Vision quest: gene therapy for inherited vision loss

AbstractNeuronal ceroid lipofuscinosis (NCL) is a family of neurodegenerative diseases caused by mutations to genes related to lysosomal function. One variant, CNL11, is caused by mutations to the gene encoding the protein progranulin. Primarily secreted by microglia, progranulin regulates neuronal lysosomal function once endocytosed. Absence of progranulin causes cerebellar atrophy, seizures, ataxia, dementia and vision loss. As progranulin gene therapies targeting the brain are developed, it is also advantageous to focus on the retina, as its characteristics are beneficial for gene therapy development: the retina is easily visible through direct imaging, can be assessed through quantitative methods in vivo, requires smaller amounts of AAV and AAV can be administered via a less invasive surgery. In this study we characterize the retinal degeneration in a progranulin knockout mouse model of CLN11 and study the effects of gene replacement at different time points. All mice heterologously expressing progranulin showed reduction in lipofuscin deposits and microglia infiltration. While mice that receive systemic AAV9.2YF-scCAG-PGRN at post-natal day 3 or 4 show a reduction in retina thinning, mice injected intravitreally at months 1 and 6 with 7m8-scCAG-PGRN show no improvement, and mice injected at 12 months of age show increased retinal thinning in comparison to their controls. Thus, delivery of progranulin proves to be time-sensitive, requiring early administration for optimal therapeutic benefit.

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Chapter 3 - Restoring Vision to the Blind: Gene Therapy for Vision Loss

Translational Vision Science & Technology ◽

10.1167/tvst.3.7.5 ◽

2014 ◽

Vol 3 (7) ◽

pp. 5 ◽

Cited By ~ 1

Keyword(s):

Gene Therapy ◽

Vision Loss

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Nanotechnology for Age-Related Macular Degeneration

Pharmaceutics ◽

10.3390/pharmaceutics13122035 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2035

Author(s):

Bo Yang ◽

Ge Li ◽

Jiaxin Liu ◽

Xiangyu Li ◽

Shixin Zhang ◽

...

Keyword(s):

Drug Delivery ◽

Gene Therapy ◽

Macular Degeneration ◽

Vision Loss ◽

Cumulative Risk ◽

Age Related Macular Degeneration ◽

Delivery Methods ◽

Age Related ◽

Therapy Strategies ◽

Endothelial Growth Factor

Age-related macular degeneration (AMD) is a degenerative eye disease that is the leading cause of irreversible vision loss in people 50 years and older. Today, the most common treatment for AMD involves repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, the existing expensive therapies not only cannot cure this disease, they also produce a variety of side effects. For example, the number of injections increases the cumulative risk of endophthalmitis and other complications. Today, a single intravitreal injection of gene therapy products can greatly reduce the burden of treatment and improve visual effects. In addition, the latest innovations in nanotherapy provide the best drug delivery alternative for the treatment of AMD. In this review, we discuss the development of nano-drug delivery systems and gene therapy strategies for AMD in recent years. In addition, we discuss some novel targeting strategies and the potential application of these delivery methods in the treatment of AMD. Finally, we also propose that the combination of CRISPR/Cas9 technology with a new non-viral delivery system may be promising as a therapeutic strategy for the treatment of AMD.

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Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Frontiers in Neurology ◽

10.3389/fneur.2021.662838 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nancy J. Newman ◽

Patrick Yu-Wai-Man ◽

Valerio Carelli ◽

Valerie Biousse ◽

Mark L. Moster ◽

...

Keyword(s):

Gene Therapy ◽

Visual Acuity ◽

Natural History ◽

Optic Neuropathy ◽

Linear Mixed Model ◽

Vision Loss ◽

Indirect Comparison ◽

External Control ◽

Leber Hereditary Optic Neuropathy ◽

Hereditary Optic Neuropathy

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

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Faculty Opinions recommendation of Gene therapy for vision loss -- recent developments.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12854956.14142054 ◽

2011 ◽

Author(s):

Margriet Vervoordeldonk ◽

Caroline Aalbers

Keyword(s):

Gene Therapy ◽

Vision Loss ◽

Recent Developments

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Ocular gene therapy strategies

10.31219/osf.io/7en3k ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Therapy ◽

Vision Loss ◽

Disease Process ◽

Disease Models ◽

Host Interactions ◽

Novel Treatments ◽

Model Study ◽

Technological Advances ◽

Animal Model Study ◽

Clinical Description

Despite the optimistic findings of recent LCA2 studies that resulted in the approval of Luxturna®, the first ocular gene therapy drug, the translation of retinal gene therapy from the laboratory bench to the bedside is still a work in progress that requires both sides to move in lockstep. Improvements from both basic and clinical research must come together to generate the next generation of breakthrough retinal trials; a thorough comprehension of degenerative molecular foundations must be combined with a full clinical description of the disease process. The growing availability and technological advances in studying animal disease models, as well as the development of innovative human disease models such as retinal organoids that can overcome some of the limitations of animal model study, are all encouraging developments in the field of eye translation. AAVs' versatility has enabled gene therapy, especially ocular gene therapy, to improve considerably over the past decade, bringing hope for treatment for a number of disorders previously believed to be incurable. More improvements in capsid and vector engineering, a better understanding of vector-host interactions, and clinical knowledge of vision loss illnesses will continue to provide clinicians and researchers with the tools they need to improve these novel treatments.

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Viral-Vector Delivered anti-Angiogenic Therapies to the Eye

10.20944/preprints202012.0602.v1 ◽

2020 ◽

Author(s):

Sanna Koponen ◽

Emmi Kokki ◽

Kati Kinnunen ◽

Seppo Ylä-Herttuala

Keyword(s):

Gene Therapy ◽

Clinical Studies ◽

Viral Vectors ◽

Vision Loss ◽

Viral Vector ◽

Great Promise ◽

Ocular Neovascularization ◽

Vessel Growth ◽

Lentivirus Vectors ◽

Endothelial Growth Factors

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in pre-clinical studies. Most of the studies has conducted with different adeno-associate serotype vectors. In addition, Adeno and lentivirus vectors have been used. Therapy has targeted to block vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded phase 2 trials further.

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Gene Therapy Reforms Photoreceptor Structure and Restores Vision in NPHP5-associated Leber Congenital Amaurosis

10.1101/2020.10.07.329821 ◽

2020 ◽

Author(s):

Gustavo D. Aguirre ◽

Artur V. Cideciyan ◽

Valérie L. Dufour ◽

Ana Ripolles García ◽

Raghavi Sudharsan ◽

...

Keyword(s):

Gene Therapy ◽

Vision Loss ◽

Normal Structure ◽

Abnormal Development ◽

Large Animal ◽

Rod Photoreceptor ◽

Leber Congenital Amaurosis ◽

Outer Segments ◽

History Of ◽

Cone Opsins

AbstractThe inherited childhood blindness caused by mutations in NPHP5, a form of Leber congenital amaurosis, results in abnormal development, dysfunction and degeneration of photoreceptors. A naturally occurring NPHP5 mutation in dogs results in a phenotype that very nearly duplicates the human retinopathy in terms of the photoreceptors involved, spatial distribution of degeneration and the natural history of vision loss. We show that AAV-mediated NPHP5 gene augmentation of mutant canine retinas at the time of active degeneration and peak cell death stably restores photoreceptor structure, function, and vision with either the canine or human NPHP5 transgenes. Mutant cone photoreceptors, which failed to form outer segments during development, reform this structure after treatment. Degenerating rod photoreceptor outer segments are stabilized and develop normal structure. This process begins within 8 weeks following treatment, and remains stable throughout the 6 month post treatment period. In both photoreceptor cell classes, mislocalization of rod and cone opsins is minimized or reversed. Retinal function and functional vision are restored. Efficacy of gene therapy in this large animal ciliopathy model of Leber congenital amaurosis provides a path for translation to human treatment.

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Gene Therapy Strategies for Glaucomatous Neurodegeneration

Current Gene Therapy ◽

10.2174/1566523221666210126152000 ◽

2021 ◽

Vol 21 ◽

Author(s):

Rafael Lani-Louzada ◽

Mariana Santana Dias ◽

Rafael Linden ◽

Vinicius de Toledo Ribas ◽

Hilda Petrs-Silva

Keyword(s):

Gene Therapy ◽

Intraocular Pressure ◽

Retinal Ganglion Cells ◽

Viral Vectors ◽

Vision Loss ◽

Ganglion Cells ◽

Experimental Studies ◽

Current Treatment ◽

Experimental Models ◽

Retinal Ganglion

: Glaucoma leads to irreversible vision loss and current therapeutic strategies are often insufficient to prevent the progression of the disease and consequent blindness. Elevated intraocular pressure is an important risk factor, but not required for the progression of glaucomatous neurodegeneration. The demise of retinal ganglion cells represents the final common pathway of glaucomatous vision loss. Still, lifelong control of intraocular pressure is the only current treatment to prevent severe vision loss, although it frequently fails despite best practices. This scenario calls for the development of neuroprotective and pro-regenerative therapies targeting the retinal ganglion cells as well as the optic nerve. Several experimental studies have shown the potential of gene modulation as a tool for neuroprotection and regeneration. In this context, gene therapy represents an attractive approach as persistent treatment for glaucoma. Viral vectors engineered to promote overexpression of a broad range of cellular factors have been shown to protect retinal ganglion cells and/or promote axonal regeneration in experimental models. Here, we review the mechanisms involved in glaucomatous neurodegeneration and regeneration in the central nervous system. Then, we point out current limitations of gene therapy platforms and review a myriad of studies that use viral vectors to manipulate genes in retinal ganglion cells, as a strategy to promote neuroprotection and regeneration. Finally, we address the potential of combining neuroprotective and regenerative gene therapies as an approach to glaucomatous neurodegeneration.

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