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At least 19 recordsLinked to original sources
PubMed2026

The Potential Role of Mesenchymal Stem Cell Therapy for Moderate-to-Severe Atopic Dermatitis: A Systematic Review and Meta-Analysis of Human Clinical Trials.

Despite currently available treatment options for moderate-to-severe atopic dermatitis (AD), some patients fail to achieve adequate disease control. Emerging evidence suggests that mesenchymal stem cells (MSCs) may represent a promising therapeutic option. This systematic review and meta-analysis included four randomized controlled trials (RCTs) and one non-randomized clinical trial. Eligible studies evaluated patients with moderate-to-severe AD treated with MSCs derived from human umbilical cord blood, autologous adipose tissue, and allogeneic bone marrow. PubMed, Embase, and Cochrane were searched from inception to December 2025. Primary outcomes included the proportion of patients achieving ≥50% and ≥75% improvement from baseline in the Eczema Area and Severity Index (EASI) and safety outcomes. The meta-analysis included 236 participants. The pooled EASI-50 response rate at week 12 was 46.76% (95% confidence interval [CI]: 32.36% to 61.72%). EASI-75 response rates were 17.41% (95% CI: 5.56% to 43.03%) at week 12 and 23.97% (95% CI: 16.48% to 33.50%) at week 16. The pooled incidence of treatment-emergent adverse events was 26.86% (95% CI: 19.56% to 35.68%), with infections and infestations 7.97% (95% CI: 4.11% to 14.88%) and gastrointestinal disorders 3.52% (95% CI: 1.33% to 9.01%) being the most frequently reported. MSC-based therapy shows early promise as a potential treatment for moderate-to-severe AD, offering a possible alternative to traditional therapies. However, the current evidence is largely based on small clinical trials, underscoring the necessity for large-scale RCTs to establish the efficacy and safety of MSC-based therapy in broader patient populations.

Humans↗
PubMed2026

Single-cell vector copy number analysis of phenotypically defined long-term hematopoietic stem cells for gene therapy safety assessment.

Hematopoietic stem cell (HSC)-based gene therapy has emerged as a transformative approach for the treatment of genetic diseases; however, accurate evaluation of vector copy number (VCN) remains critical for ensuring safety. Conventional bulk VCN assays, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR), do not resolve clonal heterogeneity and cannot identify rare high-VCN cells that may contribute disproportionately to insertional mutagenesis risk. Here, we developed an accessible single-cell VCN profiling method by combining fluorescence-activated cell sorting (FACS) of phenotypically defined long-term HSCs (Lineage- CD34+ CD38- CD90+ CD45RA- cells) with whole-genome amplification followed by conventional qPCR. This approach enabled resolution of VCN distributions at single-cell level using standard laboratory techniques. Notably, single-cell analysis revealed a high VCN tail that bulk VCN analysis could not resolve. Furthermore, in a humanized mouse transplantation model, single-cell VCN profiling demonstrated that overall VCN distributions could be analyzed after engraftment, although inter-donor and inter-mouse variability was observed. Collectively, this method provides a rapid, cost-effective, and phenotypically resolved strategy for assessing VCN heterogeneity in gene-modified HSCs. Single-cell VCN profiling offers complementary insights beyond conventional bulk assays and may enhance preclinical safety evaluation of gene and cell therapy products.

lentiviral vector↗
PubMed2025

Prime Editing for p47phox-Deficient Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a severe monogenic immunodeficiency caused by damaging variants in genes required for microbicidal NADPH oxidase activity. Autosomal recessive p47phox-deficient CGD (p47-CGD) is predominantly caused by a two-nucleotide deletion in exon 2 (delGT) of NCF1. We developed PM359, an autologous CD34+ hematopoietic stem-cell therapy in which prime editing is used to correct delGT. Two participants received PM359 after myeloid conditioning with busulfan: neutrophils and platelets engrafted promptly in both patients. Adverse events were consistent with myeloid conditioning with busulfan. NADPH oxidase activity was observed in neutrophils within 1 month and was maintained for 6 months and 4 months as of the last follow-up visit in Participants 1 and 2, respectively. These results support further investigation of prime editing of CD34+ cells to treat p47-CGD. (Funded by Prime Medicine; ClinicalTrials.gov number, NCT06559176.).

Adolescent↗
PubMed2025

Multi-omics technologies: Novel tools and methods for assessing nerve injury and regeneration.

Recently, with the rapid advancement of multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, new tools and approaches have been introduced for studying nerve injury and regeneration. This review highlights the application and progress of multi-omics in uncovering the mechanisms of nerve injury, guiding the development of regenerative strategies, and promoting clinical translation. By integrating multi-omics datasets, researchers can comprehensively track dynamic molecular changes following nerve injury, including abnormal gene expression, disrupted protein signaling, altered metabolic programs, and shifts in the immune microenvironment. Single-cell multi-omics technologies resolve cellular heterogeneity, revealing the distinct functions of neurons, glial cells, and immune cell subpopulations during the injury response. Spatially resolved transcriptomics maintain the spatial context of lesion and regeneration sites, enabling precise localization for targeted interventions. Multi-omics technologies not only identify key molecular players involved in nerve regeneration but also create opportunities for personalized medicine. Nonetheless, integrating multi-omics data poses technical challenges, including high dimensionality, batch effects, and algorithmic constraints, while ethical concerns related to stem cell therapy and gene editing require stringent oversight. To transition from structural reconstruction to functional remodeling, future research should emphasize artificial intelligence-driven data integration, organ-on-a-chip modeling, and cross-disciplinary collaboration to overcome existing technical barriers and accelerate the clinical application of neuroregenerative therapies.

artificial intelligence↗
PubMed2025

Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease.

Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson's disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice-compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025.

Humans↗
PubMed2026

A therapeutic atlas of monogenic inflammatory bowel disease.

BACKGROUND AND AIMS: Evidence-based, mechanism-guided therapies are urgently needed for treating monogenic inflammatory bowel disease (mIBD). For such rare diseases, mechanistic insight is essential to guide treatment when conventional clinical trials are often not feasible. We aimed to summarize literature-based evidence and to identify knowledge gaps. METHODS: We conducted a systematic review of published manuscripts evaluating the therapeutic efficacy in mIBD. We quantified and compared the global therapeutic response score across treatments and conditions. In a subset of conditions, biomarkers of longitudinal therapeutic response were evaluated in comparison to non-monogenic pediatric IBD cohorts. RESULTS: Responses to 35 therapeutics across the 102 known genetic causes of mIBD were evaluated in 241 articles and 669 patients, summarizing 302 gene-drug responses. The efficacy of at least one pharmacological intervention was identified in 61% (n = 62/102) of the mIBD conditions, highlighting a major unmet need for effective medications in many others. Gene- and pathway-specific responses were demonstrated for several therapies, including allogeneic hematopoietic stem cell transplantation, gene therapy, and advanced therapies such as anti-TNF agents, IL-1 inhibitors, mTOR inhibitors, as well as eculizumab in CD55 deficiency, abatacept in CTLA4 deficiency, and the immunometabolic agent empagliflozin in glycogen storage disease type 1b. CONCLUSIONS: This study highlights the potential of precision medicine approaches tailored to genetic and pathway-specific mechanisms, while underscoring the urgent need for effective therapies in many monogenic conditions that remain without established treatment options.

Humans↗
PubMed2026

Temporal mismatch in allogeneic iPSC therapies: biological risks and implications for clinical translation.

INTRODUCTION: The clinical translation of pluripotent stem cell-derived therapies has entered a new phase following conditional approval of first-in-class allogeneic induced pluripotent stem cell (iPSC)-derived products in Japan. These approvals highlight both the therapeutic promise of iPSC technologies and regulatory challenges associated with evaluating complex cell-based interventions. AREAS COVERED: This report examines the evidentiary basis supporting recent approvals and reviews key biological characteristics of allogeneic iPSC-derived therapies, including pluripotency-associated instability, immunological constraints, and manufacturing-related genomic variability. Drawing on recent clinical studies and relevant experimental literature, we analyze how these multilayered risks evolve over extended time horizons and assess their implications for the interpretation of early-phase clinical data and current regulatory frameworks. EXPERT OPINION: We argue that the central challenge extends beyond limited clinical evidence to a fundamental mismatch between the temporal dynamics of biological risk and the duration of conventional clinical evaluation. As a result, early clinical observations may systematically underestimate long-term risks. Conditional approval pathways should therefore incorporate safeguards aligned with this temporal uncertainty, including long-term follow-up, rigorous post-approval evaluation, and enhanced transparency in biological and manufacturing data. Aligning regulatory design with intrinsic properties of pluripotent stem cell-derived therapies will be essential for ensuring safe and responsible clinical translation.

Humans↗
PubMed1979

[Effect of long-term cytostatic therapy on the hematopoietic stem cells].

CFU-C and diffusion chamber studies were performed in patients with teratocarcinoma, who underwent long term chemotherapy. No significant decline of bone marrow CFU-C or diffusion chamber cell recovery was found during twelve months of cytotoxic treatment. In contrast to the results in these patients the CFU-C-content of the remission marrow in leukemic patients showed a significant decrease in relation to the duration of remission and chemotherapy.

Bleomycin↗
PubMed2026

Genomic and transcriptomic quality control for an autologous iPSC-derived cell therapy for Parkinson's disease.

Toward development of an autologous, induced pluripotent stem cell (iPSC)-based cell therapy for Parkinson's disease (PD), we demonstrate successful, reproducible genomic and transcriptomic qualification of patient-derived dopaminergic neuron precursor cells (DANPCs) across multiple donors. Our analysis includes whole-genome sequencing data from fibroblasts, iPSCs, and DANPCs and the development of NeuriTest, an RNAseq-based bioinformatic analysis of DANPCs designed to predict cell quality based on empirical animal data. Autologous cell therapies are immune matched to the patient, potentially augmenting durability of benefit compared to allogeneic cells while negating the need for immunosuppression and accompanying side effects. Patient-specific iPSCs are an autologous cell source that can be differentiated to dopaminergic neurons, the cell type lost in PD. We report here our preclinical manufacturing strategy and results demonstrating efficacy in a PD rodent model and safety in a 9-month GLP toxicology study.

Parkinson’s disease↗
PubMed2026

Dual-Reporter Gene-Based Multimodal Imaging for Tracking Mesenchymal Stem Cells in Diabetic Skin Wound Repair.

BACKGROUND: Diabetic foot ulcer (DFU) is a clinically challenging complication characterized by poor healing outcomes, and conventional therapies provide limited benefit. Mesenchymal stem cell (MSC) transplantation offers a promising strategy for DFU repair. However, the low survival of transplanted MSCs in the hostile wound microenvironment, coupled with the lack of real-time, non-invasive methods to track these cells in vivo, severely hampers their therapeutic efficacy and clinical translation. METHODS: We engineered MSCs to co-express a dual reporter system comprising near-infrared fluorescent protein (iRFP) and ferritin heavy chain (FTH1). These modified cells were then integrated with a fibrin glue (FG) scaffold to create a unified platform that supports both multimodal imaging and therapeutic function within skin wounds. First, FTH1 overexpression enhances the antioxidant capacity of MSCs, while the FG scaffold provides structural support; this combination enhances cell survival and retention. Second, the iRFP/FTH1 dual reporter enables near-infrared fluorescence imaging and MRI-based localization, establishing a multimodal platform for real-time cell tracking. RESULTS: In a full-thickness skin defect model in diabetic mice, multimodal imaging revealed that transplanted cells persisted in the wound area for approximately seven days. Treatment with iRFP/FTH1-MSCs/FG significantly accelerated wound closure and promoted hair follicle regeneration and angiogenesis. Additionally, local iron deposition resulting from FTH1 expression enhanced fibroblast migration and collagen synthesis, further facilitating extracellular matrix remodeling. Mechanistic studies demonstrated that this therapy drives macrophage polarization toward the anti-inflammatory M2 phenotype and activates the PI3K-AKT-VEGF signaling pathway. These complementary effects synergistically enhance tissue regeneration and systematically improve diabetic wound healing. CONCLUSIONS: Collectively, this multimodal stem cell-scaffold system effectively integrates dynamic cell tracking with stem cell therapy during skin wound repair. It addresses a critical technical gap in visualizing stem cells within the wound microenvironment and provides valuable methodological and theoretical foundations for optimizing regenerative strategies for diabetic skin wounds.

Animals↗
PubMed2025

Cardiac hypertrophy at the crossroads: Mechanistic insights and emerging multimodal therapeutic strategies.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually. Among their diverse manifestations, cardiac hypertrophy is a clinically significant condition that predisposes patients to heart failure, arrhythmias, and and sudden cardiac death. Clinically, hypertrophy can be classified into three forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible, pathological hypertrophy most often secondary to hypertension, valvular disease, hemodynamic stress, or sustained neurohumoral activation; and hypertrophic cardiomyopathy (HCM) represents a primary genetic disorder, most often caused by mutations in sarcomeric proteins. These distinct etiologies have important therapeutic implications, as they determine how efficiently pharmacological agents can target underlying mechanisms. Conventional pharmacological treatments are widely used in clinical practice, yet they provide limited reversal of established remodeling. This therapeutic gap has driven the development of innovative modalities such as RNA-based therapeutics, exosome-mediated interventions, stem cell-derived therapies, and genome-editing technologies, which aim to modulate maladaptive signaling and restore myocardial integrity. This review integrates clinical perspectives with mechanistic insights, delineating the drivers of pathological hypertrophy while evaluating both established therapies and emerging strategies that hold promise for precision cardiology and improved patient outcomes.

Humans↗
PubMed2024

Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.

Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.

Animals↗
PubMed2025

Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.

Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer ≥ 0.1) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.

Journal Article↗
PubMed2025

Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.

Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and determine the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer [Formula: see text]) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.

Fanconi Anemia↗