{"doi":"10.3389/fncel.2022.916065","title":"Commentary: Current Status of Gene Therapy for Spinal Muscular Atrophy","abstract":"Spinal muscular atrophy (SMA) is a genetic disease of a broad spectrum of severity, ranging from infant mortality to adult onset (Singh et al., 2021). SMA results from low levels of Survival Motor Neuron (SMN) protein due to deletions or mutations of the SMN1 gene (Wirth et al., 2020). SMN2, a nearly identical copy of the SMN1 gene, fails to compensate for the loss of SMN1 due to a single nucleotide change in a splice site that causes predominant skipping of exon 7 (Wirth et al., 2020). Correction of SMN2 exon 7 splicing by nusinersen, an antisense oligonucleotide (ASO), became the first approved therapy for SMA in 2016 (Singh N. N. et al., 2017). Onasemnogene (Synonyms: Onasemnogene abeparvovec, Zolgensma, AVXS-101), an adeno-associated virus serotype 9 (AAV9)-mediated gene therapy was approved in 2019 for the treatment of SMA (Al-Zaidy et al., 2019). Risdiplam was approved in 2020 as the first orally deliverable small molecule therapy for SMA (Singh et al., 2020b). These developments constitute unparalleled success for the treatment of an orphan disease. Like nusinersen, risdiplam promotes exon 7 inclusion from the endogenous SMN2 gene, which is universally present in SMA patients (Singh N. N. et al., 2017; Singh et al., 2020a). However, unlike nusinersen that is administered intrathecally at the interval of several months, daily oral administration of risdiplam is required for the intended therapeutic benefits. Gene therapy, on the other hand, does not depend upon the availability of endogenous SMN2 and is conceptually suited to provide the sustained source of SMN upon a single systemic administration (Al-Zaidy et al., 2019). A general challenge for SMA therapy is the irreparable loss of motor units that cannot be restored due to delayed administration of the drug and has led to the addition of SMA to the Recommended Uniform Screening Panel (RUSP) for newborn screening programs. Here we discuss recent reports underscoring the challenges associated with gene therapy. We also propose strategies to improve the future gene therapy-based approaches for an effective and risk-free treatment of SMA.","journal":"Frontiers in Cellular Neuroscience","year":2022,"id":298242,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":125499,"name":"Ravindra N Singh","orcid":"0000-0001-5399-2662","position":1,"is_corresponding":false},{"id":301313,"name":"Wilfried Rossoll","orcid":"0000-0002-9622-541X","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-19T00:31:36.269611Z","pmid":"35656408","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":[]}