Effects of VEGF Trap (Aflibercept) on the immature, developing, retina during oxygen induced retinopathy model (mouse).

Effects of Anti-VEGF Treatment on the Recovery of the Developing Retina Following Oxygen-Induced Retinopathy
Clayton C. Tokunaga; Kenneth P. Mitton; Wendelin Dailey; Charlotte Massoll; Kevin Roumayah; Ed Guzman; Noor Tarabishy; Mei Cheng; Kimberly A. Drenser
Investigative Ophthalmology and Visual Science (March 2014)

In the above paper from our Pediatric Retinal Research Lab, we have explored the effects of VEGF-trap on a mouse model used to understand retinal neovascular growth in the premature retina. Many of the most blinding retinal disease in people involve situations that create oxygen starvation in the retina. Once this happens, not only do neural cells of the “Neural Retina” perish, but growth factor concentrations are changed in an attempt to get oxygen to these areas of the retina by triggering growth of more blood vessels into these areas. Elevation of several growth factors are likely contributing to the growth of new vessels, including VEGF or “Vascular Endothelial Growth Factor”. The cells that form the tubular lumen of a blood vessel are called endothelial cells. These cells line the inside of the vessel, and they can respond to VEGF through cell surface receptor proteins (VEGF receptors) that bind the VEGF produced and excreted by other cells. Some VEGF isrequired to keep endothelial cells happy and living. Taking it away completely causes endothelial cells to self destruct. Higher levels of VEGF can help to activate endothelial cells of existing blood vessels to divide and start growing new branches from the pre-existing vessels.

Other non-neural cells of the retina, called glial cells, have the ability to sense the level of oxygen in the retina and if they sense low oxygen then they produce larger amounts of VEGF. In children and adults with diabetic retinopathy, older adults with AMD (Age-related Macular Dystrophy), and pre-mature babies with ROP (Retinopathy of Pre-maturity), regions of the neural retina become starved of oxygen, resulting in the production of higher levels of VEGF. This drives the formation of new blood vessels, a process called neovascularization. While this can bring a blood supply to the area and more oxygen, neovascular growth also results in blood vessels that are not and robust like the blood vessels formed during normal retinal development. When all goes according to plan, normal retinal vessels are completed by the time human babies are born at full-term. When babies arrive pre-maturely, the formation of the blood supply to the neural retina may be partially or mostly incomplete depending on how premature the time of birth.

Human babies get at least one important growth factor for their retinal vasculature from the mother’s blood supply. As blood vessels normally develop by spreading from the optic nerve, near the middle of the retina, toward the periphery of the retina; growth is interrupted and the peripheral retina does not get its badly needed blood supply. However, photoreceptor cells still try to mature and become active for detecting light and they also create a demand for oxygen. This results in glial cells sending out VEGF signals to attract the growth of vessels into the oxygen starved peripheral retina. The new vessels that result can be driven to grown in a rather disorganized fashion, and cells that normally coat the endothelial cells, called pericytes, fail to organize around the neovessels. Thus, the neovessels are weak and tend to be rather leaky. These growing edges of leaky vasculature can leak, clot, form fibers, and contract and tear the retina away from the back of the eye. This process leads to blindless. For different reasons, oxygen starvation can also occur in diabetic retinas and AMD patient’s retinas. Again, elevated VEGF levels can attract neovascular growth, with similar leakiness, fibrosis, retinal edema (fluid based swelling), and loss of retinal fuction (blindness). The discovery of VEGF and its roll in blood vessel growth is rather recent, since the 1990’s, and drugs in the form of antibodies to VEGF were developed to bind and block the action of excess VEGF. At first developed to try to block the formation of blood vessel supplies to tumors, VEGF-blockers or traps have found growing use in treated retinal edema and neovascular growth in AMD and more recently diabetic retinopathy. There is, expectedly, interest in using VEGF-blockers in ROP. However, VEGF is also a growth factor required to grow the normal retinal vasculature and required to keep the mature vasculature stable. Some ophthalmologists around the world have been testing these drugs out in ROP eyes. Unfortunately, we really have no guidance on what the detrimental effects could be of VEGF-traps in the immature premature baby’s eye. This paper from our Pediatric Retinal Research Lab represents some of the first exploration of using a VEGF trap in the mouse oxygen induced retinopathy model. In this popular research model, new born mice develop central areas of retina that loose blood supply, creating oxygen starved retina. Then this creates, in turn, elevation of VEGF and the formation of neovascular growth response. We learn in this paper that the timing of using VEGF-traps is important in premature eyes, because VEGF-traps can also drop the VEGF concentration very low, maybe too low and impede the repair and recovery of the vasculature of a developing retina. Thus, we need to proceed with caution to evaluate use of these drugs in premature baby eyes, even though they are being used quite often now in eyes of elderly adults with AMD.

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