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CRISPR Used to Block Angiogenesis in the Retina
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CRISPR Used to Block Angiogenesis in the Retina

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Highlights:
  • Angiogenesis is a pathological formation of new blood vessels from pre-existing ones.
  • Vascular epidermal growth factor receptor (VEGFR) 2 plays a vital role in angiogenesis.
  • Gene editing using adeno-associated virus CRISPR- Cas9 system showed depletion of VEGFR2 in both in-vitro and in-vivo models.

Several eye diseases that result in blindness have a characteristic feature of angiogenesis, wherein there is abnormal production of new blood vessels in the retina. This leads to rupture, tear and leak of the blood vessels and may result in loss of vision. Vascular epidermal growth factor receptor (VEGFR) 2 plays an important role in angiogenesis. Researchers from the Schepens Eye Research Institute of Massachusetts Eye and Ear have used adeno-associated virus CRISPR system to deplete VEGFR2. The study is published in Nature Communications.

Angiogenesis in the Eye

Pathological intraocular (inside the eye) angiogenesis is a condition where the blood vessels in the retina (thin layer of tissue on the back inside wall of the eye) begin to grow abnormally on the surface of the retina. As this progresses, the retina may swell or the vessels may burst or leak causing distorted vision.

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Abnormal angiogenesis is associated with diseases like proliferative diabetic retinopathy (PDR)6 retinopathy of prematurity (ROP) and wet age-related macular degeneration (AMD).

Diabetic retinopathy: In case of diabetes, the tiny blood vessels (capillaries) in the back of the eye can deteriorate and leak fluid into the retina. This causes the retina to swell, which may blur vision. One may also develop new, abnormal capillaries that break and bleed.
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Macular degeneration: In macular degeneration, the center of the retina begins to deteriorate. This causes symptoms such as blurred central vision or a blind spot in the center of the visual field. There are two types — wet macular degeneration and dry macular degeneration.

Current treatment

While there are anti-VEGFR like ranibizumab and aflibercept can reduce neo-vascular growth and vascular leakage, these approaches require chronic treatment. Also, a significant number of patients do not respond to the treatment. Scientists believe that targeting VEGFR2 locus using AAV-CRIPSR/Cas9 may provide a novel alternative approach.

Gene editing approach

Adeno-associated virus (AAV) mediated CRISPR-Cas9 was used to target the VEGFR2 locus. AAVs are small viruses that are not known to cause any disease. Their vectors show promise for human gene therapy.

The in-vitro analysis showed that the recombinant AAV enabled transduction to pathological vessels of mouse primary brain microvascular ECs (MVECs). 80% of VEGFR2 expressio as depleted in this case. For in-vivo analysis, eye diseases characterized by angiogenesis were simulated in mouse models. AAV-mediated CRISPR-Cas9 edited VEGFR2 showed inhibition of angiogenesis in two mouse models of oxygen-induced retinopathy and laser-induced choroid neo-vascular growth. 30% of VEGFR2 expression was depleted in-vivo.

The team believes that this approach forms a strong foundation for treating other angiogenesis associated diseases.Concluding with the words of the corresponding author, Dr. Lei said "While further study is needed to determine safety and efficacy of this approach, our work shows that the CRISPR-Cas9 system is a precise and efficient tool with the potential to treat angiogenesis-associated diseases."

References :
  1. Huang, X., Zhou, G., Wu, W., Duan, Y., Ma, G., Song, J., . . . Lei, H. (2017). Genome editing abrogates angiogenesis in vivo. Nature Communications, 8(1). doi:10.1038/s41467-017-00140-3
  2. Overview - Retinal Diseases - (http://www.mayoclinic.org/diseases-conditions/retinal-diseases/home/ovc-20312856)
Source: Medindia

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