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This review examines gene therapy approaches that correct or modify hematopoiesis, highlighting lentiviral vector addition and CRISPR-Cas9 editing and the need to reassess HSC biology and the bone marrow microenvironment. It summarizes clinical applications and details how defective HSC–niche networks and culture or electroporation stresses affect stemness, clonogenicity, and persistent outcomes.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/gene-therapy-for-hemoglobinopathies-clinical-trial-results-and-biology-of-hematopoietic-stem-cell-and-the-bone-marrow-niche/433917/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/gene-therapy-for-hemoglobinopathies-clinical-trial-results-and-biology-of-hematopoietic-stem-cell-and-the-bone-marrow-niche/433917.png","ImageObject",300,407,{"name":92,"@type":93},"Levi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-09","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What hemoglobinopathies are discussed in this review?","Question",{"text":113,"@type":114},"The review focuses on beta-thalassemia and sickle cell disease as major inherited hemoglobin disorders.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which gene therapy strategies are covered?",{"text":118,"@type":114},"It covers gene addition using lentiviral vector-engineered cells and gene editing using CRISPR-Cas9.",{"name":120,"@type":111,"acceptedAnswer":121},"Why is HSC biology and the bone marrow niche important after clinical gene therapy success?",{"text":122,"@type":114},"Success of these approaches motivates a critical revision of knowledge about HSC biology and the bone marrow microenvironment that supports genetically corrected cells.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},433917,1790918887,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},7971461740909,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","ll  \nOPEN ACCESS  \nReview  \nGene therapy for hemoglobinopathies: Clinical trial results and biology of hematopoietic stem cell and the bone marrow niche  \nAnnamaria Aprile,1,3 Maria Rosa Lidonnici,1,3 and Giuliana Ferrari1,2,*  \n1San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy  \n2University Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy  \n3These authors contributed equally  \n*Correspondence: [ferrari.giuliana@hsr.it](ferrari.giuliana@hsr.it)[ ](ferrari.giuliana@hsr.it)[https://doi.org/10.1016/j.xcrm.2025.102419](https://doi.org/10.1016/j.xcrm.2025.102419)  \nSUMMARY  \nHemoglobinopathies, including beta-thalassemia (Bthal) and sickle cell disease (SCD), are among the most prevalent inherited blood disorders. Genetic mutations affecting hemoglobin synthesis result in severe anemia and multi-organ complications. The development of gene therapy (GT) aimed at correcting or modifying the hematopoietic system, although initially impaired by several limitations, has accomplished the marketing authorization of two hematopoietic stem cell (HSC) medicinal products, engineered by lentiviral vector gene addition and by CRISPR-Cas9 gene editing. Nonetheless, the success of these approaches stimulates a critical revision of our knowledge of HSC biology and bone marrow (BM) microenvironment in these diseases. Here, we review the clinical application of GT by gene addition and gene editing, and the novel findings about HSC and BM niche features and function in hemoglobinopathies. The identification of defective networks in HSC-niche is examined with the perspective of developing combined strategies to ameliorate the BM microenvironment to better support the genetically corrected cells.  \nINTRODUCTION  \nThe most consolidated approach for clinical gene therapy (GT) of hemoglobinopathies derives from almost two decades of basic research and pivotal clinical trials using hematopoietic stem and progenitor cells (HSPCs) genetically modified with lentiviral vectors (LVs) . The recent and novel strategies of gene editing were more rapidly built up on the acquired knowledge of how ex vivo engineered purified CD34+ HSPC engraft and reconstitute the whole hematopoiesis, and on the optimization of clinical protocols for efficient HSPC mobilization and tailored conditioning regimen. Patients’ hematopoietic stem cells (HSCs) are mobilized in the peripheral blood and harvested by aphaeretic collection following the administration of granulocyte- colony stimulating factor (G-CSF) and plerixafor, as mobilizer agents. One important difference in this procedure is the use of plerixafor alone for the treatment of patients affected by sickle cell disease (SCD), because of high risk of life-threatening complications related to G-CSF in this population.1 ,2 As a result, the yield of CD34+ cells collected from patients with SCD is generally lower compared to patients with beta-thalassemia (Bthal), thus limiting to achieve an optimal drug product target dose.3 In addition, a key often neglected aspect of all strategies using ex vivo manufacturing of primitive HSC is the cellular composition and the molecular profiling of the target cells, which can be greatly influenced by the hosting diseased bone marrow (BM) . Thus, the transcriptional response  \nof HSC to ex vivo engineering and the maintenance of key stemness features are crucial for achieving a favorable and persistent clinical outcome. In addition, an intrinsic challenge of the manufacturing procedure is the impairment of the clonogenic activity and repopulating potential of HSPC following culture for LV transduction or electroporation for gene editing strategies. Several studies reported that ex vivo transduction protocols lead to a decrease in the frequency of clonogenic progenitors and primitive HSC compromising their long-term repopulating ability.4–6 Optimization of culture conditions offers the opportu","cbCaivxs0KG9zP53","https://ap.wps.com/l/cbCaivxs0KG9zP53","pdf",4632949,18,"English","# Summary\n# Introduction\n# Beta-thalassemia and Sickle cell disease","[{\"question\":\"What hemoglobinopathies are discussed in this review?\",\"answer\":\"The review focuses on beta-thalassemia and sickle cell disease as major inherited hemoglobin disorders.\"},{\"question\":\"Which gene therapy strategies are covered?\",\"answer\":\"It covers gene addition using lentiviral vector-engineered cells and gene editing using CRISPR-Cas9.\"},{\"question\":\"Why is HSC biology and the bone marrow niche important after clinical gene therapy success?\",\"answer\":\"Success of these approaches motivates a critical revision of knowledge about HSC biology and the bone marrow microenvironment that supports genetically corrected cells.\"}]","Gene therapy for hemoglobinopathies: Clinical trial results and biology of hematopoietic stem cell and the bone marrow niche | PDF",1790666182,45]