{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:47:17Z","timestamp":1788875237794,"version":"build-2803163510"},"reference-count":65,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hemophilia, an X-linked recessive bleeding disorder, results from mutations in the F8 or F9 genes, leading to factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency. While conventional treatment relies on regular factor replacement therapy, gene therapy has emerged as a promising alternative, offering the potential for sustained endogenous factor production after a single administration. This review provides an in-depth analysis of recent advances in gene therapy for both hemophilia A and B, with a focus on AAV-mediated liver-directed approaches and other approved modalities. Key limitations\u2014such as vector immunogenicity, hepatic toxicity, waning transgene expression, and limited re-dosing capacity\u2014are discussed. Additional gene delivery platforms, including lentiviral and retroviral vectors, genome editing techniques (e.g., CRISPR\/Cas9), and non-viral systems like transposons and lipid nanoparticles, are also examined. Although gene therapy for hemophilia B demonstrates greater clinical durability, hemophilia A presents unique challenges due to factor VIII\u2019s size, poor expression efficiency, and the need for higher vector doses. Future efforts will focus on overcoming immune barriers, improving delivery technologies, and developing approaches suitable for pediatric patients and individuals with pre-existing immunity. This review provides not only a descriptive overview but also a critical comparison of gene therapy approaches for hemophilia A and B. We emphasize that the durability of response is currently superior in hemophilia B, whereas hemophilia A still faces unique barriers, including declining FVIII expression and higher immunogenicity. By analyzing cross-platform challenges (AAV, lentiviral, CRISPR, and emerging LNPs), we highlight the most promising strategies for overcoming these limitations and provide a forward-looking perspective on the future of gene therapy.<\/jats:p>","DOI":"10.3390\/genes16101200","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T10:37:14Z","timestamp":1760438234000},"page":"1200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["How Close Are We to Achieving Durable and Efficacious Gene Therapy for Hemophilia A and B?"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4714-6501","authenticated-orcid":false,"given":"Patrycja","family":"Sosnowska-Sienkiewicz","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Medical University of Warsaw, \u017bwirki i Wigury 63A Street, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2332-2750","authenticated-orcid":false,"given":"Danuta","family":"Januszkiewicz-Lewandowska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","unstructured":"Salen, P., Babiker, H.M., and Hemophilia, A. (2025, August 31). StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK470265\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1056\/NEJMoa2410597","article-title":"Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A","volume":"392","author":"Srivastava","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_3","first-page":"e11216","article-title":"Skewed Inactivation of X Chromosome: A Cause of Hemophilia Manifestation in Carrier Females","volume":"12","author":"Shoukat","year":"2020","journal-title":"Cureus"},{"key":"ref_4","unstructured":"Mehta, P., and Reddivari, A.K.R. (2025, August 31). 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