A 35‑Year Bibliometric Landscape of Cell and Gene Therapy

Introduction and Background
Cell and gene therapies (CGT) have emerged as transformative approaches for diseases previously considered intractable. Cell therapy involves the transplantation of living cells—ranging from hematopoietic stem cells (HSCs) to mesenchymal stem cells (MSCs) and induced pluripotent stem cells—while gene therapy uses genetic material to modify cellular function, either by directly delivering genes into the body (in vivo) or by engineering cells outside the body before reinfusion (ex vivo). Over the past three decades, the field has witnessed both remarkable successes and significant setbacks, from early clinical trials in the 1990s to the first regulatory approvals of products like Kymriah and Luxturna in the 2010s. Adeno-associated virus (AAV) has emerged as a cornerstone of gene therapy, valued for its minimal immunogenicity and capacity for sustained transgene expression. Its primary advantage lies in the ability to deliver genetic payloads directly to target tissues, thereby bypassing the complex requirement for ex vivo cell manipulation.  Despite these advances, the pace of development has varied considerably across modalities and geographic regions. To understand these disparities and to provide a data‑driven foundation for future research policy and strategic cooperation, a team from Kyoto University and Arthur D. Little Japan conducted a comprehensive bibliometric analysis covering 35 years of CGT publications. Their study, published in Cytotherapy, systematically maps the evolution of the field, assesses the efficiency of clinical translation, and evaluates the role of international collaboration in producing high‑impact research.

Methods
The researchers integrated two complementary data sources: PubMed, which provides structured indexing through Medical Subject Headings (MeSH), and OpenAlex, a large‑scale open database of scholarly works that supplies citation counts and detailed affiliation data. They retrieved original research articles published between 1989 and 2023 using targeted MeSH queries for cell therapy, in vivo gene therapy, and ex vivo gene therapy, yielding 160,327 articles after excluding reviews, editorials, and conference proceedings. To account for potential indexing delays in MeSH assignment for recent publications, the authors performed a sampling‑based sensitivity analysis, which confirmed that the overall trends were robust.

To capture scientific impact, they defined “high‑impact papers” as those with annualized citation counts exceeding the 90th percentile among all articles published in the same year within the “Medicine” field in OpenAlex. This normalization allowed fair comparison across publication years. They further refined the cell therapy category into HSC‑based and MSC‑based subcategories using additional MeSH terms. Clinical activity was assessed using PubMed Publication Types; articles tagged as clinical trials or observational studies were classified as clinical trial papers. A novel metric—the Clinical Transition Ratio (CTR)—was introduced to quantify the efficiency of translation from nonclinical research to clinical trials. The CTR was calculated for each year by dividing the number of clinical trial papers by the cumulative number of high‑impact nonclinical papers published 5–11 years earlier, a window chosen based on the empirical distribution of citations in clinical trial papers.

Country‑level contributions were analyzed using fractional counting of author affiliations, and research productivity was measured as high‑impact papers per active researcher (authors with at least one publication in the preceding three years). International collaboration was examined through co‑authorship networks, including bilateral co‑authorship ratios and institutional degree centrality. Finally, topic dynamics were explored by analyzing the occurrence probability of MeSH terms across two 5‑year periods (2014–2018 and 2019–2023) and linking them to high‑impact proportions.

Key Results

Modality‑Specific Historical Trends
The analysis revealed starkly different trajectories across CGT modalities (Figure 1). HSC‑based therapies accounted for more than half of all cell therapy publications throughout the 35‑year period, reflecting their foundational role. Their clinical transition ratio was high in the early 2000s and stabilized at a relatively elevated level thereafter, indicating a mature field where nonclinical and clinical research have progressed in parallel and translation remains efficient. In contrast, MSC‑based research experienced a surge in high‑impact papers beginning around 2005, but clinical publications plateaued after 2010 and have since shown a modest decline. Consequently, the CTR for MSC therapy dropped from its initial peak, revealing a widening gap between sustained scientific interest and clinical application.

For gene therapy, the total publication count peaked around 2000, driven largely by in vivo approaches, then declined before resurging around 2015 due to a sharp increase in ex vivo gene therapy output. In vivo gene therapy publications have remained relatively flat since the early 2000s, and despite recent approvals of AAV‑based products such as Luxturna and Zolgensma, the CTR has continued to decline, suggesting limited expansion beyond a few rare disease indications. By contrast, ex vivo gene therapy—which includes CAR‑T cell products—showed a dramatic rise in clinical trial publications beginning around 2017, with a persistently high CTR, demonstrating a tightly coupled and efficient translational pathway.

Fig 1. Modality-specific trends in publication volume, scientific attention, and clinical transition patterns in cell and gene therapies.

Topic Dynamics and Scientific Focus
The MeSH‑based topic analysis (Figure 2) provided granular insights into emerging research areas. In HSC research, topics related to hematologic malignancies (e.g., “Leukemia, Myeloid, Acute”) remained central, while “Transplantation, Homologous” showed a declining trend, possibly reflecting competition from autologous approaches and CAR‑T therapies. In the MSC domain, “COVID‑19” and “SARS‑CoV‑2” appeared as large, fast‑growing bubbles in the upper‑right quadrant, indicating a pandemic‑driven surge in high‑impact research. Other prominent terms included “Umbilical Cord,” “Adipose Tissue,” and “Exosomes,” highlighting ongoing interest in MSC sources and their paracrine mechanisms.

For in vivo gene therapy, the most striking findings were the large bubbles for “Gene Editing,” “CRISPR‑Cas Systems,” and “Dependovirus”—the viral genus that includes AAV. These terms exhibited both strong growth and high citation impact, underscoring the central role of AAV vectors and genome editing technologies in driving recent innovation. “Hemophilia A” and “Neoplasms” also appeared as high‑impact topics, reflecting the disease areas where AAV‑based therapies have achieved regulatory approval or are in advanced development. In ex vivo gene therapy, the landscape was dominated by cancer immunotherapy terms such as “Lymphoma, Large B‑Cell, Diffuse,” “Multiple Myeloma,” and “CD19 Antigens,” consistent with the clinical success of CAR‑T therapies in hematologic malignancies. The appearance of “Tumor Microenvironment” in the upper plot area indicated growing efforts to extend these approaches to solid tumors.

Fig 2. Topic-level dynamics in growth and citation impact across submodalities of cell and gene therapies.

Global Contributions and Research Productivity
Country‑level analysis (Figure 3) showed that the United States has consistently held the largest share of both total publications and high‑impact papers across all modalities, though its relative dominance has gradually declined over the past decade. China has experienced the most rapid growth, particularly in MSC research, where its publication share now surpasses that of the United States. Moreover, China has markedly improved its high‑impact paper productivity per active researcher, reaching levels comparable to major European countries.

Japan maintained a steady output, especially in cell therapy, but lagged persistently in both high‑impact paper ratio and productivity, indicating a challenge in translating research activity into influence. European countries—notably Germany, the United Kingdom, and France—demonstrated stable contributions with high research efficiency, as reflected in their high‑impact paper ratios. When productivity (high‑impact papers per active researcher) was plotted against the high‑impact ratio, the United Kingdom consistently occupied the top‑right quadrant, indicating both high efficiency and strong influence.

Fig 3. Global contributions and high-impact research productivity.

 International Collaboration and Its Impact
A growing proportion of CGT research is conducted through international collaborations, but the extent varies markedly by region (Figure 4). European countries showed the highest collaboration rates, with approximately 20–40% of all publications and nearly 50% of high‑impact papers involving international co‑authorship. In contrast, Japan and China had collaboration rates around 10%, while the United States occupied an intermediate position. At the institutional level, broader international collaboration networks—measured by the number of distinct foreign partner institutions—were positively associated with a higher share of high‑impact publications.

Fig. 4 International research collaboration in cell and gene therapies.

Bilateral co‑authorship matrices (Figure 5) revealed that the United States is the most sought‑after collaborator for most countries. However, the quality of these collaborations differed. Logistic regression analysis showed that US‑Europe (E3) collaborations were significantly and positively associated with high‑impact publication status across most modalities, whereas US‑China collaborations showed either no significant association or, in the case of HSC research, a negative association. US‑Japan collaborations were not significantly associated with high impact.

Further institutional analysis (Figure 5E–5M) suggested that the superior performance of US‑Europe collaborations may stem from deeper institutional ties and a greater concentration of top‑tier institutions. For HSC and ex vivo gene therapy, US‑Europe institutional pairs collaborated more frequently and were more likely to involve top‑tier institutions from both sides compared to US‑China pairs. This pattern was less pronounced in MSC and in vivo gene therapy, where the field is more distributed. Notably, AAV‑based gene therapy, despite its high impact, showed relatively less differentiation in institutional composition between US‑Europe and US‑China collaborations, possibly reflecting the global diffusion of AAV vector technology.

Fig. 5 Bilateral collaborative relationship in cell and gene therapy research.

Conclusion and Impact
This 35‑year bibliometric study provides a comprehensive, data‑driven map of the cell and gene therapy landscape, revealing modality‑specific trajectories that have shaped the current state of the field. HSC and ex vivo gene therapies have successfully navigated the path from nonclinical research to sustained clinical activity, whereas MSC and in vivo gene therapies face translational bottlenecks despite continued scientific interest. The centrality of AAV vectors and CRISPR‑based gene editing in in vivo gene therapy is evident from topic trends, yet their clinical expansion remains constrained, likely due to a combination of scientific, regulatory, and business factors.

The global analysis highlights the shifting geography of CGT research. The United States remains a leader in high‑impact output, China is rapidly closing the gap, and Europe continues to excel in research efficiency through deep collaborative networks. Japan’s steady volume but low influence points to a need for strategic interventions to enhance the visibility and impact of its research.

Crucially, the study underscores the value of international collaboration, particularly between the United States and Europe, as a consistent driver of high‑impact science. The findings suggest that policies encouraging cross‑border partnerships and strengthening institutional linkages could accelerate innovation, especially in areas where translation has stalled. As the field evolves, integrating bibliometric data with patent, regulatory, and funding information will be essential to build a holistic framework for understanding how basic research—such as the development of AAV vectors—translates into approved therapies and ultimately benefits patients. This study serves as a foundational resource for researchers, policymakers, and funders aiming to navigate the complex and rapidly changing landscape of cell and gene therapy.

Packaging Capacity as a Key Determinant of Gene Therapy Trajectories

PackGene stands out as a premier AAV-focused contract development and manufacturing organization (CDMO) whose comprehensive capabilities directly address the manufacturing, scale-up, and translational bottlenecks highlighted throughout the bibliometric study, enabling researchers and biotech companies to move seamlessly from high-impact academic discoveries in AAV vector design—such as those centered on CRISPR integration and tissue-specific tropism—to GMP-compliant clinical-grade production at speeds and titers that accelerate the Clinical Transition Ratio for gene therapies. With state-of-the-art facilities supporting research-grade, preclinical, and commercial-scale AAV packaging across a full spectrum of serotypes (including AAV1 through AAV9, AAVrh10, and engineered variants), PackGene delivers high-purity, high-yield vectors through proprietary triple-transfection platforms, advanced purification processes, and rigorous quality-control analytics that meet or exceed FDA, EMA, and PMDA standards, while also offering end-to-end services such as custom plasmid engineering, helper-virus-free production, stability testing, fill-finish, and regulatory support documentation to overcome the very scale-up and reproducibility challenges that have constrained gene therapy’s CTR despite decades of strong scientific attention. By providing rapid turnaround, cost-effective scalability from milligram to kilogram quantities, and specialized expertise in AAV capsid optimization for enhanced transduction efficiency and reduced immunogenicity, PackGene empowers global collaborators—particularly those in the US–Europe networks shown to produce superior high-impact outputs—to bridge the academic-to-clinical gap identified in the paper, de-risking the modality-establishment and market-expansion phases through reliable, reproducible manufacturing that aligns public-funding-driven basic research with private-sector investment needs and ultimately brings AAV-enabled therapies to patients faster, more safely, and at greater global accessibility, thereby operationalizing the data-driven recommendations for strategic cooperation and translational acceleration.

References:

https://www.isct-cytotherapy.org/article/S1465-3249(26)00012-5/fulltext