Bypassing pre-existing antibodies extends the applicability of AAV-based retinal therapies

The field of retinal gene therapy is undergoing a revolutionary transformation, as underscored by a groundbreaking study recently published in Molecular Therapy. This study sets a new precedent by successfully demonstrating the in vivo efficacy of innovative AAV capsid variants in a non-human primate (NHP) model, specifically the crab-eating macaque. 1 Kellish P.C. Marsic D. Crosson S.M. Choudhury S. Scalabrino M.L. Strang C.E. Hill J. McCullough K.T. Peterson J.J. Fajardo D. et al. Intravitreal injection of a rationally designed AAV capsid library in non-human primate identifies variants with enhanced retinal transduction and neutralizing antibody evasion. Mol. Ther. 2023; 31: ▪▪▪-▪▪▪https://doi.org/10.1016/j.ymthe.2023.10.001 Abstract Full Text Full Text PDF Scopus (0) Google Scholar Using an approach of directed evolution to overcome the retinal barrier (for example, the inner limiting membrane 2 Dalkara D. Kolstad K.D. Caporale N. Visel M. Klimczak R.R. Schaffer D.V. Flannery J.G. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol. Ther. 2009; 17: 2096-2102 Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar ) has the potential for developing more efficient administration methods of AAV-mediated gene therapy and was made possible with the combined expertise and experience of the investigative team. These findings will directly impact the way retinal gene therapies are administered, transforming an invasive subretinal surgery into a simple outpatient procedure. The intravitreal target may allow a far better distribution of the AAV over the entire surface of the retina. Current subretinal blebs cover only a quarter or a third of the retina, meaning only a small fraction of the retina is treated. 3 Nuzbrokh Y. Kassotis A.S. Ragi S.D. Jauregui R. Tsang S.H. Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review. Ophthalmol. Ther. 2020; 9: 709-724 Crossref PubMed Scopus (0) Google Scholar The relevance of the NHP model cannot be overstated, as its retina closely mimics human physiology, 4 Moshiri A. Chen R. Kim S. Harris R.A. Li Y. Raveendran M. Davis S. Liang Q. Pomerantz O. Wang J. et al. A nonhuman primate model of inherited retinal disease. J. Clin. Invest. 2019; 129: 863-874 Crossref PubMed Scopus (60) Google Scholar providing an invaluable preview into the potential clinical applicability of these novel variants.