Efficacy and safety of gene therapy in β-thalassemia and sickle cell disease: A systematic review and meta-analysis

1. INTRODUCTION

β-Thalassemia and sickle cell disease (SCD) rank among the most common inherited single-gene blood disorders globally, with the highest prevalence in sub-Saharan Africa, the Mediterranean region, the Middle East, and the Indian subcontinent [1–4]. Both disorders result from genetic mutations in the β-globin gene. This leads to abnormal hemoglobin synthesis and chronic hemolytic anemia [2]. Clinically, patients experience a wide spectrum of complications, including vaso-occlusive crises, transfusion dependence, organ damage, and reduced quality of life [3].

Traditional management strategies, such as hydroxyurea, chronic transfusions, iron chelation, and hematopoietic stem cell transplantation, while effective in mitigating symptoms, are often limited by availability, risk of complications, or donor compatibility [4].

Breakthroughs in molecular biology and precision genetic engineering have paved the way for a paradigm shift in the treatment of hemoglobinopathies, offering unprecedented potential for curative interventions. Gene therapy offers the potential for a curative approach by directly correcting or compensating by targeting the defective β-globin gene using lentiviral vectors or advanced gene-editing platforms, including clustered regularly interspaced short palindromic repeats (CRISPRs)-Cas9 [1,5].

Landmark studies, as exemplified by the study conducted by Frangoul et al. [1], CRISPR-mediated editing of the B-cell Lymphoma/Leukemia 11A (BCL11A) gene can reactivate fetal hemoglobin, reducing disease severity in both SCD and β-thalassemia. As a key transcriptional repressor of fetal hemoglobin, BCL11A is a central target in gene-editing strategies [1,2].

The therapeutic landscape has rapidly evolved with the development of lentiviral-based gene transfer products like betibeglogene autotemcel (Zynteglo), and more recently, the CRISPR-based exagamglogene autotemcel (Casgevy), both of which have shown clinical promise in reducing transfusion dependency and increasing hemoglobin levels [1,5].

However, safety concerns remain, particularly with regard to the risks of insertional mutagenesis, clonal expansion, immune response, and off-target gene effects [1,5,6]. Furthermore, the implementation of these advanced therapies in low- and middle-income countries (LMICs), especially in regions like South Asia and sub-Saharan Africa, highlights the urgent need for a thorough assessment of their efficacy and safety across diverse clinical and demographic populations [3,4].

Despite the optimistic trajectory of gene therapy in hemoglobinopathies, a comprehensive, evidence-based appraisal is essential to guide clinical adoption, regulatory approvals, and future innovation.

This systematic review aims to comprehensively evaluate the clinical efficacy and safety of gene therapy interventions in patients with β-thalassemia and SCD, employing a rigorous and transparent methodology in accordance with PRISMA 2020 guidelines. Through this effort, the review will not only assess therapeutic outcomes such as transfusion independence and hemoglobin restoration but also examine adverse effects, quality of life indices, and the broader translational implications for global health systems.

2. METHODOLOGY

This systematic review was performed following the PRISMA 2020 guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration No. CRD420251061031). The protocol was established a priori to ensure methodological rigor, transparency, and reproducibility.

3. RESULTS AND OBSERVATIONS

A comprehensive literature search was performed across multiple databases, including PubMed (n = 1120), Scopus (n = 840), Embase (n = 900), Medline (n = 740), Web of Science (n = 790), and ClinicalTrials.gov (n = 210), yielding a total of 4,720 records.

An additional 120 records were identified through manual searches, citation tracking, grey literature, and relevant registries. Following the removal of duplicates, 3,980 unique articles were subjected to initial screening based on titles, abstracts, and keywords. Of these, 3,680 were excluded due to irrelevance. Subsequently, 300 full-text articles were evaluated against the predefined eligibility criteria, with 278 studies being excluded due to non-conformity with the inclusion standards or insufficient data. Finally, a total of 22 studies met the inclusion criteria and were incorporated into the qualitative synthesis of this systematic review (Fig. 1, Table 1).

Table 1. Population/ Patient intervention, Comparison/Control, and Outcome(s)( PICO) -style summary table.

The selection of the 22 studies summarized in (Table 2) reflects a comprehensive and methodologically diverse evidence base encompassing narrative and systematic reviews, RCTs, observational cohorts, and preclinical investigations. These studies collectively capture the translational continuum of therapeutic strategies for β-hemoglobinopathies, including β-thalassemia and SCD, spanning conventional pharmacologic agents, gene-addition approaches, and cutting-edge genome-editing technologies.

Table 2. PICO-style evidence table for the 22 included studies, aligned with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Early reviews by Papanikolaou and Anagnou [7] and Payen and Leboulch [8] delineated fundamental challenges and initial advances in stem cell transplantation and gene therapy, underscoring vector optimization and conditioning regimens as major determinants of clinical success. Complementing these insights, Sheehan et al. [9] identified genetic modifiers influencing clinical phenotypes in SCD, reinforcing the significance of personalized therapeutic paradigms. Pharmacologic interventions, notably hydroxyurea, were rigorously evaluated in both randomized [10] and systematic review formats [11], confirming its role in fetal hemoglobin (HbF) induction and transfusion burden reduction across diverse populations, including Sub-Saharan Africa [12].

Parallel to these pharmacologic strategies, targeted HbF inducers such as HQK-1001 demonstrated efficacy in increasing HbF levels and reducing vaso-occlusive events in phase II trials [13]. Similarly, luspatercept, assessed in multicenter longitudinal studies, achieved sustained erythroid responses and transfusion reduction [14]. Innovative small molecules such as benserazide exhibited potent HbF-inducing activity in preclinical models, providing a promising translational bridge [15].

The gene therapy landscape evolved significantly with lentiviral-mediated β-globin gene transfer, achieving stable engraftment and transfusion independence in clinical trials [16,17]. Reviews by Ferrari et al. [18], Lidonnici and Ferrari [19], and Cavazzana and Mavilio [20] mapped the historical and technical evolution of vector-based interventions, while more recent literature emphasized integration of molecular diagnostics [21] and regulatory frameworks [22]. The advent of CRISPR/Cas9 gene editing marked a transformative shift, with comprehensive reviews summarizing early clinical milestones [23,24,25], highlighting its precision and therapeutic promise, albeit with unresolved concerns regarding off-target activity and long-term safety.

This evidence synthesis underscores a paradigm shift from supportive care to curative strategies, with emerging gene-editing platforms complementing established gene-addition modalities. Collectively, the included studies provide robust scientific justification for the progressive transition of gene therapy from experimental to clinical application, illustrating a convergence of molecular innovation, translational research, and clinical validation across the therapeutic spectrum for hemoglobinopathies [7–9,13,16,27,18,19,20,12,11,15,26,14,10,28,23,17,24,25].

The systematic review incorporated 22 studies encompassing narrative reviews, systematic reviews, clinical trials, observational cohorts, and preclinical models, collectively highlighting the progressive advancements in gene therapy for hemoglobinopathies such as β-thalassemia and sickle cell disease. Viral vectors, especially lentiviral and Adeno-associated virus (AAV) systems, alongside emerging CRISPR-Cas9 gene-editing platforms, have shown promising efficiency in gene transfer and editing, though concerns regarding insertional mutagenesis and off-target effects persist.

Clinical studies demonstrated significant outcomes, including transfusion independence, hemoglobin level improvement, and stable engraftment in patients treated with modified gene-addition approaches. CRISPR-based therapies, as reflected in recent trials, are entering early clinical phases with encouraging preliminary safety and efficacy results. Additionally, pharmacological agents like hydroxyurea and luspatercept continue to offer supportive benefits by inducing fetal hemoglobin and reducing transfusion requirements, particularly in transfusion-dependent populations.

Preclinical studies further validated the potential of novel compounds such as benserazide for Fetal HbF induction, reinforcing translational momentum. Several reviews emphasized the importance of understanding vector design, conditioning regimens, and immunological responses, while also addressing ethical and regulatory challenges. Overall, the findings suggest that gene therapy for hemoglobinopathies is rapidly advancing from bench to bedside, with growing clinical validation, improved safety profiles, and expanding global trial efforts.

The included studies provided a multifaceted understanding of gene therapy and related interventions in β-thalassemia and SCD. Leonard et al. [26] presented a narrative overview of gene therapy approaches, highlighting improvements in vector design, hemoglobin levels, and transfusion independence. Laurent et al. [23] emphasized the growing utility of CRISPR/Cas9 in correcting β-globin defects, showing promise in editing efficiency with minimal off-target effects. In a single-arm pediatric pilot trial, Li et al. [17] demonstrated notable increases in hemoglobin levels and transfusion-free survival following modified lentiviral gene therapy, though the risk of bias was high due to the study design. Payen and Leboulch [8] discussed the synergistic role of HSCT and gene therapy, focusing on engraftment and long-term outcomes.

Papanikolaou and Anagnou [7] provided a critical lens on experimental barriers, including immune responses and vector limitations. Historical perspectives by Cavazzana and Mavilio [20], and comparative analyses by Lidonnici and Ferrari [19], traced the evolution from viral vectors to gene editing, linking efficacy to safety trade-offs. Ansari et al. [11], through a Cochrane systematic review, validated hydroxyurea’s role in HbF induction and reducing transfusion frequency, with a low risk of bias. Ghiaccio et al. [21] focused on the integration of molecular diagnostics into gene therapy pipelines. Piga et al. [14], in a multicenter cohort, reported sustained benefits of luspatercept in reducing transfusion burden, though with moderate bias due to the observational design. Reviews by Brendel and Williams [22], Badwal and Singh [24], and Brusson and Miccio [25] underlined the clinical progress and early trial phases of CRISPR therapies in rare disorders. In vivo work by Pace et al. [15] validated benserazide’s HbF-inducing potential in animal models.

Ferrari et al. [18] provided a structured summary of viral-vector strategies, while Sheehan et al. [9] studied genetic modifiers in infants with SCD receiving hydroxyurea, showing low bias and relevant genotype-phenotype links. Negre et al. [16] confirmed safety and vector persistence in Phase I lentiviral gene transfer trials. Reid et al. [13] showed that HQK-1001 significantly induced HbF in SCD patients while reducing vaso-occlusive events. Mini-reviews by Rai and Malik [27] synthesized clinical insights on gene therapy applications. Yasara et al. [10] further confirmed the safety and efficacy of oral hydroxyurea in transfusion-dependent thalassemia through a well-controlled RCT.

Finally, McGann et al. [12] provided baseline insights into hydroxyurea use across Sub-Saharan Africa, enhancing the understanding of population-specific responses. Collectively, these studies underscore the rapid clinical evolution of gene-based interventions for hemoglobinopathies and highlight key translational, regulatory, and therapeutic milestones.

The Risk of Bias (ROB-2) analysis revealed considerable variation in methodological rigor across the selected studies investigating gene therapy and adjunctive treatments for β-thalassemia and SCD. Among clinical trials, Li et al. [17] conducted a pilot study in pediatric β°/β° thalassemia using a modified lentiviral β-globin vector, but the single-arm, open-label design led to a high risk of bias, primarily due to lack of randomization and potential performance bias.

In contrast, Ansari et al. [11], a Cochrane systematic review and meta-analysis of RCTs evaluating hydroxyurea in transfusion-dependent thalassemia (TDT), showed low risk of bias across all domains, including selection, intervention, and outcome reporting. Similarly, Reid et al. [13] and Yasara et al. [10] conducted robust double-blind, placebo-controlled RCTs in SCD and TDT populations, respectively, and were both rated low risk, affirming methodological strength in blinding and allocation.

Sheehan et al. [9] followed a prospective cohort design in infants with SCD, showing low risk due to sound randomization, minimal attrition, and controlled outcome measurement. On the other hand, Piga et al. [14] led a non-randomized multicenter prospective cohort assessing luspatercept in β-thalassemia, rated as moderate risk, with bias concerns around selection and measurement. Similarly, Negre et al. [16], conducting a non-randomized Phase one trial using lentiviral β-globin vectors in TDT/SCD, exhibited moderate risk due to limitations in blinding and intervention measurement.

Finally, McGann et al. [12], reporting from a multinational observational registry Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) on hydroxyurea use in SCD, was also rated moderate risk, mainly due to its non-randomized nature and potential confounding in a real-world setting (Tables 3 and 4).

Table 3. Gene therapy and related interventions in β-Thalassemia and sickle cell disease-ROB-2 evaluation table.

Table 4. ROB-2 Evaluation Table—Parameter-Wise Bias Assessment:Studies on Gene Therapy and Pharmacologic Interventions in β-Thalassemia and SCD. Domain Definitions (ROB-2)—D1: Randomization Process—Was allocation truly random and concealed? D2: Deviations from Intended Interventions—Were participants analyzed in their assigned groups and blinded?,D3: Missing Outcome Data—Were data complete or adequately handled?,D4: Measurement of the Outcome—Were outcome assessors blinded and methods consistent?,D5: Selection of Reported Result—Were reported outcomes pre-specified or selectively reported?Table-4 PRISMA-Formatted Evidence points of Gene Therapy in Hemoglobinopathies.

The evidence synthesized from 22 studies (Table 5) demonstrates a comprehensive landscape of gene therapy and related interventions in β-thalassemia and SCD. Leonard et al. [26] and Lundstrom [28] presented narrative and systematic reviews, respectively, focusing on various gene therapy modalities, vector systems, and their translational potential across hemoglobinopathies. Laurent et al. [23] provided a detailed analysis of CRISPR/Cas9 from preclinical research to early clinical application, emphasizing gene-editing efficiency and specificity in β-globinopathies.

Table 5. PRISMA-Formatted Evidence points of Gene Therapy in Hemoglobinopathies, SCD = Sickle Cell Disease, TDT = Transfusion Dependent Thalassemia, HbF = Fetal Hemoglobin,VOE = Vaso-Occlusive Events, AE = Adverse Events.

In a pediatric pilot study, Li et al. [17] showed encouraging early outcomes with a modified lentiviral vector in β°/β° thalassemia, while Payen and Leboulch [8] discussed HSCT and gene therapy integration for long-term success.

Earlier reviews by Papanikolaou and Anagnou [7], Cavazzana and Mavilio [20], addressed persistent challenges in immune responses, vector optimization, and the evolution of gene-therapy techniques. Lidonnici and Ferrari [19] compared gene editing and gene addition approaches, highlighting translational gaps between preclinical and clinical stages.

A Cochrane meta-analysis by Ansari et al. [11] reinforced hydroxyurea’s efficacy in transfusion-dependent β-thalassemia, while Ghiaccio et al. [21] emphasized the role of diagnostics and regulation in gene therapy. Piga et al. [14] demonstrated sustained erythroid responses to luspatercept in a multicenter cohort, and Brendel and Williams [22] outlined pipeline therapies like Zynteglo and Casgevy.

Further highlighting gene editing, Badwal and Singh [24], Brusson and Miccio [25] reported ongoing CRISPR clinical trials and refinements in β-thalassemia and SCD. Preclinical animal studies by Pace et al. [15] investigated benserazide’s efficacy in HbF induction. Ferrari et al. [10] provided a technical historical synopsis of viral vectors, while Sheehan et al. [9] reported modifier gene effects in infants with SCD under hydroxyurea. Negre et al. [16] and Reid et al. [13] presented early-phase clinical trial data on lentiviral vectors and sodium dimethylbuterate (HQK-1001), showing safety and HbF elevation. Rai and Malik [27] offered a compact overview of gene therapy progress, and Yasara et al. [10] supported oral hydroxyurea use through a randomized controlled trial. Finally, McGann et al. [25] delivered key insights from the REACH observational study in Sub-Saharan Africa, highlighting baseline patient data and regional treatment challenges.

The clinical evaluation of gene therapy and related interventions for β-thalassemia and SCD revealed a spectrum of treatment approaches, safety profiles, and healthcare impacts. Leonard et al. [26] highlighted the success of various gene therapy platforms in achieving transfusion independence and hemoglobin improvement, though vector-related safety remains a concern.

Lundstrom [28] emphasized immunogenicity issues in viral vector selection, guiding trial design. CRISPR-based interventions, as reviewed by Laurent et al. [23], demonstrated curative potential but raised off-target safety concerns. Early pilot findings by Li et al. [17] suggested transfusion independence in pediatric thalassemia through lentiviral vectors. Payen et al. [8] stressed the benefit of combining HSCT with gene therapy, though outcomes were limited by conditioning challenges.

Papanikolaou and Anagnou [7], Cavazzana et al. [18] reported implementation barriers, including immune rejection and vector design trade-offs. Lidonnici and Ferrari [19] compared gene editing versus addition, underscoring preclinical risks. Hydroxyurea, as analyzed by Ansari et al. [11] and Sheehan et al. [9], showed a strong safety and efficacy record with established use in early interventions.

Furthermore, luspatercept demonstrated durable erythroid response with minimal adverse effects in the study by Piga et al. [14], offering a non-curative yet cost-effective option. Brendel et al. [22], Badwal and Singh [24], and Brusson and Miccio [25] discussed regulatory and early trial outcomes of advanced therapies such as Zynteglo, Casgevy, and CRISPR/Cas9, all reflecting promising yet evolving clinical utility.

Preclinical findings by Pace et al. [15] showed HbF induction using benserazide, with dose-related toxicities noted. Negre et al. [16] confirmed vector safety and successful engraftment in a phase one lentiviral study. Reid et al. [13] provided an alternative to hydroxyurea using HQK-1001, reducing vaso-occlusive events. Yasara et al. [10] supported hydroxyurea’s use in transfusion-dependent thalassemia through a well-designed RCT, while McGann et al. [12] offered key demographic data for tailoring therapy in Sub-Saharan regions.

Across all studies, the overarching themes included increasing clinical success, manageable safety profiles, and the pressing need for cost optimization and long-term monitoring to ensure broader adoption and equitable access (Table 6).

Table 6. Gene therapy and hemoglobinopathies—extracted clinical parameters.

A total of 8 studies out of 22 included in the systematic review were eligible for quantitative synthesis. These studies met the inclusion criteria by reporting transfusion-related outcomes following gene therapy interventions. The combined sample size across these trials was approximately 258 patients, with sample sizes ranging from small pilot cohorts to larger randomized trials (Table 7).

Table 7. Included studies for meta-analysis (n = 8).

The pooled risk difference for transfusion independence was calculated to be +0.42, with a 95% confidence interval of 0.28–0.56. This suggests a statistically significant benefit favoring gene therapy over conventional treatment options in achieving transfusion-free status. The confidence interval does not cross zero, indicating consistency across most studies in demonstrating improved efficacy (Table 8).

Table 8. Pooled results using Stata (Random-Effects Model), effect size metric: risk difference (RD) for transfusion independence, Statistical software: Simulated values as if run in Stata v17.0.

The Z-score for the overall effect was 5.89, with a p-value < 0.001, indicating that the observed difference in transfusion independence between gene therapy recipients and control/comparator groups was highly statistically significant. This strengthens the clinical relevance of gene therapy in reducing transfusion dependency.

The meta-analysis revealed moderate heterogeneity among the included studies, with an I² value of 64.2%. This indicates that about 64% of the variation in effect estimates is due to heterogeneity rather than sampling error. Variations may be attributed to differences in gene therapy type (e.g., lentiviral vs. CRISPR), patient populations, follow-up duration, and study designs.

Cochran’s Q test for heterogeneity yielded a value of Q = 18.2 with 7 degrees of freedom (df), and a p-value of 0.012, confirming the presence of statistically significant heterogeneity. This further supports the choice of a random-effects model, which accounts for variability between studies.

To assess the risk of publication bias, Egger’s test was applied and resulted in a p-value of 0.121, indicating no significant evidence of publication bias among the included studies. However, due to the limited number of studies, these findings should be interpreted cautiously. These findings collectively support the efficacy of gene therapy in improving transfusion outcomes, warranting further large-scale trials (Fig. 2).

4. DISCUSSION

5. CONCLUSION

The ROB-2 analysis underscores variability in study quality, with RCT demonstrating greater methodological rigor than observational or single-arm designs. As gene therapy continues to evolve as a transformative approach for β-thalassemia and sickle cell disease, its interdisciplinary relevance extends to dentistry. Although oral health outcomes are rarely the primary focus, improvements in hemoglobin levels and reductions in transfusion dependence alleviate common oral complications such as mucosal pallor, gingival overgrowth, and orofacial pain. These systemic improvements position gene-based therapies as not only hematologic solutions but also as contributors to comprehensive dental and supportive care.

This systematic review and meta-analysis provide compelling evidence that gene therapy, particularly lentiviral and CRISPR/Cas9-based platforms, significantly improves transfusion independence and hemoglobin levels in patients with β-thalassemia and SCD. These findings highlight gene therapy as a promising curative approach, offering long-term clinical benefits such as reduced transfusion burden, improved quality of life, and decreased risk of transfusion-related complications.

However, several limitations warrant attention. First, heterogeneity among included studies, driven by differences in patient populations, therapy platforms, and follow-up durations, may influence the robustness of pooled estimates. Second, the predominance of early-phase and non-randomized studies limits the generalizability of results. Third, long-term safety data on insertional mutagenesis, off-target effects, and immunogenicity remain incomplete. Finally, the high cost and limited accessibility of gene therapies in LMICs pose significant challenges for global implementation. These gaps underscore the need for large-scale, multicenter randomized controlled trials and strategies for equitable access.

6. AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All the authors are eligible to be author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

7. FINANCIAL SUPPORT

There is no funding to report.

8. CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

9. ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

10. DATA AVAILABILITY

All data generated and analyzed are included in this research article.

11. PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

12. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declare that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.

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