Anti-VEGF AAV2 injections: The fewer the better

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Science Translational Medicine  07 Jun 2017:
Vol. 9, Issue 393, eaan4921
DOI: 10.1126/scitranslmed.aan4921


A single intravitreal injection of AAV2 provides sustained delivery of anti-VEGF protein for the treatment of neovascular AMD.

Wet age-related macular degeneration (AMD) is characterized by abnormal blood vessel growth and fluid leakage under the macula, the high acuity center of the retina. As a result of fluid buildup and fibrosis, patients can suffer from central vision loss. Vascular endothelial growth factor (VEGF) is a potent stimulator of blood vessel formation, and injections of anti-VEGF factors can reduce buildup of fluid and rescue vision. However, continuous suppression of VEGF is necessary to retain therapeutic benefit, requiring monthly intraocular injections.

In a recent study Heier et al. report results from a phase I clinical trial administering intravitreal injections of adeno-associated virus type 2 (AAV2) encoding sFLT01, a VEGF-neutralizing protein. Through AAV gene transfer, this treatment has the potential to produce sustained expression, possibly for the lifetime of the patient. Five cohorts of patients were treated with escalating doses of viral vector. The injections were well tolerated, with mild and reversible adverse effects observed in a minority of patients. Increased expression of sFLT01 was observed in intraocular samples taken from patients receiving the highest dose, and this was sustained for 52 weeks after injection. Several patients had a dramatic reduction in fluid under the fovea, the retinal area responsible for sharp central vision, and several patients had an increase in visual acuity. Together, these results indicate the safety of intraocular AAV2 injections for sustained delivery of an anti-VEGF agent and point toward a promising new approach to treating wet AMD.

Importantly, data from this study indicate that the intravitreal route of administration of AAV to the retina is safe and well tolerated. The subset of patients that had increased expression of sFLT01 were patients with low to undetectable levels of neutralizing antibodies against AAV2, suggesting that the presence or absence of anti-AAV2 antibodies is a significant factor in determining the success of the treatment. However, one patient without anti-AAV2 antibodies who received the highest vector dose did not express the transgene at detectable levels, indicating that other factors are also likely in play. Although it is impossible to draw definitive conclusions from this study due to the inclusion of only 19 patients, these results lay important groundwork for future AAV-mediated anti-VEGF treatments for AMD, as well as other gene therapies for other retinal degenerations.

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