The normal human eye is generally considered an immune-privileged organ, but one of the concerns associated with the intraocular administration of a potential gene or stem cell-based therapy is the development of an immune-mediated response after repeat or contralateral eye dosing. Preclinical studies in animals may help to predict the immune response, but may be problematic because response may vary with animal species, specific therapy administered, site of administration, injection technique, host immune response, timing of the contralateral dose, use of immunosuppressive agents, and intra-subject eye disease.

The risks associated with repeat or contralateral dosing can be possibly minimized. Suggested strategies include general safety and adverse reaction surveillance, specific monitoring for an immune response, staggering patient enrollment, adjusted administration intervals, and immunosuppressive regimens targeted toward reducing risk, although none of the suggested strategies have been well established or validated.

Preliminary investigation of readministration of recombinant adeno-associated virus (AAV) carrying the RPE65 gene in three patients with Leber congenital amaurosis 1.7–3.3 years after they had received their initial subretinal injection indicate that readministration is both safe and efficacious after previous exposure to the vector [9]. Further work is warranted to characterize the safety and efficacy of readministration of gene products.

Many varied delivery methods for gene therapy or stem cell-based therapeutics exist. In this section, we will review the following methods: systemic, topical, trans-scleral, anterior chamber, intravitreal, subretinal, and suprachoroidal.

Systemic delivery has the advantage of being minimally invasive; however, it has an multiplicity of infection. some viral inactivation may occur, and safety concerns such as promoter control and widespread integration may exist. Systemic delivery is inappropriate for cell-based therapies.

Topical delivery is minimally invasive, but also minimally effective due to the very low levels of transduction through conjunctival and corneal epithelia and the lack of transduction to the posterior pole. The use of collagen shield may aid enhancement. Topical delivery is inappropriate for cell-based therapies.

Transsceral and transcorneal deliveries are minimally invasive as well, but suffer from low transduction efficiency. Iontophoresis is an established methodology in drug delivery that is likely to be less effective for viral vectors. Transsceral and transcorneal deliveries are inappropriate for cell-based therapies.

Delivery via the anterior chamber is minimally invasive with some transduction effect on the trabecular meshwork endothelium, corneal endothelium, ciliary body endothelium, and iris epithelium. No transduction to the posterior segment is achieved by this delivery method, rendering it inappropriate for cell-based therapies.

Intravitreal delivery is minimally invasive and has become a standard of care in the vast majority of retinal practices with the introduction of anti-VEGF intravitreal injections. Good transduction of the ciliary body epithelium is achieved. Stem cells introduced by this delivery method may proliferate, possibly leading to epiretinal membrane formation.

Standard subretinal delivery is an invasive procedure, requiring a vitrectomy with a posterior retinotomy. Excellent transduction of photoreceptors and RPE can be achieved, and this methodology is the current standard of care for gene delivery. Disadvantages of this delivery method include unpredictable bleb development and unpredictable efflux of product with a posterior retinotomy, as well as possibly higher complication rates.