Gene therapy for visual loss: Opportunities and concerns

Lee, Jia Hui; Wang, Jiang-Hui; Chen, Jinying; Фан, Ли; Edwards, Thomas L.; Hewitt, Alex W.; Liu, Guei‐Sheung

doi:10.1016/j.preteyeres.2018.08.003

Cited by 79 publications

(50 citation statements)

References 215 publications

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“…The immune privilege of the eye makes it suitable targets for AAV‐mediated gene therapy. [ 8d,10b,25 ] Previous studies showed that Cas9 nuclease could generate double‐strand breaks (DSBs) to disrupt genes function in the retina. [ 26 ] Precise editing of retinal cells by HDR was reported in newborn mice, but editing efficiency was low (<3%).…”

Section: Resultsmentioning

confidence: 99%

Development of Highly Efficient Dual‐AAV Split Adenosine Base Editor for In Vivo Gene Therapy

et al. 2020

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The adenosine base editor (ABE) is able to catalyze A•T to C•G conversion efficiently and precisely in vivo, representing a new method for gene therapy. Adeno associated virus (AAV) is a well‐studied vector for gene delivery in vivo. However, due to the limited loading capacity of AAV vector (≈4800 bp), it is difficult to package ABE (≈5400 bp) into a single AAV. To tackle this problem, ABE can be split into two smaller parts through intein‐mediated protein trans‐splicing. Here, 14 different split sites of nCas9 (Cas9 nickase) in combination with three different inteins (Mxe, Npu, and Rma) are screened through a GFP‐based reporter system to identify novel split‐ABEs. After infecting HEK293T and HeLa cells with dual AAVs, two split‐ABEs (split‐ABE‐Rma573 and split‐ABE‐Rma674) that can edit the target gene efficiently are identified. Furthermore, these dual‐AAV split‐ABEs can effectively disrupt the splicing acceptor of PCSK9 in mouse liver and the splicing donor of NR2E3 in mouse retina through AI‐MAST strategy. This study provides two new split‐ABEs to investigate gene function in vivo and in gene therapy, representing a new method to treat diseases by precisely repairing point mutations or inactivating genes through the AI‐MAST strategy.

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Section: Resultsmentioning

confidence: 99%

Development of Highly Efficient Dual‐AAV Split Adenosine Base Editor for In Vivo Gene Therapy

et al. 2020

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“…However, adverse effects associated with prolonged expression of vascular targeting proteins by gene delivery may have unwanted side effects, including retinal vascular toxicity. There are also other major obstacles to the acceleration of gene therapy from bench to bedside, such as cost of the treatment [ 19 ]. Therefore, in the present study, we rationally designed a small fragment of CAD, CAD27, which covers the core anti-angiogenic domain of CAD and can be produced by chemical synthesis at a lower cost than its parent molecule, recombinant CAD protein or CAD gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain

Bee

Chen

et al. 2018

IJMS

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Choroidal neovascularization (CNV) is a key pathological feature of several leading causes of vision loss including neovascular age-related macular degeneration. Here, we show that a calreticulin anti-angiogenic domain (CAD)-like peptide 27, CAD27, inhibited in vitro angiogenic activities, including tube formation, migration of endothelial cells, and vascular sprouting from rat aortic ring explants. In a rat model of laser-induced CNV, we demonstrate that intravitreal injection of CAD27 significantly attenuated the formation of CNV lesions as measured via fundus fluorescein angiography and choroid flat-mounts (19.5% and 22.4% reductions at 10 μg and 20 μg of CAD27 injected, respectively). Similarly, the reduction of CNV lesions was observed in rats that had received topical applications of CAD27 (choroid flat-mounts: 17.9% and 32.5% reductions at 10 μg/mL and 20 μg/mL of CAD27 instilled, respectively). Retinal function was unaffected, as measured using electroretinography in both groups receiving interareal injection or topical applications of CAD27 for at least fourteen days. These findings show that CAD27 can be used as a potential therapeutic alternative for targeting CNV in diseases such as neovascular age-related macular degeneration.

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“…However, adverse effects associated with prolonged expression of vascular targeting proteins by gene delivery may have unwanted side effects, including retinal vascular toxicity. There are also other major obstacles to the acceleration of gene therapy from bench to bedside, such as cost of the treatment [19]. Therefore, in the present study, we rationally designed a small fragment of CAD, CAD27, which covers the core antiangiogenic domain of CAD and can be produced by chemically synthesis at a lower cost than its parent molecule, recombinant CAD protein or CAD gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain

Bee

Chen

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Choroidal neovascularization (CNV) is a key pathological feature of several of the leading causes of vision loss including neovascular age-related macular degeneration. Here we show that a calreticulin anti-angiogenic domain (CAD)-like peptide 27, CAD27, inhibited in vitro angiogenic activities, including tube formation and migration of endothelial cells, and suppressed vascular sprouting from rat aortic ring explants. In rat model of laser-induced CNV, we demonstrate that intravitreal injection of CAD27 significantly attenuated the formation of CNV lesions as measured via fundus fluorescein angiography and choroid flat-mounts (19.5% and 22.4% reductions at 10μg and 20μg of CAD27 injected, respectively). Similarly, the reduction of CNV lesions was observed in the groups of rats that had received topical applications of CAD27 (choroid flat-mounts: 17.9% and 32.5% reductions at 10μg/mL and 20μg/mL of CAD27 installed, respectively). Retinal function was unaffected, as measured using electroretinography in both groups received interareal injection or topical applications of CAD27 at least for 9 days. These findings show that CAD27 can be used as a potential therapeutic alternative for targeting CNV in the diseases such as neovascular age-related macular degeneration.

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Gene therapy for visual loss: Opportunities and concerns

Cited by 79 publications

References 215 publications

Development of Highly Efficient Dual‐AAV Split Adenosine Base Editor for In Vivo Gene Therapy

Development of Highly Efficient Dual‐AAV Split Adenosine Base Editor for In Vivo Gene Therapy

Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain

Inhibition of Experimental Choroidal Neovascularization by a Novel Peptide Derived from Calreticulin Anti-Angiogenic Domain

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