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INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA.

ABSTRACT: This case series highlights the novel use of intravitreal melphalan for nonvitreous retinoblastoma. It assesses the efficacy and toxicity of intravitreal melphalan for nonvitreous retinoblastoma.This observational small case series investigates three patients treated with intravitreal melphalan for nonvitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery. Patients' demographics, response to treatment, and toxicity of treatment as clinically evaluated are measured by electroretinogram.Three eyes of three patients received a median of 7 weekly intravitreal melphalan injections (30 ?g/0.07 cc) for persistent retinal or subretinal tumors refractory to treatment with multiple-course ophthalmic artery chemosurgery.Eyes remain tumor free at a median of 14-month follow-up. One eye was enucleated because of a vitreous hemorrhage that obscured fundus details. One eye had extinguished electroretinogram recordings before injections and two eyes had a decrease in electroretinogram responses over the intravitreal treatment course. The eye with subretinal seeding demonstrated marked retinopathy by ophthalmoscopy and fluorescein angiography and one eye was enucleated because of the development of a vitreous hemorrhage.This small case series highlights that nonvitreous disease that is, refractory or persistent despite previous ophthalmic artery chemosurgery can regress with intravitreal melphalan. However, this treatment may result in retinal toxicity.

SUBMITTER: Francis JH

PROVIDER: S-EPMC4917462 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA.

Francis Jasmine H JH Marr Brian P BP Brodie Scott E SE Gobin Pierre P Dunkel Ira J IJ Abramson David H DH

Retinal cases & brief reports 20160101 4

<h4>Purpose</h4>This case series highlights the novel use of intravitreal melphalan for nonvitreous retinoblastoma. It assesses the efficacy and toxicity of intravitreal melphalan for nonvitreous retinoblastoma.<h4>Methods</h4>This observational small case series investigates three patients treated with intravitreal melphalan for nonvitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery. Patients' demographics, response to treatment, and toxicity of treatme ...[more]

PMID: 26630243

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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.

Project description:PurposeCurrent melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity.MethodsIn vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression.ResultsThe maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted.ConclusionsMolecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.

Project description:Viral-mediated gene augmentation offers tremendous promise for the treatment of inherited retinal diseases. The development of effective gene therapy requires an understanding of the vector's tissue-specific behavior, which may vary depending on serotype, route of delivery, or target species. Using an ex vivo organotypic explant system, we previously demonstrated that retinal tropism and transduction of adeno-associated virus type 2 (AAV2) vary significantly depending on serotype in human eyes. However, the ex vivo system has limited ability to assess route of ocular delivery, and relatively little literature exists on tropic differences between serotypes and routes of delivery in vivo. In this study, we demonstrate that retinal tropism and transduction efficiency of five different AAV2 serotypes (AAV2/1, AAV2/2, AAV2/6, AAV2/8, and AAV2/9) expressing enhanced green fluorescent protein driven by a cytomegalovirus promoter vary greatly depending on serotype and route of delivery (intravitreal, subretinal, or suprachoroidal) in rats. With subretinal delivery, all serotypes successfully transduced the retinal pigmented epithelium and outer nuclear layer (ONL), with AAV2/1 displaying the highest transduction efficiency and AAV2/2 and AAV2/6 showing lower ONL transduction. There was minimal transduction of the inner retina through subretinal delivery for any serotype. Tropism by suprachoroidal delivery mirrored that of subretinal delivery for all AAV serotypes but resulted in a wider distribution and greater ONL transduction. With intravitreal delivery, retinal transduction was seen primarily in the inner retina (retinal nerve fiber, ganglion cell, and inner nuclear layers) for AAV2/1 and AAV2/6, with AAV2/6 showing the highest transduction. When compared with data from human explant models, there are substantial differences in tropism and transduction that are important to consider when using rats as preclinical models for the development of ocular gene therapies for humans.

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.

Dataset Information

INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA.

Publications

INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA.

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