Adeno-Associated Virus (AAV) - Based Gene Therapies for Retinal Diseases: Where are We?

Ail, Divya; Malki, Hugo; Zin, Emilia A; Dalkara, Deniz

doi:10.2147/tacg.s383453

Cited by 23 publications

(17 citation statements)

References 139 publications

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“…A good capsid variant possesses immense commercial value and holds promising prospects for application 13 , 51 . Its significance extends beyond its high transduction efficiency, encompassing attributes such as exceptional stability, ease of purification, and remarkable packaging efficiency.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple engineered AAV variants have gone to therapeutic applications. Among the ongoing clinical trials for retinal diseases, 34% used engineered AAV serotypes 13 . These include AAV2tYF (generated by rational design, clinical trials include NCT02599922, NCT02935517, NCT03316560 and NCT02416622), AAV2.7m8 (generated by directed evolution, clinical trials include NCT04645212, NCT03748784, NCT04418427 and NCT03326336) and 4D-R100 (generated by directed evolution, clinical trials include NCT04483440 and NCT04517149).…”

Section: Introductionmentioning

confidence: 99%

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An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species

Luo,

Jiang,

et al. 2024

Nat Commun

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Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species

Luo,

Jiang,

et al. 2024

Nat Commun

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“…Indeed, we observed overexpression of UBA5 at 9 days following SINEUP application, with >3.5 fold increase. It would be beneficial to explore delivery of SINEUP via other delivery methods including adeno-associated virus and lipid nanoparticles (89)(90)(91)(92). These delivery vehicles do not allow for genome integration and have been approved for human trials by the FDA (89)(90)(91)(92).…”

Section: Discussionmentioning

confidence: 99%

Patient derived model ofUBA5-associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies

Chen,

Wang,

Blan

et al. 2024

Preprint

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UBA5 encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in ER homeostasis. The clinical phenotypes of UBA5-associated encephalopathy include developmental delays, epilepsy and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences of UBA5 pathogenic variants. We developed and characterized patient-derived cortical organoid cultures and identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and microcephaly phenotypes in patient-derived organoids. Mechanistically, we show that ER homeostasis is perturbed along with exacerbated unfolded protein response pathway in cells and organoids expressing UBA5 pathogenic variants. We also assessed two gene expression modalities that augmented UBA5 expression to rescue aberrant molecular and cellular phenotypes. Our study provides a novel humanized model that allows further investigations of UBA5 variants in the brain and highlights novel systemic approaches to alleviate cellular aberrations for this rare, developmental disorder.

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“…The AAV serotype 2 was the first to be vectorized and several pseudo-types have been generated with cell- or tissue-specific tropism 25,26 . These vectors achieve stable transgene expression, and have been extensively employed in pre-clinical studies on various disease models as well as in clinical trials 27 28–45 Several AAV-mediated gene therapy clinical trials, which have been approved by both the Food and Drug Administration and the European Medicines Agency, 24 are currently in place for different LSDs, including Gaucher disease, GM1- and GM2-gangliosidoses, Krabbe disease, several mucopolysaccharidoses (I, II, IIIA, B, C, D, VII), metachromatic leukodystrophy, Pompe disease, Batten disease (neuronal ceroid lipofuscinoses; CLN1 – 8), Fabry disease, and Danon disease 20,46–50 .…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated gene therapy for Sialidosis

van de Vlekkert,

Hu,

Fremuth

et al. 2023

Preprint

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Sialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids. The disease belongs to the group of orphan disorders with no therapy currently available. Here, we have tested the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis in a mouse model of the disease. One-month-oldNeu1−/−mice were co-injected with two scAAV2/8 vectors, expressing NEU1 and its chaperone PPCA, and sacrificed at 3 months post-injection. Treated mice were phenotypically indistinguishable from their WT controls. Histopathologically, they showed diminished or absent vacuolization in cells of visceral organs, including the kidney, as well as the choroid plexus and other areas of the brain. This was accompanied by restoration of NEU1 activity in most tissues, reversal of sialyl-oligosacchariduria, and normalization of lysosomal exocytosis in the CSF and serum of treated mice. AAV injection prevented the occurrence of generalized fibrosis, which is a prominent contributor of disease pathogenesis inNeu1−/−mice and likely in patients. Overall, this therapeutic strategy holds promise for the treatment of sialidosis and may be applicable to adult forms of human idiopathic fibrosis with low NEU1 expression.

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Adeno-Associated Virus (AAV) - Based Gene Therapies for Retinal Diseases: Where are We?

Cited by 23 publications

References 139 publications

An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species

An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species

Patient derived model ofUBA5-associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies

AAV-mediated gene therapy for Sialidosis

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