{"doi":"10.1101/2025.11.28.688728","title":"AAV-mediated generation of neurons in injury-induced and inherited retinal degenerations","abstract":"Abstract Loss of retinal neurons is a leading cause of irreversible vision impairment, yet adult mammalian retinas lack the ability to regenerate these cells. In this study, we developed an adeno-associated virus (AAV)-based strategy to reprogram endogenous Müller glia into retinal neurons. Using stringent genetic lineage tracing, immunohistochemistry, electrophysiology and single-cell multiomic profiling, we show that AAV delivery of a stabilized, phospho-insensitive Neurogenin2 variant (Neurog2-9SA) efficiently converts Müller glia into multiple types of retinal neurons, including bipolar, starburst amacrine, and a small population of photoreceptor-like cells, in both injury-induced and inherited retinal degeneration models. The generated neurons exhibit electrical properties of retinal neurons, light-evoked responses and integrate into existing retinal circuitry. Single-cell multiomics analysis reveal that Neurog2-9SA induces reprogramming by remodeling chromatin accessibility, activating neurogenic transcriptional networks, and represses glial identity programs. Inhibiting Notch signaling markedly enhances reprogramming efficiency. Together, these findings establish Neurog2-9SA as a potent and clinically relevant factor for AAV-mediated reprogramming and provide a foundation for approaches to regenerate neuronal cells and restore function in retinal diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559612,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9445,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1461442,"name":"Sherine Awad","orcid":null,"position":1,"is_corresponding":false},{"id":1461443,"name":"Amelia Chung","orcid":null,"position":2,"is_corresponding":false},{"id":1460877,"name":"J Dang","orcid":"0000-0001-8550-087X","position":3,"is_corresponding":false},{"id":1461444,"name":"Madelyn Chong","orcid":null,"position":4,"is_corresponding":false},{"id":431258,"name":"Zachary Flickinger","orcid":null,"position":5,"is_corresponding":false},{"id":772345,"name":"Kwoon Y. Wong","orcid":"0000-0001-9279-7827","position":6,"is_corresponding":false},{"id":813023,"name":"Thanh Hoang","orcid":"0000-0003-1142-0935","position":7,"is_corresponding":false},{"id":1432485,"name":"Meng-Ling Yang","orcid":"0000-0002-4141-9049","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:55:34.849815Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}