Molecular biology insights bring new treatments to fore

By Dan Keller

WASHINGTON, DC — A new understanding of the molecular biology of the retinal vascular defects associated with ROP should lead to new treatment approaches for the disease.
Speaking at a seminar of the Research to Prevent Blindness Foundation, Lois Smith MD, PhD described her research indicating that the level of insulin-like growth factor-1 (IGF-1) in the body appears to be a key regulator of vessel growth, acting through vascular endothelial growth factor (VEGF).
The research shows that blood vessel growth depends on both molecules. The still-developing eye of premature infants lacks the IGF-1 normally provided by the placenta and the amniotic fluid.

Vessel growth stops and developing structures in the eye become starved of oxygen, sending out signals to increase VEGF. But in vivo experiments demonstrated that VEGF will not cause normal retinal vascular growth without IGF-1.
As an infant’s organs mature, levels of IGF-1 rise. Suddenly, vessels form under the influence of the existing VEGF. The result is neovascular proliferation that can lead to blindness. She proposed that maintaining IGF-1 at levels found in utero would prevent the abnormal retinal vascular development and other complications.

In premature infants, retinal vessel development is interrupted. The area of a peripheral avascular zone depends on gestational age. In the first phase of ROP, normal vascular development ceases and some existing vessels are lost. As the infant develops, the retina becomes more metabolically active, with resulting hypoxia.
In the second phase of ROP, around 34 weeks of post-menstrual age, neovascularisation occurs at the blunted vessels near the boundary of the avascular zone.
VEGF expression in the avascular, hypoxic zone causes new vessels to grow into the area. This neovascularisation is similar to other proliferative retinopathies, such as in diabetes.

The new vessels may be leaky, leading to fibrin deposition under the retina. As the fibrin contracts, retinal detachment can occur.
In a mouse model, Dr Smith found that blocking VEGF synthesis with an antisense oligonucleotide, or blocking the VEGF receptor with an antibody, prevented neovascularisation.
She and her colleagues also found that VEGF is elevated in the vitreous of patients with neovascular eye disease, including diabetic retinopathy and proliferative retinopathy in ROP.

The problem of VEGF as a therapeutic target is that it is also necessary for normal vascular development in the retina and elsewhere, and it may also be needed for normal vessel maintenance. So, Dr Smith looked for other growth factors related to ROP and to diabetic retinopathy.
Low levels of IGF-1 are related to prematurity itself and as the infant’s body matures, it produces more IGF-1 in the liver under the influence of the pituitary growth hormone. Maximal induction of new vessel growth mediated by VEGF in Phase II of ROP requires IGF-1.

Lack of IGF-1 is implicated in the first phase of ROP. After the birth of a premature infant, its IGF-1 level drops below in utero levels because the chemical is no longer supplied by the placenta and amniotic fluid.
So normal retinal vessel development can not proceed in the early neonatal period, leading to an area of avascular retina and then to proliferative ROP. Knocking out the IGF-1 gene in mice produced similar effects.

These results suggested to Dr Smith that restoring IGF-1 to uterine levels may be therapeutic since it is a lack of IGF-1 that causes Phase I of ROP to occur.
IGF-1 levels rise rapidly in utero in the third trimester but they rise only slowly as the premature neonate’s liver develops after birth. Dr Smith found that infants with ROP had lower mean levels of IGF-1 compared to gestational age-matched infants without ROP.
“If we can increase IGF-1 to the normal in utero levels, we believe we can then allow normal blood vessel growth to proceed and therefore prevent Phase II from occurring,” she noted.

Unfortunately, Dr Smith said pharmaceutical companies are reluctant to do trials of IGF-1 for ROP because of liability issues of testing in neonates as well as the small profits to be made – only very small amounts of drug will be needed to treat an infant.
“Dr Smith's work is a significant breakthrough, redefining the disease as a disease of an immature liver in an immature fetus struggling to live outside the womb when it should be in the womb and moving it away from the concept that it’s basically an eye disease,” Dwight Cavanagh MD, PhD remarked.

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