Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

Abstract

Dysfunction and death of retinal pigment epithelium (RPE) and or photoreceptors can lead to irreversible vision loss. The eye represents an ideal microenvironment for stem cell-based therapy. It is considered an "immune privileged" site, and the number of cells needed for therapy is relatively low for the area of focused vision (macula). Further, surgical placement of stem cell-derived grafts (RPE, retinal progenitors, and photoreceptor precursors) into the vitreous cavity or subretinal space has been well established. For preclinical tests, assessments of stem cell-derived graft survival and functionality are conducted in animal models by various noninvasive approaches and imaging modalities. In vivo experiments conducted in animal models based on replacing photoreceptors and/or RPE cells have shown survival and functionality of the transplanted cells, rescue of the host retina, and improvement of visual function. Based on the positive results obtained from these animal experiments, human clinical trials are being initiated. Despite such progress in stem cell research, ethical, regulatory, safety, and technical difficulties still remain a challenge for the transformation of this technique into a standard clinical approach. In this review, the current status of preclinical safety and efficacy studies for retinal cell replacement therapies conducted in animal models will be discussed.

Establishment of a Rapid, Lesion-Controllable Retinal Degeneration Model in Monkey for Preclinical Stem Cell Therapy

“…Several approaches, such as intravenous injection, intravitreous injection and SI, have been reported that could deliver retinotoxic reagents into the animal eyes to induce RD models [13]. Each approach has its own advantages and disadvantages.…”

“…Intravenous injection was a common and easy method to damage the bilateral retina with large lesion areas in small and medium animals [26,27]. However, systemic administration of retinotoxic agents would also affect the general health status of the experimental animals, and even lead to death and tumor formation [13]. Furthermore, higher dose of retinotoxic agents for large animals like monkeys was used to induce retinal damage, which caused severe renal toxicity or death [20].…”

“…To overcome the lethal side effect of systemic delivery of retinotoxic reagents or random or uneven distribution of the retinal lesion after their intravitreal delivery [13], and to facilitate the study of potential therapeutic interventions, such as stem cell grafts and retinal prosthesis, we subretinally injected 100 μL of SNP solutions at three doses (0.05 mM, 0.1 mM and 0.2 mM) or NS into the posterior pole of the monkey retina next to the fovea under a surgical microscope ( Figure 1A). Within 1 h after SI, SD-OCT images showed that SNP solutions or NS caused a hypo-re ective retinal bleb of about 9 mm in diameter, indicating the successful delivery ( Figure 1B).…”

“…RD animal models are required to evaluate the safety and e cacy of stem cell therapy, and to develop the surgical tools and procedures for cell transplantation in patients [13]. To this end, animals with eyeball size and structure closely similar to human counterparts would be preferred.…”

“…However, some limitations exist in these models. For instance, laser or light exposure caused focal damage of retina with small lesion size or unconsistent damage degree [18,19]; intravenous injection of retinotoxic agents such as sodium iodate and N-methyl-N-nitrosourea (MNU) led to systemic complications with high mortality, while intravitreous injection of the above agents caused uncontrollable or random distribution of retinal lesions [13,[20][21][22]. A new method of subretinal injection (SI) has been applied to deliver cobalt chloride to induce a lesion-controllable RP model in monkeys for retinal sheet transplantation [17].…”