Mapping the global clinical landscape of stem cell therapies for neurological diseases from 1998 to 2023: an analysis based on the Trialtrove database

Abstract

Stem cell therapies have in many respects revolutionized the way we explore and treat neurological diseases. Characterizing past and ongoing clinical trials using stem cells for neurological diseases will provide important insights for academia, industry and government. Based on the Trialtrove database, we retrospectively analyzed 530 clinical trials initiated by the end of 2023.

Stem cell therapy is emerging as a promising treatment option for various neurological diseases, offering hope for patients with conditions previously considered untreatable. Recently, the exploration of stem cells for neurological conditions has gained increasing attention [1, 2]. However, comprehensive data on the global clinical landscape of this field, including time trends, geographic distribution, and other key aspects, remains limited. Thus, we utilized an extensive online repository that aggregates data from ClinicalTrials.gov and over 58,000 other sources, namely the Informa Trialtrove database, to develop a landscape of past and ongoing clinical trials using stem cells for neurological diseases [3]. Based on the database, we describe these trials in detail and discuss considerations for current research hotspots and future trends in this area.

We retrieved clinical trials investigating stem cell therapies for neurological diseases from the Trialtrove database, using a search methodology that included the terms (Drug Type: cell type, stem cell OR Full Text: stem cell OR Full Text: stem cells) AND Therapeutic Area: CNS. As of December 31, 2023, 1005 trials were initially identified, and 528 were selected after manual screening. We further cross-referenced our findings with ClinicalTrials.gov and the EMA web portal, identifying two additional trials in ClinicalTrials.gov that were not included in the Trialtrove database, bringing the total to 530 trials (Supplementary files 1, 2). Figure 1a shows the status of these trials, with the majority being completed (299, 56.4%). Among these, 72 trials (24.1%) reported positive outcomes (or primary endpoint(s) met) according to Trialtrove, while 15 trials (5.0%) reported negative outcomes (or primary endpoint(s) not met). The outcomes of the remaining 212 trials are either indeterminate or not otherwise specified (Table S1). A total of 127 trials (24.0%) are either planned or ongoing, indicating a continued exploration of the safety and efficacy of various stem cell types in treating neurological diseases. A small proportion of trials were terminated (65, 12.3%), with reasons including poor enrollment, business decisions, lack of funding, and lack of efficacy.

Fig. 1

Global landscape of stem cell therapy trials for neurological diseases. a: Stem cell therapy trials, by status, as of December 31, 2023. b: The number of clinical trials worldwide from 1998 to 2023, divided into five-year periods, with a standalone analysis for 2023. Each period includes the total number of trials and a breakdown by phase. c: Number of clinical trials in the top 15 countries and regions. d: Top 10 neurological diseases treated with different stem cell types. MSC: mesenchymal stem cells, HSC: hematopoietic stem cells, NSC: neural stem cells, ESC: embryonic stem cell, iPSC: induced pluripotent stem cell. Others include epithelial stem cells and dopaminergic progenitors

From 1998 to 2007, the number of trials was relatively low. However, a notable rise in the total number of trials began in the 2008–2012 period. This upward trend continued through the 2013–2017 and 2018–2022 periods (Fig. 1b). Phase II trials accounted for the highest proportion (174, 32.8%), followed by Phase I (153, 28.9%) and Phase I/II (142, 26.8%) trials (Table S1). This trend highlights a growing interest in and commitment to exploring stem cell therapies over the past decade. The trials were primarily sponsored by academia (385 trials, 72.6%), industry (176 trials, 33.2%), and the government (53 trials, 10.0%), with some trials having multiple sponsors (Table S1).

Despite the significant increase in trial numbers, the limited Phase III/IV and industry-sponsored trials suggests that stem cell therapy for neurological diseases is still in its early exploratory stages. This highlights the challenges in translating preliminary findings into broader clinical applications. In the future, industries will need more experts to meet the growing demand for stem cell treatments and to navigate the complexities of this emerging area. Policymakers should consider increasing funding and developing accelerated regulatory strategies for the review and approval process.

Most studies were conducted in the US (123, 23.2%). Among the top 15 countries and regions conducting clinical trials involving stem cells, six are from Asia, with China (93,17.5%) being the most represented Asian country. Spain leads in Europe with 25 trials (4.7%) (Fig. 1c, supplementary Excel). In contrast, only one African country, Egypt, is represented in these trials, reflecting disparities in research capacity and participation across different countries/regions. This underscores challenges such as limited resources, funding, infrastructure, and regulatory frameworks that may hinder the involvement of African countries in advanced clinical research like stem cell trials. Addressing these gaps through international collaboration could promote more equitable research and treatment opportunities.

Among the 530 clinical trials, the majority focus on conditions such as stroke (100,18.9%), multiple sclerosis (97, 18.3%), amyotrophic lateral sclerosis (60, 11.3%) and spinal cord injuries (54, 10.2%) (Fig. 1d). These trials explore the use of different stem cell types, including mesenchymal stem cells (MSCs), hematopoietic stem cells, neural stem cells (NSCs), embryonic stem cell (ESC)-derived stem cells, and induced pluripotent stem cell (iPSC)-derived stem cells. MSCs dominate the landscape (274, 51.7%) (Fig. 1d), likely due to their immunosuppressive properties and ease of acquisition. NSCs have also shown significant potential in this area, with notable contributions from Italy in recent years [4,5,6]. Meanwhile, research into ESC-derived and iPSC-derived stem cells is growing, offering potential for more targeted and effective therapies. Clinical trials using ESC and iPSC derivatives have been particularly reported in the treatment of diseases like Parkinson's disease (PD). Researchers from Lund University provided strong evidence supporting the clinical translation of human ESC derivatives (STEM-PD), which led to the initiation of the first-in-human STEM-PD Phase I/IIa trial in 2022 (NCT05635409) [7]. The US FDA also approved ESC derivatives (BRT-DA01) for a Phase I clinical trial (NCT04802733), showing no major safety issues and improvements in exploratory endpoints among 12 PD participants [8]. iPSCs have gained attention for PD treatment, with clinical trials approved in countries like Japan [9] and the US [10]. iPSCs offer the possibility of creating patient-specific therapies, which reduce the risk of immune rejection and ethical concerns, while potentially improving efficacy.

The use of the Trialtrove database, while comprehensive, may have overlooked certain trials registered exclusively on other platforms. To address this, we cross-referenced data with ClinicalTrials.gov and the EMA web portal. Nonetheless, no database is entirely exhaustive, and future updates may be required as new trials emerge.

In conclusion, clinical trials involving stem cells in the treatment of neurological diseases have developed rapidly worldwide in the past decade, offering new hope for patients and novel avenues for research. However, the clinical development of this field remains in its early stages. The future direction of stem cell therapy in neurological diseases depends on securing increased public funding, establishing clear and accelerated regulatory guidelines, sourcing diverse stem cell types, fostering global collaboration, and, most importantly, confirming the benefits of stem cells for neurological diseases.