Subretinal Injection Techniques for Retinal Disease: A Review

Abstract

Inherited retinal dystrophies (IRDs) affect an estimated 1 in every 2000 people, this corresponding to nearly 2 million cases worldwide. Currently, 270 genes have been associated with IRDs, most of them altering the function of photoreceptors and retinal pigment epithelium. Gene therapy has been proposed as a potential tool for improving visual function in these patients. Clinical trials in animal models and humans have been successful in various types of IRDs. Recently, voretigene neparvovec (Luxturna^®) has been approved by the US Food and Drug Administration for the treatment of biallelic mutations in the RPE65 gene. The current state of the art in gene therapy involves the delivery of various types of viral vectors into the subretinal space to effectively transduce diseased photoreceptors and retinal pigment epithelium. For this, subretinal injection is becoming increasingly popular among researchers and clinicians. To date, several approaches for subretinal injection have been described in the scientific literature, all of them effective in accessing the subretinal space. The growth and development of gene therapy give rise to the need for a standardized procedure for subretinal injection that ensures the efficacy and safety of this new approach to drug delivery. The goal of this review is to offer an insight into the current subretinal injection techniques and understand the key factors in the success of this procedure.

Keywords: retinal gene therapy; subretinal injection; subretinal injection technique; vitreoretinal surgery.

Figure 1

Schematic of subretinal injection. An iatrogenic retinal detachment is produced after accessing the subretinal space (SRS), the area between the neurosensory and the retinal pigment epithelium (RPE). Subretinal injection allows direct contact of the drug with photoreceptors and RPE layers.

Figure 2

Flowchart diagram related to searching process.

Figure 3

Subretinal injection of rTPA after pars plana vitrectomy in a case of large submacular hemorrhage associated with age-related macular degeneration. Subretinal injection is performed after internal limiting membrane (ILM) peeling. Note the blanching of the retina when reaching the subretinal space.

Figure 4

Subretinal injection technique in animal models. Anterior transscleral approach. (A) A retinotomy is performed in the limbus. (B) A blunted cannula used for subretinal injection.

Figure 5

Subretinal injection location. The superior vascular arcade is the preferred location for subretinal injection. It is recommended to avoid areas of RPE atrophy where the retina is more predisposed to detach.

Figure 6

Left image shows the injection syringe and the high pressure extension tube when the injection is performed by two surgeons; when purging the treatment fluid there is loss of treatment in the extension tube. Right image shows the single-surgeon foot-pedal-controlled automated injection system using the viscous fluid injection mode of the vitrectomy system. MicroDose Injection Device (MedOne, Sarasota, FL, USA).

Figure 7

Retinography and intraoperative OCT (iOCT) taken during surgery for Luxturna gene therapy. (A) Blanching of the retina and indentation in the iOCT. (B) Indentation in the iOCT just before pressing the plunger for the subretinal injection (arrow). (C) “Fleur-de-lis” sign at the beginning of the subretinal injection (circle). (D) Subretinal bubble, localized retinal detachment and blunt cannula at the edge of the retinotomy (arrow).

Figure 8

Schematic of suprachoroidal injection. Needles reaching nanodimensions are optimal for accessing suprachoroidal space, avoiding iatrogenic trauma in the vitreoretinal space.