Progress in anti-VEGF gene therapy for age-related macular degeneration

Age-related macular degeneration (AMD) is one of the most common disease of the retina and the main cause of vision loss in adults over 60 years. It is estimated that 3 million people worldwide are affected, and its incidence increases as life expectancy grows in developed countries.

AMD is a progressive disease that affects the macula, the area near the centre of the retina responsible for colour vision and visual acuity. Its most aggressive form, wet AMD (also known as exudative or neovascular AMD), is characterized by the abnormal growth of blood vessels in the retina that leak fluid or blood under the retina causing vision loss.

The current standard treatment for wet AMD is intravitreal injections of anti-angiogenic drugs, such as bevacizumab and ranibizumab, which block the growth of new blood vessels. Both are monoclonal anti-VEGF antibodies that selectively bind vascular endothelial growth factor (VEGF), needed for vessel growth. These drugs prevent vision loss in patients with wet AMD, but to be effective periodical treatments must be administered with intraocular injections every 4 to 12 weeks.

Two US biotechnology companies, Regenxbio and Adverum Biotechnologies, have developed single dose gene therapies to prevent multiple intraocular injections of anti-VEGF antibodies in patients with wet AMD. The therapies are based on a modified virus containing a segment of DNA that encodes an antibody fragment designed to inhibit VEGF, which is administered by a single intravitreal injection. The aim being that retinal cells will synthesize anti-VEGF antibodies and patients would not have to be treated with periodical injections. Currently, these therapies are being evaluated in phase 1/2 clinical trials.

Regenxbio therapy, named RGX-314, has shown sustained effects over two years after administration with good tolerance at different doses. Visual acuity is improved, and retinal thickness is maintained in the treated patients. In the group of patients with a follow-up of over two years, the number of anti-VEGF injections required was also reduced, and in half of them (3/6) no further injections were required. In another group of patients, with follow-up data between 9 months and 2 years, 67% of them (4/6) did not require additional injections.

Adverum Biotechnologies therapy, named ADVM-022, is being investigated in several groups of patients; and long-term effects of the therapy have been shown in patients treated with the highest dose: 100% of patients (6/6) did not need anti-VEGF injections one year after this therapy.

The results of the two gene therapies are very promising because a reduction in anti-VEGF injections would greatly reduce their damaging side effects. Additionally, a similar gene therapy could be used developed to treat chronic retinal diseases whose treatment is also based on anti-VEGF antibodies, such as diabetic retinopathy. In this regard, Adverum plans to start a phase 2 clinical study with patients with diabetic retinopathy later this year.

Image: A fundus photograph showing intermediate age-related macular degeneration (National Eye Institute, National Institutes of Health via Wikimedia Commons).

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