Lentiviral Gene Transfer-Mediated Cone Vision Restoration in RPE65 Knockout Mice

Bemelmans, Alexis-Pierre; Kostic, Corinne; Cachafeiro, M. Carmen Blanco; Crippa, S.; Wanner, D.; Tekaya, M.; Wenzel, Andreas; Arsenijévic, Yvan

doi:10.1007/978-0-387-74904-4_9

Cited by 8 publications

(7 citation statements)

References 22 publications

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“…The LV-RPE65 LV solution used in this study is a GMP-like production of a vector whose recombinant genome is similar to the one evaluated previously in RPE65-deficient mice. 30,31,35 Briefly, the LV-RPE65 is an integrative, third-generation, replication-defective, self-inactivating human immunodeficiency virus (HIV)-1-derived LV, with a mutated Woodchuck hepatitis virus Posttranscriptional Regulatory Element (WPRE) sequence devoid of promoter activities or open-reading frames. 36 It contains the R0.8 promoter (800 bp of the human RPE65 promoter) 28,37 which drives directly the expression of the RPE65 cDNA (without introns).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates

Matet

Kostic

Bemelmans

et al. 2017

Translational Research

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Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis. For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days after subretinal injection using multimodal imaging in 5 NHPs. We revealed prolonged reattachment times in LV-RPE65-injected eyes compared to vehicle-injected eyes. Low- (n = 2) and high-dose (n = 2) LV-RPE65-injected eyes presented a reduction of the outer nuclear and photoreceptor outer segment layer thickness in the macula, that was more pronounced than in vehicle-injected eyes (n = 4). All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite foveal structural changes, full-field electroretinography indicated that the overall retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial, or leucocyte ocular activation between low-dose, high-dose, and vehicle-injected eyes. Moreover, LV-RPE65-injected animals did not show signs of vector shedding or extraocular targeting, confirming the safe ocular restriction of the vector. Our results evidence a limited ocular tolerance to LV-RPE65 after subretinal injection without adjuvant anti-inflammatory prophylaxis, with complications linked to this route of administration necessitating to block this transient inflammatory event.

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Section: Methodsmentioning

confidence: 99%

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates

Matet

Kostic

Bemelmans

et al. 2017

Translational Research

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“…RPE is readily transduced by a variety of viruses48. Most recently, lentivirus has been used to transfer the mouse cDNA to the five day old Rpe65 −/− mouse leading to long-lasting transgene expression in the RPE cells and maintenance of normal ERG function and cone number until at least 4 months49,50.. Untreated mice demonstrated the typical deficits in ERG function and degeneration of almost all cones by that time49,50.…”

Section: Gene Therapymentioning

confidence: 99%

RPE65: Role in the Visual Cycle, Human Retinal Disease, and Gene Therapy

Cai

Conley

Naash

2009

Ophthalmic Genetics

123

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RPE65 is an isomerohydrolase expressed in retinal pigment epithelium. It is critical for the regeneration of the visual pigment necessary for both rod and cone-mediated vision. Mutations in human RPE65 cause Leber's congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness. Several RPE65 animal models including two different mouse models and a naturally occurring canine model have been thoroughly characterized to determine the mechanisms that underlie RPE65 associated retinal dystrophies. More recently, substantial effort has gone into designing gene therapies for these diseases. Based on several encouraging reports from animal models, at least three clinical trials are currently underway for the treatment of LCA using modified AAV vectors carrying the RPE65 cDNA and have reported positive preliminary results.

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“…[15][16][17][18][19][20][21] Notably, these retinosomes can be visualized by TPM under both ex vivo and in vivo conditions. 20 Animal models have been extensively used to investigate the pathology and develop treatments for LCA such as gene transfer [21][22][23][24] and pharmacological therapy 21,25,26 because genetic, physiological, and biochemical attributes are broadly shared between the mouse, dog, and human retina. In Lrat À/À and Rpe65 À/À mice, rod photoreceptor cells degenerate slowly whereas cone photoreceptors show an early onset of cell death.…”

Section: Resultsmentioning

confidence: 99%

QLT091001, a 9-cis-Retinal Analog, Is Well-Tolerated by Retinas of Mice with Impaired Visual Cycles

Maeda

Dong

Jin

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Lentiviral Gene Transfer-Mediated Cone Vision Restoration in RPE65 Knockout Mice

Cited by 8 publications

References 22 publications

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates

RPE65: Role in the Visual Cycle, Human Retinal Disease, and Gene Therapy

QLT091001, a 9-cis-Retinal Analog, Is Well-Tolerated by Retinas of Mice with Impaired Visual Cycles

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