Exosomes are now reaching the clinic in trials for a wide variety of diseases. One of their most exciting applications is the treatment of retinal degeneration which may even be able to reverse the process of sight loss.
The eye is one of our most important sensory organs and its structure is highly complex, but high complexity is often difficult to repair if damaged. Our retina, the sensory membrane that lines the inner surface of the back of the eyeball is responsible for receiving, converting and relaying visual information through the optic nerve into the brain. Being comprised of 10 layers and hosting at least 58 cell types across 6 classes, it is the most sophisticated component of the eye.
On the base of the eye, 5 distinct types of neurons (2 types of photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells) are wired together forming a network comparable to a circuit board. These cells are being kept healthy by a single cell layer, the retinal pigment epithelium (RPE). This layer sits tightly between the photoreceptors and the basement membrane transporting nutrients from the bloodstream to the retina and removing the toxic by-products created by activated photoreceptors. RPE cells are unable to regenerate when damaged, causing a decrease in the nutrient supply and toxin removal which ultimately leads to cell death of photoreceptors and thus to an impairment or complete loss of vision.
The most common retinal degenerative diseases are age-related (age-related macular degeneration (AMD), diabetic eye disease (DED) and retinal vein occlusions (RVO), with an estimated number of approximately 40 million people currently affected in Europe alone. With a global demographic shift to an aging population, this number will continue to rise. While there are treatment options to prevent progression, such as anti-VEGF intraocular injections, laser surgery and photodynamic therapy, there is no cure if the degeneration is severe and the damage has happened.
One major focus in the development of retina regeneration is stem cell therapy with two approaches for RPE regeneration currently in clinical trials: injection of a suspension of stem cell-derived RPE cells into the retina, and transplanting a preformed stem cell-derived RPE layer.
Many challenges remain, however, which include avoiding immune rejection, ensuring long-term cell survival and the basic problem of scaling up stem cell production. But what if it was possible to have the benefits of stem cell therapy while circumventing the disadvantages? The utility of exosomes as therapeutic vehicles is presently under investigation for a broad variety of diseases. Their long sera half-life, cargo versatility and ability to cross the blood-brain barrier, but especially their low immunogenicity, allowing transplant from an unmatched donor, makes them almost perfect therapeutics. In retina repair, stem-cell-derived exosomes from various sources are showing promising results in both in vitro and in vivo.
For instance, in a mouse model of retinal laser injury, intravitreal injection of MSC-exosomes had a comparable therapeutic effect to MSCs in limiting damage progression, reducing cell apoptosis and improving visual function. In another study, bone marrow-derived MSC (BMSC) exosomes showed a significant neuroprotective and neurogenic effect in an optic nerve injury model in rats. Weekly injection of BMSC exosomes reduced retinal ganglion cell loss from 80-90% to 30% 21 days after optic nerve injury.
Studies are not limited to animal models only. A study from 2018 showed that MSC-derived exosomes have been used successfully in the treatment of refractory macular holes (MHs). MSC-derived exosomes were injected into the macular hole region of five patients at the end of a regular pars plana vitrectomy. Four out of five patients experienced macular hole closure and three out of five had satisfactory improvement in their best-corrected visual acuity, leading to the conclusion that MSC-Exo therapy may be a useful and safe method for improving the visual outcomes after surgery for refractory MHs.
The progress being made in the clinic is exciting and it seems only a matter of time before exosome therapies become routine.
IMAGE credit: Ben Bogart Creative commons.