Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Ochakovski GA

PROVIDER: S-EPMC5376580 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Ochakovski G Alex GA Bartz-Schmidt K Ulrich KU Fischer M Dominik MD

Frontiers in neuroscience 20170403

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 <i>in vivo</i>, 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. Strateg ...[more]

PMID: 28420956

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Project description:PurposeSafe and reproducible delivery of gene therapy vector into the subretinal space is essential for successful targeting of the retinal pigment epithelium (RPE) and photoreceptors. The success of surgery is critical for the clinical efficacy of retinal gene therapy. Iatrogenic detachment of the degenerate (often adherent) retina in patients with hereditary retinal degenerations and small volume (eg, 0.1?ml) subretinal injections pose new surgical challenges.MethodsOur subretinal gene therapy technique involved pre-operative planning with optical coherence tomography (OCT) and autofluorescence (AF) imaging, 23?G pars plana vitrectomy, internal limiting membrane staining with Membrane Blue Dual (DORC BV, Zuidland, Netherlands), a two-step subretinal injection using a 41?G Teflon tipped cannula (DORC) first with normal saline to create a parafoveal bleb followed by slow infusion of viral vector via the same self-sealing retinotomy. Surgical precision was further enhanced by intraoperative OCT (Zeiss Rescan 7000, Carl Zeiss Meditec AG, Jena, Germany). Foveal functional and structural recovery was evaluated using best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, microperimetry and OCT.ResultsTwo patients with choroideremia aged 29 (P1) and 27 (P2) years, who had normal and symmetrical levels of best-corrected visual acuity (BCVA) in both eyes, underwent unilateral gene therapy with the fellow eye acting as internal control. The surgeries were uncomplicated in both cases with successful detachment of the macula by subretinal vector injection. Both treated eyes showed recovery of BCVA (P1: 76-77 letters; P2: 84-88 letters) and mean threshold sensitivity of the central macula (P1: 10.7-10.7?dB; P2: 14.2-14.1?dB) to baseline within a month. This was accompanied by normalisation of central retinal thickness on OCT.ConclusionsHerein we describe a reliable technique for subretinal gene therapy, which is currently used in clinical trials to treat choroideremia using an adeno-associated viral (AAV) vector encoding the CHM gene. Strategies to minimise potential complications, such as avoidance of excessive retinal stretch, air bubbles within the injection system, reflux of viral vector and post-operative vitritis are discussed.

Project description:Inherited retinal degenerations are a leading and untreatbale cause of blindness, and as such they are targets for gene therapy. Numerous gene therapy treatments have progressed from laboratory research to clinical trails, and a pioneering gene therapy received the first ever FDA approval for treating patients. However, currently retinal gene therapy mostly involves subretinal injection of the therapeutic agent, which treats a limited area, entails retinal detachment and other potential complications, and requires general anesthesia with consequent risks, costs and prolonged recovery. Therefore there is great impetus to develop safer, less invasive and cheapter methods of gene delivery. A promising method is intravitreal injection, that does not cause retinal detachment, can lead to pan-retinal transduction and can be performed under local anesthesia in out-patient clinics. Intravitreally-injected vectors face several obstacles. First, the vector is diluted by the vitreous and has to overcome a long diffusion distance to the target cells. Second, the vector is exposed to the host's immune response, risking neutralization by pre-existing antibodies and triggering a stronger immune response to the injection. Third, the vector has to cross the inner limiting membrane which is both a physical and a biological barrier as it contains binding sites that could cause the vector's sequestration. Finally, in the target cell the vector is prone to proteasome degradation before delivering the transgene to the nucleus. Strategies to overcome these obstacles include modifications of the viral capsid, through rational design or directed evolution, which allow resistance to the immune system, enhancement of penetration through the inner limiting membrane or reduced degradation by intracellular proteasomes. Furthermore, physical and chemical manipulations of the inner limiting membrane and vitreous aim to improve vector penetration. Finally, compact non-viral vectors that can overcome the immunological, physical and anatomical and barriers have been developed. This paper reviews ongoing efforts to develop novel, safe and efficacious methods for intravitreal delivery of therapeutic genes for inherited retinal degenerations. To date, the most promising results are achieved in rodents with robust, pan-retinal transduction following intravitreal delivery. Trials in larger animal models demonstrate transduction mostly of inner retinal layers. Despite ongoing efforts, currently no intravitreally-injected vector has demonstrated outer retinal transduction efficacy comparable to that of subretinal delivery. Further work is warranted to test promising new viral and non-viral vectors on large animal models of inherited retinal degenerations. Positive results will pave the way to development of the next generation of treatments for inherited retinal degeneration.

Dataset Information

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

Publications

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

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