The emerging platform of viral gene therapy could be harnessed to create a lasting treatment for wet AMD, according to research from a team at Johns Hopkins University School of Medicine.
Published online in The Lancet, the phase I trial assessed the safety and tolerability of an AAV2 vector containing the gene for sFLT01, a novel fusion protein designed to neutralize the angiogenic activity of vascular endothelial growth factors (VEGFs).
The team administered a single injection of viral particles in escalating doses to 19 subjects with advanced neovascular AMD. All study eyes had baseline best-corrected visual acuity (BCVA) of 20/100 or less and were deemed by a retina specialist as unlikely to regain vision from conventional treatments.
The first cohort of 3 patients received an intravitreal injection of 2 × 108 AAV2-sFLT01 vector genomes (VG) in 0.05 cc of fluid, and were observed for 4 weeks for possible adverse reactions prior to initiation of the next, higher dose. This was repeated for each subsequent dose group: 2 × 109 VG, 6 × 109 VG, and 2 × 1010 VG (3 patients each). Finally, an additional 7-patient group also received the maximum 2 × 1010 VG dose. All subjects were followed for 52 weeks.
Only 2 patients, both from the first 2 × 1010 VG group, displayed possible treatment-related adverse effects, namely pyrexia and intraocular inflammation, which resolved with a topical steroid.
"Even at the highest dose, the treatment was quite safe,” said senior author Peter Campochiaro, MD, a professor of ophthalmology at Johns Hopkins. “We found there were almost no adverse reactions in our patients."
Out of the 19 patients, 11 were judged at enrollment to have reversible intraretinal or subretinal fluid. Following treatment, 4 showed near-complete fluid resolution and substantial improvement in vision, in line with an ideal outcome for a patient with less severe disease receiving standard treatment. Two additional subjects showed partial decrease in fluid by study end, yet 5 showed no fluid reduction.
Analysis of baseline serum samples showed that these 5 patients had pre-existing antibodies towards the AAV2 vector, perhaps explaining why they did not respond to treatment. Unfortunately, exposure to viruses in the adeno-associated genus is common; an estimated 50% or more of adults harbor anti-adenoviral neutralizing antibodies (NAb). Many previous attempts to exploit the AAV2 vector—ideal due to its lack of inherent pathogenicity—have also been hampered by the immune system eradicating the particles before they can transduce sufficient cells.
However, because the eye is an immune-privileged organ, many researchers believe that diseases such as AMD are ideal candidates for gene therapy platforms that might not work elsewhere in the body. "The numbers are small and simply show a correlation, so we don't know if serum antibodies are definitely an impediment, but more work is needed to determine this,” said Dr. Campochiaro in a Johns Hopkins press release.
"This preliminary study is a small but promising step towards a new approach that will not only reduce doctor visits and the anxiety and discomfort associated with repeated injections in the eye, but may improve long-term outcomes because prolonged suppression of VEGF is needed to preserve vision,” he concluded, “and that is difficult to achieve with repeated injections because life often gets in the way."