Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

Abstract

Compared to intravitreal injection, subretinal injection has more direct effects on the targeting cells in the subretinal space, which provides a new therapeutic method for vitreoretinal diseases, especially when gene therapy and/or cell therapy is involved. To date, subretinal delivery has been widely applied by scientists and clinicians as a more precise and efficient route of ocular drug delivery for gene therapies and cell therapies including stem cells in many degenerative vitreoretinal diseases, such as retinitis pigmentosa, age-related macular degeneration, and Leber's congenital amaurosis. However, clinicians should be aware of adverse events and possible complications when performing subretinal delivery. In the present review, the subretinal injection used in vitreoretinal diseases for basic research and clinical trials is summarized and described. Different methods of subretinal delivery, as well as its benefits and challenges, are also briefly introduced.

Gene delivery to the rat retina by non-viral vectors based on chloroquine-containing cationic niosomes

“…Although this route of administration is highly effective to locally transfect cells close to the site of the injection, the occasionally observed side effects, related to this invasive route, such as retinal detachment, hemorrhages or alterations in RPE cells can hamper its practice [43]. In any case, subretinal injections have been widely used on clinical trials to treat some devastating genetic disorders of the retina reporting excellent outcomes [44]. In addition, the recently FDA/EMA-approved Luxturna medicine to deliver healthy copies of the RPE65 gene to the retina is administered by subretinal injection.…”

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

“…In advanced choroideremia, in which the area of intact, treatable retina, choroid and RPE is limited, subretinal delivery may offer the most targeted approach currently available. In this case, the MOI is maximized, off-target exposure is minimal, and the potential for an inflammatory response is reduced because the vector is delivered directly to the target cells within an immune-privileged environment (80,81). Conversely, in early-stage choroideremia, before considerable retinal degeneration has occurred, an intravitreal approach could be considered because a larger area of the retina will be exposed to the vector.…”

“…However, to treat a broader area of the retina, a higher concentration of vector would be required to achieve an effective MOI over the larger treatment area. This circumstance in turn potentially raises additional safety considerations with regard to toxicity of the viral vector and inflammation; the higher total vector dose may increase the risk of shedding and biodistribution, which may be more likely to provoke a potentially harmful immune response (80,81). One option could be the use of multiple subretinal blebs instead of one single bleb; the concentration of vector would not need to be increased and there would be no increased risk of systemic exposure due to the vector being delivered directly to the target cells, as with a single bleb.…”

“…One option could be the use of multiple subretinal blebs instead of one single bleb; the concentration of vector would not need to be increased and there would be no increased risk of systemic exposure due to the vector being delivered directly to the target cells, as with a single bleb. However, multiple blebs may increase the risk for macular hole formation and complications such as retinal detachment (81,82). …”

Mammalian Near-Infrared Image Vision through Injectable and Self-Powered Retinal Nanoantennae

“…These retinal photoreceptorbinding upconversion nanoparticles (pbUCNPs) act as miniature energy transducers that can transform mammalian invisible NIR light in vivo into short wavelength visible emissions (Liu et al, 2017;Wu et al, 2009). As sub-retinal injections are a commonly used ophthalmological practice in animals and humans (Hauswirth et al, 2008;Peng et al, 2017), our pbUCNPs were dissolved in PBS and then injected into the sub-retinal space in the eyes of mice. These nanoparticles were then anchored and bound to the photoreceptors in the mouse retina.…”