There are advantages to the subretinal space compared to an intravitreal injection in gene therapy, Dr. Kiss said.
For instance, subretinal delivery allows for the best expression, meaning broader coverage and a higher protein expression. Subretinal delivery does appear to be safe, as has been shown in several neovascular AMD trials, Dr. Kiss said.
“It would be great if we could do this intravitreally in our offices,” he added. “However, pre-existing antibodies present in 70% of patients may prevent that”–noting the technique is more invasive than injections and requires a surgical procedure.
Moreover, there is “up to 1,000-fold less expression when you give gene therapy via an intravitreal injection,” Dr. Kiss said. “That’s been shown in non-human primates.”
Dr. Kiss explained that is due to limited transduction–intravitreal injection only transduces cells in the fovea due to the internal limiting membrane that acts as a barrier for further dissemination.
Pre-existing adeno-associated viral vector (AAV) neutralizing antibodies may neutralize any gene therapy being delivered via intravitreal injection, Dr. Kiss said.
“Those pre-existing neutralizing antibodies may block transduction and limit therapeutic usefulness,” he added. “This is true even if you’re delivering the best molecule.”