescue stressed retinal pigment epithelium (RPE),2 and a similar approach enhanced delivery of lipophilic compounds with engineered liposomes to improve retinal penetration,3,4 circumvented the issues involved in ocular drug delivery.
The investigators also cited data from an in vitro study showing that exosomes affected the pharmacokinetics of bevacizumab (Avastin, Genentech), which is internalised and secreted by RPE cells through CD63+ vesicles.5 A great deal of research findings have been reported about the beneficial role of EVs derived from mesenchymal stem cells (MSCs) in different pathological scenarios, such as, conferring protective effects on retinal ganglion cells in a model of laser-induced retinal injury that prevented apoptosis and inflammation6; the mechanism was through a decrease in the MCP-1 level.
Most evidence in the literature, according to Dr Manai and colleagues, shows the beneficial effects of MSC-EVs in diabetes/DR or hyperglycemic damage.7 In addition, the uptake/distribution distribution of MSC-EVs in the retina also has been described recently in in vitro, ex vivo, and in vivo models, which expanded the knowledge of this treatment approach.8
Regarding glaucoma and retinal degeneration, the authors commented that MSC-derived EVs delivered beneficial effects in in vitro and in vivo models of glaucoma or AMD.9-11 Regarding retinal degeneration, micro-RNA-21, a non-specific biomarker, is considered a key player in neuroprotective effects.12 EVs from embryonic stem cells also can slow retinal degeneration by up-regulating Oct413 to promote retinal Müller cell retrodifferentiation, and this was similar to the characteristics exhibited by other micro-RNAs in an in vivo model of RP. MSC-EVs induced anti-inflammatory responses in rd10 mice, this being mainly mediated through the miR-146a-Nr4a3 axis.14
Despite the beneficial effects of MSC-derived EVs in different retinal pathologies, the investigators pointed out the limitations of in vitro experiments in that their inherent environmental context can affect the response evoked by these vesicles.
However, Dr Manai and colleagues see a bright future for EVs.They point to the evidence emerging from experimental disease models and human material that strongly suggests future diagnostic and/or therapeutic exploitation of these biologic agents in various ocular disorders with a good possibility to improve the patient’s quality of life.
They concluded, “The characterisation of EVs and their molecular cargos has contributed to elucidating the roles of these structures in the ethiopathogenesis and progression of several diseases. In many respects, it can be stated that for what concern EVs, we are witnessing the opening of a new era of potential biologic therapies. Recent observations have revealed that the use of EVs as biomarkers and as EV-based treatments holds the potential to change the current management of ocular pathologies. In particular, EV-mediated therapies may provide breakthroughs in the treatment of retinal and optic nerve diseases, such as AMD, DR, RP, or glaucoma. When one considers the many advantageous features of EVs, it can be argued that it may be possible to administer them by all the presently used routes to exert ocular effects, and even topical application may not be ruled out. Thus, in the future, EV-based therapies may have moved from being an intriguing paradigm to a common treatment mode in eye clinics.”