Orphanet Journal of Rare Diseases | Bibliometric and Knowledge Graph Analysis of Gene Therapy for Sickle Cell Disease, Hemophilia, and Thalassemia

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This study systematically reviews gene therapy research for sickle cell disease, hemophilia, and thalassemia from 1986 to 2024, revealing a significant growth trend transitioning from basic research to clinical translation. Visual analysis highlights the central role of CRISPR/Cas9 and AAV vectors in hemoglobinopathies and hemophilia.

 

Literature Overview
This article published in the Orphanet Journal of Rare Diseases, titled 'Knowledge mapping and bibliometric insights into gene therapy for rare inherited hematologic pathologies: focus on sickle cell disease, hemophilia, and thalassemia', summarizes the global research status of gene therapy for these three major monogenic inherited blood disorders. The study employs bibliometric and knowledge graph methodologies to analyze publication trends, research hotspots, national and institutional contributions, and keyword co-occurrence networks from Scopus database entries between 1986 and 2024.

Background Knowledge
Sickle Cell Disease (SCD), β-Thalassemia (β-thalassemia), and Hemophilia (A/B) represent three major monogenic inherited blood disorders caused by β-globin gene mutations and F8/F9 gene deficiencies leading to coagulation dysfunction. Current treatments like blood transfusions, iron chelation, or clotting factor replacement only alleviate symptoms without curative effects. Gene therapy offers molecular repair, replacement, or regulation mechanisms through AAV vector delivery of functional clotting factor genes (for hemophilia) or CRISPR/Cas9 editing of BCL11A enhancer (for SCD and thalassemia) to reactivate fetal hemoglobin (HbF) expression. Despite recent advances in genome editing and viral vector optimization, challenges like immunogenicity, insertional mutagenesis risk, and stem cell manipulation efficiency still limit clinical translation.

 

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Research Methods and Experiments
The study systematically searched Scopus database for publications between 1986 and 2024 using title-abstract keywords related to gene therapy for sickle cell disease, hemophilia, and thalassemia. VOSviewer was employed to construct multiple network maps including author collaboration, keyword co-occurrence, title/abstract term co-occurrence, and time-dynamic keyword evolution to reveal research hotspots, international collaboration patterns, and thematic development trends.

Key Findings and Perspectives

• 1399 publications were retrieved, showing two-phase growth: slow increase (1986–2018) followed by rapid expansion (2019–2024) with 28% annual growth rate.
• Major disciplines: Medicine (39.5%), Biochemistry/Genetics/Molecular Biology (30.7%), Immunology (8.1%), Pharmacology/Toxicology (7.5%), demonstrating strong interdisciplinary nature.
• USA leads in publications (863, 61.7%), followed by China (157) and UK (147). Domestic collaboration dominates in USA while European countries prefer international partnerships.
• Top institutions: Children's Hospital of Philadelphia (105) and University of Pennsylvania (83), focusing on AAV and CRISPR applications in gene therapy.
• Keyword analysis identifies AAV vectors, genome editing, CRISPR/Cas9, hematopoietic stem cell gene therapy, and transgene modification as core terms. CRISPR and clinical translation research show recent exponential growth.
• Network mapping reveals three major research themes: AAV-mediated gene therapy for hemophilia, genome editing for hemoglobinopathies, and clinical translation with quality-of-life improvement.

Research Implications and Future Directions
This study identifies research hotspots and international collaboration patterns in gene therapy for SCD, hemophilia, and thalassemia, demonstrating the field's transition from basic research to clinical applications. The maturation of technologies like CRISPR and AAV diversifies therapeutic strategies while introducing new challenges including vector immunogenicity, off-target effects, and long-term efficacy evaluation. Future research should focus on optimizing vector systems, improving genome editing efficiency, and strengthening clinical trial design and regulatory support to achieve precision medicine goals.

 

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Conclusion
Through systematic bibliometric analysis, this study maps global research trends in gene therapy for sickle cell disease, hemophilia, and thalassemia. The research demonstrates significant growth acceleration after 2019 with 28% annual increase. USA dominates scientific output while European countries excel in international collaboration. Thematic analysis confirms AAV vectors as primary tools for hemophilia treatment and CRISPR/Cas9 genome editing gradually replacing traditional gene addition strategies in hemoglobinopathies. Co-occurrence networks of keywords and terms validate the field's transition from experimental research to clinical translation and quality-of-life improvement. This work provides a comprehensive landscape for researchers, strategic reference for policymakers, and data support for clinical translation and global collaboration networks. Gene therapy is now transitioning from laboratory to clinic, becoming a viable option for inherited blood disorders.

 

Moutaz W Sweileh. Knowledge mapping and bibliometric insights into gene therapy for rare inherited hematologic pathologies: focus on sickle cell disease, hemophilia, and thalassemia. Orphanet Journal of Rare Diseases.