Early and late stage gene therapy interventions for inherited retinal degenerations

Botto, Catherine; Rucli, Marco; Tekinsoy, Müge Defne; Pulman, Juliette; Sahel, José‐Alain; Dalkara, Deniz

doi:10.1016/j.preteyeres.2021.100975

Cited by 107 publications

(77 citation statements)

References 150 publications

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“… 15 As a result, a minority of photoreceptors that are already in their degenerative phase will have a comparatively worse condition to start with and hence end up with a more impaired function and morphology compared to the majority of cells that move slowly into degeneration and/or be less responsive to the gene replacement therapy given their disrupted local environment. 27 , 37 , 38 It is also likely that it is harder to infect the photoreceptors of middle-aged mice (P120) than young mice (P21).…”

Section: Discussionmentioning

confidence: 99%

AAV8-Mediated Gene Therapy Rescues Retinal Degeneration Phenotype in a Tlcd3b Knockout Mouse Model

Qian

Liu

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to assess the therapeutic efficacy of rAAV8-hGRK1-Tlcd3b in a Tlcd3b − / − mouse model of retinal generation and validate TLCD3B's role as a ceramide synthase in vivo. Methods Using Tlcd3b − / − mice as an inherited retinal disease animal model, we performed subretinal injection of rAAV8-hGRK1-Tlcd3b and evaluated the efficacy of gene replacement therapy. Tlcd3b − / − mice were treated at two time points: postnatal day 21 (P21) and postnatal day 120 (P120) with various dosages. Results Tlcd3b overexpression rescued retinal degeneration in the mutant mice, as indicated by significantly improved photoreceptor function and preservation of photoreceptor cells over the course of 1 year. Although Tlcd3b is expressed in all cell types in the retina, photoreceptor cell-specific expression of Tlcd3b is sufficient to rescue the phenotype, indicating the primary function of TLCD3B is in photoreceptors. Consistent with the idea that TLCD3B is a ceramide synthase, mass spectrometry analyses of the mutant retina indicate the reduction of C16-, C18-, and C20-ceramides in the retina, which are restored with Tlcd3b overexpression. Conclusions Our findings demonstrated the therapeutic efficacy of gene therapy in treating Tlcd3b mutant retina, laying the foundation for developing future therapy for TLCD3B retinopathy.

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Section: Discussionmentioning

confidence: 99%

AAV8-Mediated Gene Therapy Rescues Retinal Degeneration Phenotype in a Tlcd3b Knockout Mouse Model

Qian

Liu

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…This pioneering work led to the historical approval of the first gene therapy product, Luxturna, by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat Leber congenital amaurosis. This groundbreaking advancement of RPE65 gene therapy paved the way for numerous breakthrough clinical phase I/II trials exploring gene replacement for monogenic recessive diseases of the retina, such as choroideremia, retinoschisis, achromatopsia, Usher syndrome, and Leber hereditary optic neuropathy (Buck and Wijnholds, 2020;Botto et al, 2021;Crane et al, 2021). Thanks to new generation of viral vectors, successful gene replacement strategies targeting key deafness genes have been established, using single or double AAV vector-mediated delivery (see Sacheli et al, 2013;Askew and Chien, 2020;Géléoc and El-Amraoui, 2020).…”

Section: Gene Therapy For Inherited Retinal Dystrophies and Auditory Deficitsmentioning

confidence: 99%

“…The structures of these two senses make them excellent models for studying the functioning of the central nervous system and for developing and validating new innovative therapeutic strategies for neurodegenerative diseases. Building on the accumulated knowledge about the disease mechanisms underlying vision and/or hearing loss, several treatment strategies, notably viral mediated gene replacement therapies, have been implemented to prevent or correct blindness and/or deafness phenotypes (Delmaghani and El-Amraoui, 2020;Botto et al, 2021). Also, recent advances in gene editing in sensory organs have provided a basis for potential one-shot treatments for vision and hearing loss, and these promising advances are likely to be at the forefront of further developments in gene editing to correct pathogenic mutations underlying hereditary diseases in the years to come.…”

Section: Introductionmentioning

confidence: 99%

Progress in Gene Editing Tools and Their Potential for Correcting Mutations Underlying Hearing and Vision Loss

Botto

Dalkara²,

El-Amraoui³

2021

Front. Genome Ed.

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Blindness and deafness are the most frequent sensory disorders in humans. Whatever their cause — genetic, environmental, or due to toxic agents, or aging — the deterioration of these senses is often linked to irreversible damage to the light-sensing photoreceptor cells (blindness) and/or the mechanosensitive hair cells (deafness). Efforts are increasingly focused on preventing disease progression by correcting or replacing the blindness and deafness-causal pathogenic alleles. In recent years, gene replacement therapies for rare monogenic disorders of the retina have given positive results, leading to the marketing of the first gene therapy product for a form of childhood hereditary blindness. Promising results, with a partial restoration of auditory function, have also been reported in preclinical models of human deafness. Silencing approaches, including antisense oligonucleotides, adeno-associated virus (AAV)–mediated microRNA delivery, and genome-editing approaches have also been applied to various genetic forms of blindness and deafness The discovery of new DNA- and RNA-based CRISPR/Cas nucleases, and the new generations of base, prime, and RNA editors offers new possibilities for directly repairing point mutations and therapeutically restoring gene function. Thanks to easy access and immune-privilege status of self-contained compartments, the eye and the ear continue to be at the forefront of developing therapies for genetic diseases. Here, we review the ongoing applications and achievements of this new class of emerging therapeutics in the sensory organs of vision and hearing, highlighting the challenges ahead and the solutions to be overcome for their successful therapeutic application in vivo.

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“…Gene therapies developed for individuals across the RDD spectrum have made remarkable progress in recent years 22 ; however, with more than 200 distinct causative genes, 16 curative interventions remain out of reach for most patients. Cell therapies—the delivery of live cells to treat or cure disease—have emerged as a promising alternative (or adjunct 23 ) to gene therapy, offering a broad-spectrum and gene-independent strategy for restoring vision.…”

Section: Introductionmentioning

confidence: 99%

Outer Retinal Cell Replacement: Putting the Pieces Together

Ludwig

Gamm

2021

Trans. Vis. Sci. Tech.

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Early and late stage gene therapy interventions for inherited retinal degenerations

Cited by 107 publications

References 150 publications

AAV8-Mediated Gene Therapy Rescues Retinal Degeneration Phenotype in a Tlcd3b Knockout Mouse Model

AAV8-Mediated Gene Therapy Rescues Retinal Degeneration Phenotype in a Tlcd3b Knockout Mouse Model

Progress in Gene Editing Tools and Their Potential for Correcting Mutations Underlying Hearing and Vision Loss

Outer Retinal Cell Replacement: Putting the Pieces Together

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