Expert Consensus on Characteristics, Etiology, and Management of Chorioretinal Atrophy in Patients Treated with Voretigene Neparvovec

Voretigene neparvovec (VN), developed for the treatment of inherited retinal dystrophy (IRD) associated with confirmed biallelic RPE65 mutations (RPE65-IRD), is the first approved retinal gene therapy. Recently, reports have emerged of chorioretinal atrophy (CRA) developing in a subset of patients treated with VN. Although researchers have started to investigate the etiology, detection, classification, and clinical course of CRA after treatment with VN, information gaps remain. Here, we review current data on CRA in patients treated with VN, propose standardized terminology for describing CRA, and provide guidance on the management of CRA in patients treated with VN.

Review of the scientific literature and expert consensus.

An international group of experts in IRD with experience treating with VN.

A literature search of PubMed was performed using broad search terms to return all publications relating to VN, which were manually screened for relevance to CRA. The expert panel discussed the literature and proposed updated consensus nomenclature and suggestions for monitoring.

According to most reports, development of CRA does not impact visual and functional outcomes after subretinal VN injection. Longer follow-up is needed to ascertain whether CRA continues to enlarge and whether treatment outcomes can be maintained. Chorioretinal atrophy growth might be caused by a combination of multiple factors, and several hypotheses on CRA etiology based on published clinical evidence are discussed. Standard terminology and metrics for CRA would support these future research efforts. We propose using the term "injection site CRA" to refer to CRA which develops specifically at the location where the cannula touches down onto the retina. For all other CRA, we propose defining atrophy based on its retinal localization, as either "central CRA" or "peripheral CRA." Regular follow-up visits using a combination of imaging modalities with efficacy readouts are recommended to track efficacy and adverse outcomes, including CRA.

Numerous questions remain regarding causes of CRA in RPE65-IRD treated with VN, which will require further clinical experience and research to answer. Here we propose terminology and key metrics for monitoring CRA to support such future efforts.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.