Direct Comparison of Administration Routes for AAV8-mediated Ocular Gene Therapy

Igarashi, Tsutomu; Miyake, Keisuke; Asakawa, Nagisa; Miyake, Noriko; Shimada, Takashi; Takahashi, Hiroshi

doi:10.3109/02713683.2013.779720

Cited by 53 publications

(40 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apart from these safety aspects, transduction efficiency of target cells is a key variable in the context of efficacy. When applying rAAV2 and rAAV8 (the most commonly serotypes in clinical use) intravitreally, both serotypes show limited transduction efficiency confined to inner retinal cells (Li et al, 2008; Igarashi et al, 2013). One study showed two orders of magnitude lower transduction of whole retina after IVT of rAAV8 compared to subretinal injection in non-human primates (Seitz et al, 2016).…”

Section: Intravitreal Injectionmentioning

confidence: 99%

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

2017

View full text Add to dashboard Cite

An exceptionally high number of monogenic disorders lead to incurable blindness, making them targets for the development of gene-therapy. In order to successfully apply therapeutic vector systems in vivo, the heterogeneity of the disease phenotype needs to be considered. This necessitates tailored approaches such as subretinal or intravitreal injections with the aim to maximize transduction of target cell populations, while minimizing off-target effects and surgical complications. Strategic decisions on parameters of the application are crucial to obtain the best treatment outcomes and patient safety. While most of the current retinal gene therapy trials utilize a subretinal approach, a deeper understanding of the numerous factors and considerations in choosing one delivery approach over the other for various ocular pathologies could lead to an improved safety and treatment efficacy. In this review we survey different vector injection techniques and parameters applied in recent retinal (pre-)clinical trials. We explore the advantages and shortcomings of each delivery strategy in the setting of different underlying ocular pathologies and other relevant factors. We highlight the potential benefits for patient safety and efficacy in applying those considerations in the decision making process.

show abstract

Section: Intravitreal Injectionmentioning

confidence: 99%

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

2017

View full text Add to dashboard Cite

show abstract

“…Although this usually resolves within a few days of its creation, detachment of the retina can have immediate deleterious effects on the retinal cells due to the separation of the retina from the RPE and choroid. 23–26 Damage to the retina in the context of active disease or degeneration may be even more detrimental. A subset of gene therapy treated LCA2 patients suffered retinal complications that may, in part, be related to the subretinal method of vector delivery.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach

et al. 2013

View full text Add to dashboard Cite

Recombinant adeno-associated viruses are important vectors for retinal gene delivery. Currently utilized vectors have relatively slow onset and for efficient transduction it is necessary to deliver treatment subretinally, with the potential for damage to the retina. Amino-acid substitutions in the viral capsid improve efficiency in rodent eyes by evading host responses. As dogs are important large animal models for human retinitis pigmentosa, we evaluated the speed and efficiency of retinal transduction using capsid-mutant vectors injected both subretinally and intravitreally. We evaluated AAV serotypes 2 and 8 with amino-acid substitutions of surface exposed capsid tyrosine residues. The chicken beta-actin promoter was used to drive green fluorescent protein expression. Twelve normal adult beagles were injected, 4 dogs received intravitreal injections, 8 dogs received subretinal injections. Capsid-mutant viruses tested included AAV2(quad Y-F) (intravitreal and subretinal), and self-complementary scAAV8(Y733F) (subretinal only). Contralateral control eyes received injections of scAAV5 (subretinal) or scAAV2 (intravitreal). Subretinally delivered vectors had a faster expression onset than intravitreally delivered vectors. Subretinally delivered scAAV8(Y733F) had a faster onset of expression than scAAV5. All subretinally injected vector types transduced the outer retina with high efficiency, and the inner retina with moderate efficiency. Intravitreally delivered AAV2(quad Y-F) had a marginally higher efficiency of transduction of both outer retinal and inner retinal cells than scAAV2. Because of their rapid expression onset and efficient transduction, subretinally delivered capsid-mutant AAV8 vectors may increase the efficacy of gene therapy treatment for rapid photoreceptor degenerative diseases. With further refinement, capsid-mutant AAV2 vectors show promise for retinal gene delivery from an intravitreal approach.

show abstract

“…Intravitreally applied AAVs allow for the transduction of cells within the inner retina, mainly RGCs and Müller glia cells [3]. The serotypes AAV2/2, AAV2/6 and AAV2/8 possess the highest transduction efficiency of retinal cells after intravitreal injection [39,46,47]. Additionally, the injection into the eye's vitreous results in a more widespread distribution of the AAVs.…”

Section: The Choice Of Promoter For Cell Type-specific Transgene Exprmentioning

confidence: 98%

Retinal gene delivery by adeno-associated virus (AAV) vectors: Strategies and applications

Schön

Biel

Michalakis

2015

European Journal of Pharmaceutics and Biopharmaceutics

View full text Add to dashboard Cite

Direct Comparison of Administration Routes for AAV8-mediated Ocular Gene Therapy

Abstract: Results suggest that both SR and VT injections of AAV8 vectors are useful routes for administering ocular gene therapy, and stress the importance of selecting an appropriate administration route, i.e. one that targets specific cells, for treating ocular disorders.

Cited by 53 publications

References 22 publications

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials

Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach

Retinal gene delivery by adeno-associated virus (AAV) vectors: Strategies and applications

Contact Info

Product

Resources

About