Overview of Research on Gene Therapy for Rare Inherited Blood Disorders: Sickle Cell Disease, Hemophilia, and Thalassemia

Inherited hematologic disorders such as sickle cell disease (SCD), thalassemia, and hemophilia are rare diseases characterized by debilitating symptoms, lifelong morbidity, and, in some cases premature mortality [1, 2]. Globally, SCD is affecting people mainly in the Sub-Sharan Africa and the United States, especially in the African American communities [3]. Current treatment of the SCD include blood transfusion and hydroxyurea which are not curative. Thalassemia, is another hemoglobinopathy, caused by a mutation that reduce or eliminate the production of alpha or beta globin chains [4]. In beta-thalassemia, patients require lifelong blood transfusion and iron chelation. The disease is primarily present in people living in the Mediterranean area.

Hemophilia is an X-linked bleeding disorder caused by deficiencies in clotting factors VIII (hemophilia A) or IX (hemophilia B) [5]. The disease affects mainly males and leads to spontaneous bleeding and joint damage. Standard therapy includes frequent administration of missing clotting factors. These three diseases arise from well-defined single gene mutation, making them ideal candidates for gene therapy, a field that seeks to correct, replace, or compensate, for defective genetic material at the molecular level [6]. Gene therapy in the context of hematologic diseases is built upon a profound understanding of the molecular pathology of each condition. In SCD, a single nucleotide substitution (Glu6Val) in the Beta globin gene results in the production of abnormal hemoglobin S (HbS), leading to erythrocyte sickling, vaso-occlusion, and multi-organ damage [7]. Thalassemia, including alpha and beta-thalassemia arises from mutations that impair the synthesis of globin chains, leading to ineffective erythropoiesis and anemia [8]. Hemophilia A and B, on the other hand, are caused by mutations in the F8 and F9 genes respectively, resulting in deficient clotting factor VIII or IX activity and a tendency for spontaneous bleeding [9].

The principle of gene therapy for these disorders is either (1) to repair the defective gene (gene editing), or (2) replace it with a functional copy (gene addition) by integrating the functional copy into the target cell genome randomly, semi-randomly, or targeted, but the affected gene is not replaced, or (3) modulate gene expression to restore physiological function. Molecular approaches have evolved from early viral vector-mediated gene transfer to sophisticated genome editing technologies, which allow precise correction of pathogenic mutations in endogenous loci [6]. For SCD and thalassemia, a major therapeutic strategy involves the reactivation of fetal hemoglobin (FHb) through targeted disruption of regulators such as BCL11A, thereby bypassing the defective adult B-globin gene [10]. Alternatively, direct gene addition using lentiviral vectors encoding functional B-globin has reached clinical translation exemplified by betibeglogene autotemcel [11]. In the context of hemophilia, adeno-associated virus (AAV)—mediated gene therapy has achieved landmark success with therapies such as etranacogene dezaparvovec and valctocogene roxaparvovec delivering durable expression of factor IX and VIII, respectively and significantly reducing bleeding episodes [12, 13].

At the molecular level, successful gene therapy must address several challenges including efficient gene delivery to target cells, primarily haemopoietic stem cells for SCD and thalassemia, and hepatocytes for hemophilia), precise regulation of transgene expression to physiological levels, minimization of insertional mutagenesis risks, immune responses to viral vectors, and long-term durability of therapeutic effects [14, 15]. Recently, the introduction of gene editing techniques has opened new horizons for people with inherited genetic diseases including SCD, hemophilia, and thalassemia [16 –20]. Genetic editing, also referred to as genome editing, is a transformative field of molecular biology that enables scientists to precisely alter an organism's DNA. Through these techniques, specific segments of genetic material can be deleted, inserted, or replaced within the genome [21 –24]. The journey of genetic editing began in the 1970 s with the advent of recombinant DNA technology, allowing for the first manipulation of genetic sciences using restriction enzymes. In the late twentieth century, more sophisticated tools emerged, including Zinc Finger Nucleases (ZFNs) and transcription activator-like effector nucleases (TALEN), both of which rely on engineered proteins to target and cleave DNA at specific locations [25]. However, these tools required complex protein engineering, limiting their widespread adoption. The landscape shifted dramatically in 2012 when Jennifer Doudna and Emmanuelle Charpentier introduced CRISPR-Cas9, a technology derived from the bacterial immune system that uses a guide RNA to direct nuclease to a specific DNA sequence, enabling highly targeted genome editing [21, 26 –29].

Knowledge mapping and bibliometric analysis are two complementary methodologies used to systematically evaluate the landscape of scientific research on a specific topic. Knowledge mapping refers to the process of visualizing structure, development, key thematic areas within a body of literature, helping researchers identify how knowledge is generated, interconnected, and evolving over time. Meanwhile, bibliometric analysis quantitatively assesses publications using metrics such as average annual growth rate (AAGR), citation counts, and key contributors [30]. Unlike traditional narrative reviews, which are often subjective and selective, or systematic reviews, which focus narrowly on clinical outcomes or interventions using strict inclusion criteria, bibliometric analysis provides a broad, objective, and data-driven overview of the structure and dynamics of scientific research [31, 32]. Bibliometric analysis is particularly useful in fast evolving fields such as gene therapy in rare diseases, where the volume and diversity are rapidly expanding. The objective of the current study is to provide a comprehensive insight of the current research landscape on gene therapy in relation to SCD, thalassemia, and hemophilia, identify key contributors and collaborative networks, and highlights emerging areas in the field. By doing so, the paper aims to guide future research priorities, support strategic funding decisions, and foster interdisciplinary collaboration. Moreover, the insights derived from this study have the potential to accelerate the development of bench-to-bedside translation, innovative diagnostic tools and therapeutic intervention of rare genetic diseases, many of which remain under-researched and under-served in global health agenda.

The current study adheres to the preliminary guideline for reporting bibliometric reviews of biomedical literature (BIBLIO) [33]. This guideline emphasizes methodological transparency, reproducibility, and scientific rigor by outlining essential components such as clear research objectives, defined search strategies, data source selection, and the use of validated bibliometric indicators. By adhering to BIBLIO, the study ensures its findings are both credible and aligned with emerging standards in bibliometric research.

This bibliometric analysis was conducted to systematically map and evaluate the research landscape of gene therapy for inherited hematologic disorders, with a focused lens on SCD, thalassemia, and hemophilia. By analyzing publication trends, citation patterns, key contributors, and thematic developments, the study aims to uncover the driving force, collaborative networks, and emerging innovations that have shaped this dynamic field. The findings not only reflect the maturation of gene therapy research, but also highlight the profound shift from the technological challenges to recent clinical breakthroughs, underscoring the informative potential of gene editing and advanced vector systems in addressing these rare life-threatening genetic diseases.

The growth of publications in the field was characterized by slow growth before 2017 which can be attributed to several key and technical challenges that limited early progress [52]. During the initial decades of gene therapy research, significant barriers existed, including inefficient gene delivery systems, limited control over transgene expression, immune reactions to vectors, and safety concerns related to insertional mutagenesis [53]. Early gene therapy efforts primarily relied on retroviral vectors, which, while capable of stable integration into host genomes, carried high risks of oncogenesis, as tragically evidenced in early clinical trials where patients developed leukemia after gene therapy of immunodeficiencies [54 –56]. These setbacks led to increased regulatory caution, heightened public skepticism, and general slowdown in clinical development across the field. Another important factor was the complexity of hematologic disorders themselves. Diseases such as SCD and thalassemia involve intricate regulation of globin gene expression, necessitating not just gene addition but fine-tuned control of transcriptional environments in hematopoietic stem cells [17, 57]. Similarly, hemophilia gene therapy efforts were constrained by challenges in achieving therapeutic levels of clotting factors without provoking neutralizing immune responses to the introduced proteins or viral vectors [58, 59]. Additionally, the technology to isolate, manipulate, and safely reintroduce hematopoietic stem cell ex vivo was still in its infancy during the 1990 s and early 2000 s [60 –63]. A key distinction in gene therapy strategies for rare hematological genetic diseases lies in the mode of delivery and cellular targets. Hemoglobinopathies such as ß-thalassemia and SCD primarily rely on ex vivo gene therapy approaches, where autologous hematopoietic stem and progenitor cells (HSPCs) are harvested from the patient, genetically modified outside the body using lentiviral vectors or CRISPR/Cas9-based genome editing tools, and then reinfused following myeloablative conditioning. This approach allows for precise editing or insertion of therapeutic transgenes such as anti-sickling ß-globin variants or reactivation of fetal hemoglobin through BCL11A disruption. However, ex vivo therapy is limited by challenges in stem cell mobilization, efficient transduction/editing, toxicity of conditioning regimens, and the need for specialized infrastructure for cell manipulation and transplantation [45, 64]. In contrast, gene therapy for hemophilia A and B has predominantly employed in vivo approaches, where AAV vectors are administered systemically to deliver functional copies of F8 or F9 genes directly to hepatocytes. This strategy eliminates the need for stem cell manipulation but introduces unique bottlenecks, notably pre-existing immunity to AAV capsids, vector dose limitations due to hepatotoxicity, and the risk of immune responses against the transgene product or vector components, which may attenuate therapeutic efficacy or necessitate immunosuppression. These differences underscore the disease-specific tailoring required in gene therapy design, and how the cellular targets (stem cells vs. hepatocytes) and delivery strategies (ex vivo vs. In vivo) critically shape the risks, challenges, and clinical implementation pathways [65 –67].

The steep rise in the growth of publications after 2018 reflects a scientific turning point driven by major technological innovations and clinical successes. The development of AAV vectors, particularly serotype-optimized and liver-targeted variants, dramatically improved the safety and efficiency of gene transfer, making hemophilia gene therapy a tangible clinical reality [38, 43]. For SCD and thalassemia, the emergence of CRISPR-Cas9 genome editing enabled precise correction oh disease-causing mutations or reactivation of fetal hemoglobin pathways, providing curative strategies at the genetic level [17, 45, 68 –74]. These advances were further supported by improved hematopoietic stem cell isolation, expansion, and transplantation techniques, which allowed for effective ex vivo editing followed by successful engraftment [17, 45, 68 –74]. Importantly, regulatory pathways evolved to accommodate gene therapies more efficiently, culminating in the approval of multiple gene therapy products for inherited blood disorders, such as Zynteglo (betibeglogene autotemcel for B-thalassemia) and Hemgenix (etranacogene dezaparvovec for hemophilia B) [12, 75 –79]. These approvals validated the feasibility and safety of gene therapy, spurring an influx of academic research, clinical trials, and industrial investment. Collectively, the rapid growth seen in the past few years reflects the convergence of safer vector system, powerful genome editing tools, improved clinical delivery methods, favorable regulatory shifts, and successful high-profile clinical trials, all of which reinvigorated global research interest and confidence in the promise of gene therapy for inherited hematologic disorders.

The dominance of subject areas such as medicine, biochemistry, genetics and molecular biology, immunology and microbiology, and pharmacology, toxicology, and pharmaceutics in the retrieved articles can be explained by the intrinsic multidisciplinary nature of the field and the biological complexity of these diseases. First and foremost, medicine was the leading subject area because gene therapy is fundamentally aimed at treating or curing clinical diseases. The clinical translation of gene therapy, from laboratory innovation to patient-centered interventions, ensures that medical journals remain the primary platform for disseminating findings [80 –82]. Second, the strong presence of biochemistry, genetics, and molecular biology reflects the essential molecular underpinnings of gene therapy. These disorders arise from single-gene mutations (such as the B-globin gene mutation in SCD or mutations in F8/F9 in hemophilia), making the understanding of DNA structure, transcriptional regulation, portion function, and vector engineering critical for any therapeutic advancement [70, 83 –86]. Fundamental research on viral vectors (e.g., AAV, lentivirus), gene editing technologies (e.g., CRISPR-Case9, base editing), and the molecular mechanisms of hemoglobin switching (e.g., BCL11A targeting) underlies most therapeutic strategies [70, 84 –86]. Without this molecular groundwork, clinical gene therapy would not be feasible. Third, the involvement of immunology and microbiology stems from the immune challenges associated with gene therapy. Delivery vectors such as AAV and lentiviruses often trigger immune responses that can neutralize therapeutic effects or lead to adverse events [87 –90]. The understanding and management of host immune responses, vector immunogenicity, and immune tolerance induction are therefore crucial components of successful and durable gene therapy [65, 91, 92]. Finally, the significant share of articles categorized under Pharmacology, Toxicology, and Pharmaceutics reflects the rigorous safety and dosing studies required for advancing gene therapies toward regulatory approval [93, 94]. Pharmacological studies are needed to assess biodistribution, optimal dosing regimens, vector persistence, and toxicity profiles, while toxicological assessments are vital for evaluating the risks of insertional mutagenesis, off-target effects of genome editing, and long-term adverse outcomes [95, 96].

The identification of leading journal such as Blood, Hemophilia, Molecular Therapy, Human Gene Therapy, and Blood Advances among the most prolific sources for publications on gene therapy for inherited blood disorders is not coincidental, but rather reflects the scientific maturity, clinical focus, and specialized audience these journals serve. Blood has broad readership that includes both basic scientists and clinicians, making it an ideal venue for studies that bridge laboratory discoveries and patient-centered applications. Hemophilia's strong presence among the leading journals is explained by its niche specialization. As a journal specifically dedicated to bleeding disorders, it provides a focused platform for reporting advances in gene replacement therapy, factor IX and VIII gene delivery, and clinical outcomes in hemophilia patients. Molecular Therapy, the official journal of American Society of Gene and Cell Therapy (ASGCT), is another expected leader. it has established itself as a premier outlet for cutting-edge advances in gene transfer technologies, genome editing, and cellular therapies, As the field transitioned from experimental vectors to clinically validated therapies, Molecular Therapy became the natural choice for high-impact publications on vector optimization, CRISPR-based interventions, and first-in human gene therapy trials or both hemoglobinopathies and bleeding disorders. Finally, Blood Advances -an open-access journal launched by the American Society of Hematology-has rapidly gained attention due to its fast publication timelines and wide accessibility. Its emergence among the top journals reflects the growing demand for high-visibility, open = -access dissemination of gene therapy results, particularly as the field has entered a stage of clinical validation and patient-centered outcomes research.

The dominance of the United States in the field can be understood in the context of scientific leadership, national research priorities, funding mechanisms, clinical infrastructure, and international collaboration dynamics [97 –100]. Historically, the United States has been the birthplace of many key technological innovations such as AAV vector development, lentiviral vector optimization, and early clinical trials in gene therapy. In addition, major institutions in the United States like the Children's Hospital of Philadelphia, University of Pennsylvania, NIH, and Harvard Medical School have been heavily invested in translational research, offering robust infrastructures that combine cutting-edge laboratory science with world-class clinical trial capabilities. Furthermore, significant governmental (e.g., NIH) and private sector funding (e.g., through biotechnology firms) has sustained the field through the decades. In addition, regulatory flexibility, evident in the U.S. FDA's evolving pathways for gene therapy approval, and strong industry-academic partnerships have accelerated both basic research and clinical translation, helping U.S.-based researchers maintain a self-sufficient, strong intra-country collaboration network.

The maps clearly revealed three dominant and interconnected thematic clusters. One cluster was centered on hemophilia gene therapy, reflecting the mature clinical development of AAV-based gene therapies for hemophilia, where therapeutic products have already reached late-phase trials and regulatory approval. The second major cluster was associated with SCD and thalassemia, demonstrating a newer and rapidly expanding frontier, where precision genome editing and ex vivo hematopoietic stem cell modification are offering curative prospects for hemoglobinopathies. The third cluster, more clinical in nature, signals the field's growing maturity and a shift toward evaluating not just molecular correction but meaningful patient-centered outcomes. While hemophilia therapies have converged largely around AAV-mediated liver-directed delivery, hemoglobinopathy gene therapies are diverging into multiple strategies, gene addition, fetal hemoglobin reactivation, and direct gene correction, reflecting a highly innovative and competitive research landscape. This cluster indicates that gene therapy is no longer viewed as experimental but is being assessed for integration into routine clinical care, requiring new models of follow-up, ethics, and long-term patient support.

The overlay visualization maps added a temporal dimension to this understanding, showing that early research (pre-2015) was dominated by viral vector development, preclinical modeling, and basic gene transfer studies, while recent years (2018 onward) have witnessed the explosion of genome editing research, the translation of gene therapies into clinical practice, and the emergence of long-term outcome studies. The recent dominance of keywords like CRISPR/Cas9, gene editing, clinical trial, and quality of life indicates that the field has moved beyond technical feasibility to real-world application and longitudinal evaluation. The field has transitioned from a technology-focused phase (vector development, delivery efficiency) to a clinical impact phase (long-term outcomes, regulatory approval, and patient experience). For hemophilia, gene therapy has neared full clinical translation, with some therapies already commercialized. For SCD and thalassemia, the field is mid-transition, with CRISPR-based and lentiviral therapies moving rapidly from phase I/II studies into late-stage clinical evaluation.

The manuscript presents a strong and timely contribution to the field. One of the major strengths of the manuscript lies in its focused topic, which addresses a transformative area of research that is reshaping therapeutic approaches for rare, life-threatening disorders. The study provides a robust bibliometric analysis, offering a quantitative and evidence-based evaluation of the evolution of gene therapy over nearly four decades. By systematically analyzing the growth trends, subject areas, leading journals, authors, institutions, and collaboration networks, the manuscript moves beyond a descriptive narrative to deliver a structured and insightful mapping of the field's development. Another point of strength is the clear thematic organization of the findings, supported by keyword and term co-occurrence maps that reveal the scientific landscape and major research clusters. Particularly valuable is the way the manuscript connects scientific progress with clinical translation, emphasizing the transition from early technological innovation to a mature phase where patient outcomes and quality of life considerations are increasingly prioritized.

The current bibliometric study systematically mapped the research landscape of gene therapy in inherited hematological disorders over the past four decades. The evolution showed a dynamic pattern with rapid expansion characterized by the introduction of novel technologies. The United States was the overwhelming leader with high intra-country collaboration. The contribution of countries in Europe and North America was dependent heavily on international research collaboration. Research output was heavily concentrated in a few specialized journals and was led by prominent institutions in the United States. A strong interdisciplinary nature of the field was evident as publications were distributed across different subject areas. Co-occurrence map showed that AAV-based gene therapy in hemophilia constituted a separate theme while ex vivo genome editing of hemoglobinopathies constituted the second major theme. Temporal analysis indicated that there is a time shift in research from early vector development in gene therapy into clinical applications and outcome. This analysis provides an essential resource for understanding the maturation of gene therapy research in inherited hematologic disorders and underscores emerging trends that will shape the future, including genome editing and its clinical translation in other rare diseases.