Purpose: To review barriers to effective transduction of cells in the subretinal plane during gene therapy surgery for inherited retinal dystrophies (IRD). Design: Perspective. Methods: Case-based learning in clinical trials and commercial applications of gene therapy in a tertiary care, university-affiliated hospital. MEDLINE search for publications relevant to retinal surgical technique for gene therapy, clinical trials results for gene therapy of IRD, adenoviral-associated viral vector design, and immune response to viral vectors. Results: The most important surgical issues are safe access to the subretinal space, intraoperative visualization with optical coherence tomography to protect the macula, and quantitation of viral dose. Other issues for retinal surgeons are patient selection, target zone planning, and control of inflammation. Vector-related issues that may affect the precision of treatment involve capsid interaction with the innate and adaptive immune systems and selective targeting of cell types. Conclusions: Most current gene therapy vectors for monogenic IRD require physical proximity to target tissues under the retina in order to work. New surgical skills and new instrumentation are under development. So far, the host immune response does not seem to cause rejection of genes delivered by viral vectors but the efficiency of transduction can only be indirectly assessed by long-term visual outcomes.
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