Nonclinical Safety Evaluation of scAAV8- RLBP1 for Treatment of RLBP1 Retinitis Pigmentosa

MacLachlan, Timothy K.; Milton, Mark; Turner, Oliver C.; Tukov, Francis Fonyuy; Choi, Vivian W.; Penraat, Jan; Delmotte, Marie-Hélène; Michaut, Lydia; Jaffee, Bruce; Bigelow, Chad E.

doi:10.1016/j.omtm.2017.12.001

Cited by 29 publications

(21 citation statements)

References 27 publications

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“…AAV Cre activity was confirmed in HEK293-loxP-GFP-RFP (Cat#: SC018-Puro, GenTarget Inc). Both eyes of 9 month old animals were injected subretinally as previously described 71 at a dose of 1 × 10^9 genome copies per eye. Mice were taken down 5 months post injection for dissection and western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrprd6 mouse

Sluch

Banks

et al. 2018

Sci Rep

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The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration. Here we report that ADIPOR1 protein is primarily found in the eye and brain with little expression in other tissues. Further analysis of AdipoR1 KO mice revealed that these animals exhibit early visual system abnormalities and are depleted of RHODOPSIN prior to pronounced photoreceptor death. A KO of AdipoR1 post-development either in photoreceptors or the retinal pigment epithelium (RPE) resulted in decreased expression of retinal proteins, establishing a role for ADIPOR1 in supporting vision in adulthood. Subsequent analysis of the Mfrprd6 mouse retina demonstrated that these mice are lacking ADIPOR1 in their RPE layer alone, suggesting that loss of ADIPOR1 drives retinal degeneration in this model. Moreover, we found elevated levels of IRBP in both the AdipoR1 KO and the Mfrprd6 models. The spatial distribution of IRBP was also abnormal. This dysregulation of IRBP hypothesizes a role for ADIPOR1 in retinoid metabolism.

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Section: Methodsmentioning

confidence: 99%

ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrprd6 mouse

Sluch

Banks

et al. 2018

Sci Rep

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“…However, gene therapy currently exists for patients carrying RPE65 mutations (63-65) that share some clinical features with RLBP1/CRALBP-disease. Moreover, subretinal injection of an adenoassociated vector driving the expression of human CRALBP in Cralbp -/mice improved both cone and rod electroretinographic responses (66,67).…”

mentioning

confidence: 99%

Effects of deficiency in the RLBP1-encoded visual cycle protein CRALBP on visual dysfunction in humans and mice

Carvalho

Kim

Ueda

et al. 2020

Journal of Biological Chemistry

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Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

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“…Proof of concept of the efficacy of gene replacement in RLBP1related RP came from a study conducted on a mouse model of the disease, in which self-complementary AAV8 vector carrying the gene for human RLBP1 under control of a short RLBP1 promoter (scAAV8-pRLBP1-hRLBP1, or CPK850) was delivered via SRI, resulting in an improved electroretinographic response (189). The success of the preclinical study, followed by the publication of non-clinical safety data by the same group of authors (190), paved the way to clinical trials. To date, there is one ongoing phase 1/2 trial opened for recruiting, aimed at exploring the maximum tolerated dose, safety, and potential efficacy of CPK850 delivered through a single SRI.…”

Section: Gene Therapymentioning

confidence: 99%

Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art

et al. 2021

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Background: Gene therapy cannot be yet considered a far perspective, but a tangible therapeutic option in the field of retinal diseases. Although still confined in experimental settings, the preliminary results are promising and provide an overall scenario suggesting that we are not so far from the application of gene therapy in clinical settings. The main aim of this review is to provide a complete and updated overview of the current state of the art and of the future perspectives of gene therapy applied on retinal diseases.Methods: We carefully revised the entire literature to report all the relevant findings related to the experimental procedures and the future scenarios of gene therapy applied in retinal diseases. A clinical background and a detailed description of the genetic features of each retinal disease included are also reported.Results: The current literature strongly support the hope of gene therapy options developed for retinal diseases. Although being considered in advanced stages of investigation for some retinal diseases, such as choroideremia (CHM), retinitis pigmentosa (RP), and Leber's congenital amaurosis (LCA), gene therapy is still quite far from a tangible application in clinical practice for other retinal diseases.Conclusions: Gene therapy is an extremely promising therapeutic tool for retinal diseases. The experimental data reported in this review offer a strong hope that gene therapy will be effectively available in clinical practice in the next years.

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Nonclinical Safety Evaluation of scAAV8- RLBP1 for Treatment of RLBP1 Retinitis Pigmentosa

Cited by 29 publications

References 27 publications

ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrprd6 mouse

ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrprd6 mouse

Effects of deficiency in the RLBP1-encoded visual cycle protein CRALBP on visual dysfunction in humans and mice

Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art

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