Coats' and VEGF therapy


This is a recently updated link that gives a status of all anti-angiogenic drugs being tested for Age Related Macular Degeneration. It is not clear whether or not any of these drugs would help children with Coats' disease.


VEGF (Vascular Endothelial Growth Factor) is a secreted protein that assists in the development of new blood vessels. Blocking the VEGF protein is beneficial in a number of diseases. In eye diseases such as ROP (Retinopathy of Prematurity) or Wet AMD (Age Related Macular Degeneration),  anti-VEGF drugs such as Avastin, Lucentis or Macugen help to block the growth of new blood vessels, and can prevent the progression of the disease. In many cases, vision can actually be improved with timely and effective treatment.  VEGF drugs can also be beneficial in the treatment of some cancers. The theory is that if you cut off the development of new blood vessels, you "starve" the tumor and prevent the spread of the disease. Avastin is an example of one of the cancer drugs.

We have always wondered whether or not anti-VEGF drugs might be an effective treatment for Coats' disease. In fact, there is one anti-angiogenesis drug in clinical trials now for Coats' disease called Retaane (anecortave acetate). The trial will only accept patients over 18, which is way too late for most Coats' patients. We talked to the lead investigator of the trial, and he would not administer the drug to Jake because of his age and his prior surgeries. Some testing in animal models suggests that anti-VEGF drugs would work differently on children than they do on adults. Fears of very serious side effects were raised, and there is a lot of resistance to testing these drugs on children Jake's age. The Medscape article below gives a both a history of and a forward look at VEGF drugs, so you can get a sense of the possibilities and the barriers. While we have heard of rare cases where drugs such as Avastin have been tried on young children with Coats' disease, we are not aware of the results in those cases.

The posting of this article is purely for informational purposes. We are not suggesting that this therapy is safe or recommended for children.



VEGF-Targeted Therapy for Ocular Disease: Past, Present, and Future

Posted 02/23/2006

Ivana K. Kim, MD; Joan W. Miller, MD 

Recent advances in the treatment of age-related macular degeneration (AMD) represent the culmination of over a decade of research into the mechanisms of ocular angiogenesis. The field of angiogenesis arose from early observations of increased vascularity associated with the growth of tumors. The existence of secreted factors that could promote growth of blood vessels was first proposed by Ide and colleagues in 1939, stemming from studies of vascular development accompanying the growth of transplanted rabbit epithelioma. Similarly, in 1948, Michaelson suggested that a diffusible "Factor X" from the retina stimulated the retinal and iris neovascularization seen in diabetic retinopathy. However, many years passed before the isolation and identification of such proposed angiogenic factors could be achieved.

Discovery of Vascular Endothelial Growth Factor

Judah Folkman presented the idea of inhibiting angiogenesis as a means of treating cancer in 1971 and spearheaded the efforts to discover tumor angiogenesis factors. The identification of one of the key mediators of angiogenesis happened in 1983 when Senger, Dvorak, and colleagues discovered a protein secreted from a guinea-pig tumor cell line that was a potent inducer of vascular leakage and named it vascular permeability factor (VPF). In 1989, Napoleone Ferrara and colleagues identified a molecule in the conditioned media from bovine pituitary follicular cells that promoted the proliferation of endothelial cells; they called it vascular endothelial growth factor (VEGF). Ultimately, the cloning of VPF by Daniel Connelly and others and VEGF by Ferrara's group demonstrated that the 2 factors were the same protein.

Further characterization of VEGF revealed the presence of at least 4 active human isoforms, produced by alternative splicing, consisting of 121, 165, 189, and 206 amino acids. VEGF and VEGF are diffusible forms, although VEGF retains heparin-binding ability. The other, longer isoforms remain bound to extracellular matrix. VEGF is the predominant form and possesses greater mitogenic activity. Some recent work in rodent models suggests that this isoform is the primary mediator of pathologic neovascularization. Two tyrosine kinases serve as VEGF receptors, VEGFR-1 (fms-like tyrosine kinase 1, flt-1) and VEGFR-2 (kinase domain region, KDR or fetal liver kinase, flk-1). VEGFR-2 appears to play the major role in signaling the mitogenic, angiogenic, and permeability effects of VEGF.




VEGF as a Mediator of Ocular Neovascularization

In 1992, two independent groups demonstrated that hypoxia could upregulate VEGF expression. It had long been appreciated that neovascularization of the retina and iris was temporally and spatially correlated with retinal ischemia due to various etiologies, and the property of hypoxia inducibility made VEGF a plausible candidate for the "Factor X," proposed by Michaelson as the mediator of abnormal blood vessel growth in the eye.

Evidence from both clinical and animal studies accumulated in the next several years to support the critical role of VEGF in ocular neovascularization. VEGF expression was shown to be correlated with iris neovascularization in a primate model of ischemic retinal vein occlusion. A similar correlation was demonstrated in a neonatal mouse model of retinal neovascularization.Additionally, injection of VEGF in normal primate eyes produced iris neovascularization, neovascular glaucoma, and retinal microangiopathy. Inhibition of VEGF through the use of chimeric proteins acting as soluble VEGF receptors in the mouse model of retinal neovascularization and neutralizing antibodies in the primate model of iris neovascularization effectively suppressed neovascularization in both systems.

Human clinical studies also confirmed the association of VEGF expression with pathologic ocular neovascularization. Measurements of vitreous VEGF levels demonstrated significantly higher VEGF concentrations in patients with active proliferative diabetic retinopathy compared with patients with other retinal disorders not characterized by abnormal blood vessel growth. Another study that analyzed both aqueous and vitreous levels of VEGF in a variety of conditions characterized by ocular neovascularization correlated elevated VEGF concentrations in ocular fluids of patients with active neovascularization. This study also demonstrated reduction of VEGF levels after panretinal photocoagulation for retinal neovascularization.



VEGF in Choroidal Neovascularization

Such early studies clearly defined the critical role of VEGF in retinal and iris neovascularization. Although hypoxia is not clearly a stimulus for the development of choroidal neovascularization (CNV), VEGF does appear to function in CNV formation. Overexpression of VEGF through gene transfer using viral vectors induces CNV in rat and primate models. Microspheres containing VEGF also promote CNV when implanted into the subretinal space of primates. Additionally, increased VEGF expression has been demonstrated in rodent and primate models of laser-induced CNV. Blockade of the VEGF pathway using monoclonal antibodies in the primate model of laser-induced CNV and kinase inhibitors in a mouse model  prevents CNV formation. This type of experimental data is also supported by clinical evidence demonstrating the presence of VEGF in choroidal neovascular membranes removed from patients with neovascular AMD.



Anti-VEGF Therapy

The strong supportive evidence from animal studies defined VEGF as an optimal therapeutic target for treatment of ocular diseases in which neovascularization leads to blindness. The need for better treatments for neovascular AMD, a leading cause of blindness in individuals over age 50 years, provided the opportunity to develop anti-VEGF agents for clinical use. While regression of retinal neovascularization due to proliferative diabetic retinopathy and ischemic retinal vein occlusion can, in most cases, be successfully achieved with laser photocoagulation, laser treatment for subfoveal CNV due to AMD is suboptimal due to the inevitable destruction of the foveal retina. The introduction of photodynamic therapy (PDT) in 2000 offered the first selective treatment for CNV, allowing for closure of choroidal neovascular membranes with relative sparing of the overlying retina. However, the visual results left room for improvement.

Pegaptanib emerged as the first antiangiogenic agent with proven efficacy in clinical trials for neovascular AMD. It is a modified 28-base RNA aptamer that selectively binds VEGF165. The efficacy of pegaptanib in preventing moderate vision loss from subfoveal CNV due to AMD was demonstrated by the VEGF Inhibition Study in Ocular Neovascularization (VISION), which showed a treatment benefit across all lesion subtypes and sizes (up to 12 disc areas). The proportion of patients who avoided moderate vision loss at 1 year was 70% in the pegaptanib-treated group vs 55% in the control group. The number of patients who gained 3 or more lines of vision was small: 6% in the pegaptanib group vs 2% in the control group. Although treatment with pegaptanib required repeated intravitreal injections every 6 weeks for the entire year, no significant safety concerns emerged, with low rates of endophthalmitis (1.3%), traumatic lens injury, and retinal detachment (0.6%). The US Food and Drug Administration approval of pegaptanib for the treatment of AMD in December 2004 marked the advent of anti-VEGF therapy for ocular disease. The era of antiangiogenic treatment for cancer had been launched only months earlier in February 2004, with the approval of bevacizumab, a monoclonal antibody against VEGF, for the treatment of metastatic colorectal cancer.

More recently, ranibizumab, a humanized monoclonal antibody fragment against VEGF related to bevacizumab, has also proven efficacious in the treatment of subfoveal CNV due to AMD. It differs from pegaptanib in that it binds to all VEGF isoforms. One-year results of phase 3 clinical trials demonstrated a treatment benefit for patients with minimally classic and occult CNV receiving ranibizumab. After 1 year, 95% of patients treated with ranibizumab avoided moderate vision loss compared with 62% of the control group. The most exciting aspect of the results was the observation that a significant proportion of patients experienced visual improvement of 3 lines or more: 25% to 34% in the ranibizumab groups compared with 5% in the control group.

In a more recent study, ranibizumab appeared similarly efficacious for predominantly classic lesions, and superior to PDT. One-year results showed that 94% (0.3 mg) and 96% (0.5 mg) of patients treated with ranibizumab avoided moderate vision loss compared with 64% of patients treated with verteporfin PDT. Again, the finding of average visual improvement in the ranibizumab groups compared with average visual loss in the PDT group was a landmark in treatment for AMD and proves encouraging for the future of anti-VEGF therapy.



Future Directions

The early experience with pegaptanib and ranibizumab has validated VEGF as a target in the treatment of ocular neovascularization. The use of anti-VEGF therapy in ocular conditions characterized by abnormal vascular permeability resulting in vision-limiting macular edema is also being investigated, as are other strategies for VEGF inhibition. RNA interference is a powerful technology for silencing the expression of selected genes, and its application to VEGF inhibition for ocular disease is under way. Two different short interfering RNA molecules, one directed against VEGF[34] and the other against VEGFR-1,[35] are currently in clinical trials. VEGF Trap is a molecule that contains immunoglobulin domains of both VEGFR-1 and VEGFR-2 fused to the constant region of human immunoglobulin G.[36] It functions as a high-affinity soluble receptor that binds and neutralizes both VEGF and placental growth factor, which is another member of the VEGF family that may play a role in CNV. Phase 1 trials of VEGF Trap administered systemically in patients with neovascular AMD have been completed, and trials involving intravitreal delivery are planned.[37]

The early success with anti-VEGF therapy for neovascular AMD is encouraging. However, the effects of long-term VEGF blockade in the eye will require monitoring. The constitutive expression of VEGF and its receptors in normal adult retina and choriocapillaris[38] suggests that it plays a role in the survival of neuronal as well as vascular elements, and evidence supporting the neuroprotective effects of VEGF continues to emerge.[39]

More than 3 decades after Folkman first proposed antiangiogenic therapy for cancer, the strategy has proven valuable in the treatment of blinding eye conditions. VEGF is only the first of many potential targets, and the continued development of other agents promises future combination therapies that may provide greater and sustained visual improvement. Additional advances in drug delivery will facilitate long-term intraocular delivery of such molecules, further enabling better and safer treatments.

Funding Information

Supported by an independent educational grant from Genentech.


Ivana K. Kim, MD, Instructor, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Staff Physician, Retina Service, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts

Joan W. Miller, MD, Henry Willard Williams Professor of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Chairman of Ophthalmology, Massachusetts Ear and Eye Infirmary, Boston, Massachusetts