X-linked retinoschisis (XLRS) is a monogenic recessive inherited retinal disease caused by defects in retinoschisin (RS1). It manifests clinically as retinal schisis cavities and a disproportionate reduction of b-wave amplitude compared with the a-wave amplitude. Currently there is no approved treatment. In the last decade, there has been major progress in the development of gene therapy for XLRS. Previous preclinical studies have demonstrated the treatment benefits of hRS1 gene augmentation therapy in mouse models. However, outcomes in clinical trials have been disappointing, and this might be attributed to dysfunctional assembly of RS1 complexes and/or the impaired targeted cells. In this study, the human synapsin 1 gene promoter (hSyn) was used to control the expression of hRS1 to specifically target retinal ganglion cells and our results confirmed the specific expression and functional assembly of the protein. Moreover, our results demonstrated that a single intravitreal injection of rAAV2-hSyn-hRS1 results in architectural restoration of retinal schisis cavities and improvement in vision in a mouse model of XLRS. In brief, this study not only supports the clinical development of the rAAV2-hSyn-hRS1 vector in XLRS patients but also confirms the therapeutic potential of rAAV-based gene therapy in inherited retinal diseases.

2018-11-14·Investigative ophthalmology & visual science2区 · 医学

Intravitreal Injection of AAV Expressing Soluble VEGF Receptor-1 Variant Induces Anti-VEGF Activity and Suppresses Choroidal Neovascularization

2区 · 医学

ArticleOA

作者: Ha, Joohun ; Lee, Heuiran ; Kim, Jin ; Shin, Oh Kyu ; Park, Tae Kwann ; Lee, Joo Yong ; Cho, Young-Hwa ; Kim, Hee Jong ; Lee, Steven Hyun Seung ; Choi, Jun-Sub ; Park, Keerang

Purpose:

With anti-VEGF-based treatments for wet AMD requiring frequent injections, it is often burdensome to both patients and healthcare providers. To explore its possibility as a desirable alternative, we investigated the therapeutic potential of a recombinant adeno-associated virus 2 expressing a soluble variant of VEGF receptor-1 (rAAV2-sVEGFRv-1) in a laser-induced choroidal neovascularization (CNV) model, as CNV is a defining feature of AMD progression.

Methods:

C57/B6 mice were intravitreally administered with rAAV2-sVEGFRv-1, rAAV2-GFP, or clinically used bevacizumab after CNV lesions were induced via laser photocoagulation. Immunostaining was performed with phalloidin and CD31 to measure CNV extensiveness, F4/80 and CD11b for inflammatory cell infiltration, and pan-cytokeratin to visualize fibrotic progression.

Results:

rAAV2-sVEGFRv-1 (5.0 × 107 viral genomes) possesses antiangiogenic, anti-inflammatory, and antifibrotic properties. rAAV2-sVEGFRv-1 was demonstrated to significantly decrease retinal CNV lesion size (1336 ± 186) when compared to rAAV2-GFP-treated (2949 ± 437, P = 0.0043), mock-treated (3075 ± 265, P = 0.0013), and bevacizumab-treated models (995 ± 234). Infiltration by inflammatory cells significantly decreased with rAAV2-sVEGFRv-1 administration, while groups treated with rAAV2-GFP did not. Additionally, antiapoptotic activity was observed via TUNEL assay in rAAV2-sVEGFRv-1 (16.0 ± 3.6) and rAAV2-GFP (46.0 ± 7.5, P = 0.003). Overall, the rAAV2-sVEGFRv-1 viral vector was positively comparable to bevacizumab, indicating it as effective as approved therapeutics.

Conclusions:

The ability of a low dose of rAAV2-sVEGFRv-1 to exert a therapeutically relevant anti-VEGF effect in a CNV model is demonstrated, and strongly suggests gene therapy as an effective and convenient treatment for sustained VEGF suppression.

2018-04-01·Neurochemical research3区 · 医学

Human Neural Stem Cells with GDNF Site-Specific Integration at AAVS1 by Using AAV Vectors Retained Their Stemness

3区 · 医学

Article

作者: Zhang, Jinju ; Zhang, Yun ; Wang, Zhaoyan ; Zhang, Chun ; Yang, Yinxiang ; Luan, Zuo ; Liu, Xiaomei

The neural stem cells (NSCs) have the ability to self-renew, and to migrate to pathologically altered regions of the central nervous system. Glial cell derived neurotrophic factor (GDNF) could protect dopamine neurons and rescue motor neurons in vivo, which has been proposed as a promising candidate for the treatments of degenerative neurological diseases. In order to combine the advantages of neurotrophic factors and stem cells in clinical therapy, we established the modified hNSCs that has site-specific integration of GDNF gene by using recombinant adeno-associated virus (rAAV) vectors. The hNSCs were co-infected by rAAV2-EGFP-GDNF and rAAV2-SVAV2 which provide integrase to specifically integrate GDNF gene into AAVS1 site. The GDNF-hNSCs maintained their original stem cell characteristics and the ability to differentiate into neurons in vitro. In the animal model, the GDNF-hNSCs were specifically transplanted into CA1 area of hippocampi and could migrate to the dentate gyrus region and differentiate into neuronal cells while maintaining GDNF expression. hNSCs with GDNF gene site-specific integration at AAVS1 by using AAV vectors retained their stemness and effectively expressed GDNF, which indicates the potential of employing transplanted hNPCs for treatment of brain injuries and degenerative neurological diseases.

100 项与 rAAV2-sVEGFRv-1 (CuroGene Life Sciences/University of Ulsan) 相关的药物交易

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