Retina transduction by rAAV2 after intravitreal injection: comparison between mouse and rat

Dias, Mariana Santana; Araujo, Victor Guedes de; Vasconcelos, Taliane; Li, Qiuhong; Hauswirth, William W.; Linden, Rafael; Petrs‐Silva, Hilda

doi:10.1038/s41434-019-0100-9

Cited by 14 publications

(8 citation statements)

References 56 publications

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“…Subretinal injection leads to superior retinal gene transfer compared with intravitreal injection in nonhuman primates. 38 , 39 Moreover, intravitreal injection causes increased and persistent distribution of vector genomes in blood and lymphatic tissues, raising concerns regarding the immune response and off-target transduction. 38 , 40 In this case, subretinal injection of AAV8-nVEGFi was used in this study.…”

Section: Discussionmentioning

confidence: 99%

Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration

She

Wang

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Inhibition of vascular endothelial growth factor (VEGF) is the standard therapy for neovascular age-related macular degeneration (nAMD). However, anti-VEGF agents used in the clinic require repeated injections, causing adverse effects. Gene therapy could provide sustained anti-VEGF levels after a single injection, thereby drastically decreasing the treatment burden and improving visual outcomes. In this study, we developed a novel VEGF Trap, nVEGFi, containing domains 1 and 2 of VEGFR1 and domain 3 of VEGFR2 fused to the Fc portion of human IgG. The nVEGFi had a higher expression level than aflibercept under the same expression cassettes of adeno-associated virus (AAV)8 in vitro and in vivo . nVEGFi was found to be noninferior to aflibercept in binding and blocking VEGF in vitro . AAV8-mediated expression of nVEGFi was maintained for at least 12 weeks by subretinal delivery in C57BL/6J mice. In a mouse laser-induced choroidal neovascularization (CNV) model, 4 × 10 8 genome copies of AAV8-nVEGFi exhibited a significantly increased reduction in the CNV area compared with AAV8-aflibercept (78.1% vs. 63.9%, p < 0.05), while causing no structural or functional changes to the retina. In conclusion, this preclinical study showed that subretinal injection of AAV8-nVEGFi was long lasting, well tolerated, and effective for nAMD treatment, supporting future translation to the clinic.

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Section: Discussionmentioning

confidence: 99%

Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration

She

Wang

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…This procedure is in routine clinical practice for the delivery of anti-angiogenesis agents to treat neovascularization associated with diseases such as age-related macular degeneration (Todorich et al, 2014). However, material delivered intravitreally typically has poor penetration into the outer retina (Farjo et al, 2006;Dias et al, 2019), due both to the content of the vitreous itself as well as to the inner limiting membrane which forms a physical barrier between the retina and the vitreous. Identifying ways to improve delivery of genetic material to the outer retina after intravitreal delivery has been a critical research goal in the past several years.…”

Section: Delivery Of Genes To the Retinamentioning

confidence: 99%

“…Identifying ways to improve delivery of genetic material to the outer retina after intravitreal delivery has been a critical research goal in the past several years. Many methods have been tried, including making genetic modifications to AAV capsids (Petrs-Silva et al, 2009;Dalkara et al, 2013), including agents to digest or disrupt the inner limiting membrane (Dalkara et al, 2009;Cehajic-Kapetanovic et al, 2011), application of electrical currents (Song et al, 2019, and the inclusion of adjuvants such as tyrosine kinase inhibitors or proteasome inhibitors (Dias et al, 2019). Modification of viral capsids led to almost complete transduction of the outer retina after intravitreal injection in the mouse retina, but did not achieve this milestone in larger animal models such as dog and non-human primate (Mowat et al, 2014;Boyd et al, 2016;Ramachandran et al, 2017).…”

Section: Delivery Of Genes To the Retinamentioning

confidence: 99%

Gene Therapy to the Retina and the Cochlea

et al. 2021

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Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic therapies for any of the several hundred known causative genes underlying inherited retinal and cochlear disorders has been of great interest. Recent exciting advances in gene therapy have shown promise for the clinical treatment of inherited retinal diseases, and while clinical gene therapies for cochlear disease are not yet available, research in the last several years has resulted in significant advancement in preclinical development for gene delivery to the cochlea. Furthermore, the development of somatic targeted genome editing using CRISPR/Cas9 has brought new possibilities for the treatment of dominant or gain-of-function disease. Here we discuss the current state of gene therapy for inherited diseases of the retina and cochlea with an eye toward areas that still need additional development.

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“…Applying a low trans-ocular electric current also allowed efficient transduction of RPE and photoreceptors by rAAV8 upon intravitreal injection in adult mice [ 306 ]. Finally, the application of tyrosine kinase inhibitors might improve the passage of rAAV through the ILM or OLM [ 307 ]. The novel methods might make the intravitreal injection more common for photoreceptor and Müller glial cell infection.…”

Section: Transgene and Bioactivity Assays In Ocular Tissuementioning

confidence: 99%

Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays

Buck

Wijnholds

2020

IJMS

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Inherited retinal dystrophies and optic neuropathies cause chronic disabling loss of visual function. The development of recombinant adeno-associated viral vectors (rAAV) gene therapies in all disease fields have been promising, but the translation to the clinic has been slow. The safety and efficacy profiles of rAAV are linked to the dose of applied vectors. DNA changes in the rAAV gene cassette affect potency, the expression pattern (cell-specificity), and the production yield. Here, we present a library of rAAV vectors and elements that provide a workflow to design novel vectors. We first performed a meta-analysis on recombinant rAAV elements in clinical trials (2007–2020) for ocular gene therapies. We analyzed 33 unique rAAV gene cassettes used in 57 ocular clinical trials. The rAAV gene therapy vectors used six unique capsid variants, 16 different promoters, and six unique polyadenylation sequences. Further, we compiled a list of promoters, enhancers, and other sequences used in current rAAV gene cassettes in preclinical studies. Then, we give an update on pro-viral plasmid backbones used to produce the gene therapy vectors, inverted terminal repeats, production yield, and rAAV safety considerations. Finally, we assess rAAV transgene and bioactivity assays applied to cells or organoids in vitro, explants ex vivo, and clinical studies.

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Retina transduction by rAAV2 after intravitreal injection: comparison between mouse and rat

Cited by 14 publications

References 56 publications

Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration

Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration

Gene Therapy to the Retina and the Cochlea

Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays

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