As a major worldwide retinal degenerative disease that causes blindness, the hereditary modes of RP can be autosomal dominant (30–40%), autosomal recessive (50–60%), or a X-linked trait (5–15%)[18]. The inherited nature of RP leads to progressive photoreceptor apoptosis and irreversible visual loss. However, when RP is combined with ME, the impairment of visual function becomes worse. The impairment of the blood retinal barrier (BRB) is thought to be the main cause of ME in RP[19, 20]. With the progression of RP, both retinal vascular endothelium and RPE lose their normal intercellular junctions, which gives rise to increased retinal vascular permeability and a flow of interstitial fluid from the choroid to the retinal tissue [19, 21, 22]. Inflammation and auto-immune processes play an important role in the pathogenesis of vascular endothelium and RPE dysfunction and the subsequent breakdown of the BRB[23–25].
Different methods have been used to treat ME in RP patients, such as systemic administration of carbonic anhydrase inhibitors or steroids, intravitreal injection of steroids or anti-VEGF agents, laser photocoagulation and surgery[26, 27]. Triamcinolone acetonide (TA) is a kind of synthetic long-acting steroid and has been widely used in the treatment of ME because of its pharmacological actions of anti-inflammation, immune modulation, BRB stabilization and VEGF downregulation[13, 28]. As far as systemic side effects and local risks are concerned, delivering steroids by a sub-Tenon’s capsule injection is a relatively safe approach for treating ME and has been applied in different retinal diseases[29]. Unlike a retrobulbar injection, the sub-Tenon’s capsule injection is able to keep and restrict drugs in the sub-Tenon’s capsule space for a relatively long time without allowing diffusion into the orbit tissue, which makes more drugs permeate into the choroid and retina. To treat ME more precisely, we modified the sub-Tenon’s capsule injection technique by replacing the traditional short, sharp needle with a long, curved, blunt needle that is able to run along the surface of the sclera and reach the posterior pole of the eyeball, where the placement of the needle accurately corresponds to the ME lesion. Delivery of TA by a modified sub-Tenon’s capsule injection can facilitate the drug diffusion while avoiding risks and complications secondary to intraocular administration.
Given the wide range of biological effects, such as anti-inflammation, immune modulation, neurotrophy and paracrine, UCMSCs have been applied in many systemic diseases and have been shown to have promising therapeutic effects[8–10]. In animal models of RP, intravenously administered UCMSCs were found to produce large amounts of neurotrophic factors, and therefore, the photoreceptors were partially protected from apoptosis[30–32]. Additionally, the infused UCMSCs can directionally migrate to retinal lesions and exert their biological effects to promote the growth of blood vessels, improve the function of BRB and help reconstruct normal retinal structure[33, 34]. Local injection of UCMSCs has been applied in RP patients and has shown beneficial outcomes[35]. In our previous study, we found intravenous administration of USMSCs demonstrated beneficial effects on the improvement of overall visual function of RP patents and their vision related life quality as well[11]. However, it has not been reported if intravenous infusion of UCMSCs can help improve ME, a major pathological condition secondary to RP.
We compared the effects of these two agents in alleviating ME. All patients tolerated these two approaches well. There were no severe systemic or local adverse effects that occurred during the entire follow up, although a minority of patients in both groups showed a rise of IL-6 level early after treatment. In TA injection group, patients showed a more rapid reduction of the macular thickness in the first 2 months and then the macular thickness rebounded to the baseline level, which implied the quick but relatively short-term effect of the TA injection in relieving ME. Whereas in UCMSCs infusion group, the macular thickness did not change significantly until the sixth month, when it was lower than the TA injection group, which indicated a slow but more persistent action of the UCMSCs. The BCVA and visual field sensitivity of all of the patients in the two groups did not change significantly, and there was no significant difference between the two groups, implying a limited improvement of photoreceptor function following the relief of ME. The FVEP in the UCMSCs infusion group improved the most at six months, at which point it was significantly higher than that in the TA injection group. This result implied that the UCMSCs infusion may be more beneficial than the TA injection in terms of improving the overall visual function, which may be due to the UCMSCs having more biological effects besides anti-inflammation, such as neurotrophy, paracrine, or even cell replacement.