The study, which involved a collaboration among researchers at Eyetech Pharmaceuticals and Schepens Eye Institute at Harvard Medical School, was designed to characterise the role of different VEGF isoforms in inflammation and pathological neovascularisation and utilised three models, retinopathy of prematurity (ROP), laser-induced choroidal neovascularisation (CNV) and delayed-type hypersensitivity (DTH), to examine the pro-inflammatory and angiogenic outcomes in a population of study mice who were VEGF164-deficient, but still had two other VEGF isoforms VEGF120 and VEGF188. VEGF164 is the mouse equivalent of isoform VEGF165 in humans.
Results of the ROP model, which was used to quantify the physiological and pathological neovascularization in the eye, suggest that there were no developmental differences between wild-type mice and those deficient in the VEGF164 isoform.
However, the ROP model showed that pathological neovascularization in the study mice was reduced by 90 per cent compared to wild-type mice, an outcome which the authors attribute to the significant decrease in retinal inflammatory cells, which are known to drive the abnormal angiogenesis in ROP.
Results in the CNV model showed that laser-induced CNV lesions in the eyes of the study mice were 44 per cent smaller than in the wild-type mice. Data from these two models indicate that VEGF164 is not required for normal development of the retina, but instead specifically induces inflammation and pathological neovascularisation, and is more potent in doing so than the other VEGF isoforms.
Data from the DTH model, which was used to measure inflammation and characterise the role of VEGF164 outside of the eye, confirmed that the absence of VEGF164 resulted in a significant decrease in inflammatory response, characterised by leukocyte accumulation and tissue oedema in the ear skin of mice. This response showed that the pro-inflammatory nature of VEGF164 is not isolated to ocular tissues.
The results suggest that specific isoforms may play important roles in neovascular disease in the human eye. Results from the study in mice provide evidence that the presence of a specific isoform called VEGF164 is not required to drive normal vascular development in the retina.
However, by specifically targeting this isoform, there is a reduction in abnormal blood vessel growth (pathological angiogenesis), which results in diseases of the retina.
VEGF and its role in the cause and progression of certain eye diseases such as neovascular age-related macular degeneration (neovascular AMD) have become increasingly important. VEGF is a protein that is responsible for stimulating abnormal blood vessel growth and blood vessel leakage in diseases such as neovascular AMD, diabetic retinopathy and retinal vein occlusion.
"This study provides further evidence that by specifically targeting the pathologic or 'bad' isoform, we can block undesirable blood vessel growth while still permitting the 'good' blood vessel growth and maintenance required for healthy and normal function of the eye," said Anthony Adamis, chief scientific officer of Eyetech.
"Therefore, selective inhibition of pathological forms of VEGF may provide a more optimal balance of safety and efficacy in treating an underlying cause of neovascular AMD," he added.
AMD is a chronic, progressive disease of the macula that results in the loss of central vision. The most common symptoms are a central blurred or blank spot, distortion of objects or simply blurred vision. Peripheral vision usually remains intact. The disease typically affects patients initially in one eye, with a high likelihood of it occurring in the second eye over time.
Because AMD is strongly correlated with aging, we believe that it is likely for the disease to recur, notwithstanding treatment, as the aging process continues. Thus, patients who have been administered the existing therapies for AMD frequently have required additional treatment.
AMD is the leading cause of severe vision loss and blindness in patients over the age of 50 in the developed world. According to the Macula Vision Research Foundation, as many as 15 million people in the United States suffer from some form of AMD, with more than 1.6 million experiencing the active blood vessel growth and blood vessel leakage associated with wet AMD.
In addition, AMD Alliance International reports that approximately 200,000 new cases of wet AMD arise each year in the United States. According to the Centre for Disease Control and Prevention, or CDC, the rate of AMD increases sharply with age, from 18 per cent among people 70-74 years of age to 47 per cent among people 85 years and older.
According to the U.S. census bureau, the number of people in the United States aged 50 or older is approximately 80 million and is expected to increase by approximately 40 per cent over the next two decades. This number is expected to increase in the number of elderly people resulting in a significant increase in the number of cases of AMD in the United States.