Therapeutic potential of stem cells in pediatric neurology: Insights from clinical trials

Abstract

Pediatric neurological disorders comprise diverse conditions that impair nervous system function in children and contribute substantially to global disease burden. Stem cell therapy has become a promising treatment in neurology due to the cells' ability to self‐renew, ensuring a continuous supply of cells. Cells are harvested from various origins, notably embryonic tissues and adult sources such as bone marrow, adipose tissue, and umbilical cord. Therapeutic effects arise from cell or enzyme replacement, trophic support, immunomodulation, and paracrine actions of the secretome. This review summarizes clinical applications of stem cell therapies across pediatric neurological diseases—including autism spectrum disorder, cerebral palsy, traumatic brain and spinal cord injury, epilepsy, neuromuscular disorders, and lysosomal storage diseases—and appraises evidence from preliminary descriptive studies that update the field and reveal methodological limitations. Reported therapeutic effect differs markedly by cell type, disease biology, timing of intervention, dose, and delivery method, producing inconsistent clinical results. Positive functional or developmental improvements have been documented in selected reports, but safety concerns, heterogeneity in study design, short follow‐up, and variable potency assays limit conclusions. Because stem cell populations share phenotypic features but vary in therapeutic capacity, a universal, one‐size‐fits‐all strategy is unlikely to succeed. Critical gaps remain regarding long‐term safety, durability, standardized manufacturing, and optimal clinical endpoints. Continued rigorous translational research, standardized clinical trials, and expanded long‐term surveillance are essential to optimize these therapies and improve outcomes for affected children and to ensure equitable access for diverse pediatric populations worldwide and sustainable implementation.

Key characteristics of stem cells. Stem cells are essential in therapy due to their ability to self‐renew, ensuring a continuous supply of cells. They can derive from various sources, primarily embryonic tissue, and adult organs such as bone marrow and adipose tissue. In cell replacement therapy, they can differentiate into specific cell types to replace damaged cells. Additionally, their secretome, which contains a variety of bioactive molecules, plays a crucial role in regulating the immune response and promoting tissue repair. HSC, hematopoietic stem cells; iPSC, induced pluripotent stem cell; MSC, mesenchymal stem cells; NSC, neural stem cells; UCB, umbilical cord blood.

Highlights

• Reviews clinical trial outcomes of stem cell‐based therapies for pediatric neurological disorders (PNDs).

• Highlights preliminary findings in underexplored PNDs.

• Promising results in autism spectrum disorder and cerebral palsy, but treatments are still investigational.

• Therapeutic effects vary by disease type, stem cell source, and intervention timing.

1. INTRODUCTION

Pediatric neurological disorders (PNDs) encompass a range of conditions that disrupt the normal functioning of the nervous system in children. These disorders contribute significantly to the global burden of diseases, leading to premature death or lifelong disabilities. ¹ Some of the most commonly encountered PNDs include autism spectrum disorder (ASD), epilepsy, cerebral palsy (CP), neuromuscular diseases, and brain injuries. Additionally, lysosomal storage diseases (LSDs) result in severe neurological decline, although their causes and clinical presentations differ from those of other neurological disorders. ² The factors contributing to these neurological disorders are multifaceted and can include genetic predisposition, neurotoxins, hypoxia, infections, and injuries. They usually manifest as impairments in physical, motor, speech, and cognitive functions. ³ Unfortunately, current treatment options for neurological diseases are limited, and the approved medications have yet to achieve the desired therapeutic effect. ⁴

Nevertheless, cell‐based therapy is emerging as a promising avenue in regenerative medicine, with the potential to alleviate the severity of major diseases and injuries—particularly in the field of neurology. Both allogeneic and autologous stem cell‐based transplants have shown promise in clinical trials for ASD, ⁵ CP, ⁶ and neuronal ceroid lipofuscinosis (NCL). ⁷ Despite certain similarities, stem cells can differ significantly, especially in their epigenetic and protein profiles, which complicates the development of a universal stem cell‐based therapy applicable to all clinical scenarios. ⁸ Stem cell research faces many challenges, as the US Food and Drug Administration has established a policy framework and guidelines that restrict large sample sizes to safeguard subjects. As noted by Kelly, ⁹ most treatments don't progress beyond phase II trials; this has been particularly true for many PNDs. Nonetheless, these clinical trials provide valuable insights. While the majority of interventions center on stem cells, several trials incorporate mixed cell populations, warranting cautious interpretation.

This review examines the clinical application of stem cell‐based therapies in PNDs, encompassing both direct stem cell interventions and heterogeneous approaches such as umbilical cord blood (UCB) and bone marrow‐derived mononuclear cells (BM‐MNCs). It synthesizes current evidence with a focus on preliminary clinical findings in rare pediatric populations, where conventional treatment options remain limited. Given the scarcity of robust trials, studies with limited methodological rigor were included to highlight early signals of feasibility and therapeutic promise. By critically appraising both preclinical and clinical data, the review underscores the need for standardized trial protocols to enable meaningful outcome comparisons and guide the development of scalable, evidence‐based therapies for these underexplored conditions.

2. FUNDAMENTALS OF STEM CELL‐BASED THERAPIES

Cell‐based therapies in pediatric neurology predominantly rely on stem cells, which are a unique group of unspecialized cells known for their ability to self‐renew and differentiate into specialized cells through symmetric or asymmetric divisions. ¹⁰ Such plasticity supports the therapeutic potential of regenerative medicine, where researchers aim to create new cell therapies for conditions that are currently hard to treat. ¹¹

In the context of PNDs, stem cells employed in therapeutic approaches can be categorized according to their differentiation potential. Pluripotent stem cells, such as embryonic stem cells (ESCs), possess the capacity to differentiate into all cell types derived from the three germ layers: ectoderm, mesoderm, and endoderm. In contrast, multipotent stem cells, including mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), and neural stem cells (NSCs), exhibit a more restricted lineage potential, typically differentiating into cell types within a specific tissue or organ system. ¹² MSCs, which can be derived from BM, adipose tissue, or the UC, provide therapeutic benefits mainly through immunomodulation and the secretion of neurotrophic factors. ¹³ NSCs, on the other hand, focus on replacing lost neuronal cells. ¹⁴ HSCs are primarily derived from BM, and are commonly used in metabolic disorders such as LSD, where they contribute by enzyme replacement and aiding systemic repair. ¹⁵ It is essential to underscore the potential for immunological rejection following allogeneic transplantation. Fortunately, they are generally regarded as a preferred source of multipotent cells owing to their low immunogenicity; this characteristic enables them to effectively modulate the host immune response post‐transplantation. Furthermore, a viable approach to mitigating graft rejection involves selecting a donor with human leukocyte antigen (HLA) compatibility closely matching that of the recipient. Additionally, UC stem cells offer advantages over BM stem cells, as a perfect HLA match is not strictly necessary. This is attributed to the immaturity of cells obtained from UCB, which limits the risk of graft‐versus‐host disease (GVHD). ¹⁶

MSCs remain among the most widely explored stem cell types. Their paracrine activity, mediated through the secretion of bioactive molecules, plays a central role in modulating nearby cells. Preclinical studies demonstrate that MSCs‐derived extracellular vesicles can enhance neuronal recovery in models of neurological disorders via targeted delivery to injured cells. Specific exosomal microRNAs, such as miR‐216a for traumatic brain injury (TBI) and the miR‐17‐92 for stroke, have shown promising neuroprotective effects. These microRNAs act as key regulators of gene expression, mitigating neuropathological changes across various conditions. Additionally, BM‐MSCs exhibit potent immunosuppressive properties, attributed to their elevated secretion of anti‐inflammatory cytokines like interleukin‐10 (IL‐10) and transforming growth factor‐beta 1 compared to other MSCs sources. ¹⁷

Moreover, clinical trials have incorporated heterogeneous cell populations, including UCB, BM‐MNCs, and adipose‐derived regenerative cells (ADRCs). Although these populations contain only limited subpopulations of stem cells, they still exert significant paracrine and immunomodulatory effects. For instance, UCB consists of a mixture of red blood cells and MNCs. Clinically, treatment protocols involve isolating the mononuclear fraction to obtain a more defined population composed of hematopoietic and nonhematopoietic progenitors, lymphocytes, monocytes, and a small proportion of MSCs. These cells typically express the anti‐inflammatory cytokine interleukin‐10 while exhibiting reduced levels of pro‐inflammatory cytokines (IL‐2, IL‐6, tumor necrosis factor‐alpha [TNF‐α]). This cytokine profile supports anti‐inflammatory activity and contributes to the prolonged immunodeficient state observed after UCB transplantation. ¹⁸ Similarly, BM‐MNCs comprise a heterogeneous mixture of self‐renewing MNCs, including diverse stem and progenitor cell types—HSCs and MSCs—as well as stromal elements (bone spicules, adipocytes, and fibroblasts), and mature blood cells. Transplanting such a mixed population enables a broad spectrum of therapeutic effects. ¹⁹ Furthermore, ADRCs have emerged as a promising candidate due to their accessibility, abundance, and versatile regenerative capabilities. Unlike BM, adipose tissue offers a minimally invasive and plentiful reservoir of regenerative cells, making it an ideal candidate for autologous therapies. ADRCs are a heterogeneous population that includes adipose‐derived stem cells, endothelial cells, endothelial progenitor cells, pericytes, fibroblasts, immune‐modulatory cells, smooth muscle cells, and a variety of cytokines. Acting synergistically, these components contribute to tissue repair through multiple mechanisms. Paracrine signaling plays a central role, with ADRCs secreting a wide collection of factors that stimulate angiogenesis and support tissue restoration and remodeling. ²⁰

Lastly, stem cell‐based therapies are sometimes combined with progenitor or precursor cells, which are differentiated derivatives of stem cells with restricted lineage potential. In the context of PNDs, such combinatorial approaches have included BM‐derived CD133‐positive cells and neural progenitor cells (NPCs). CD133‐positive cells are hemangioblasts that represent a highly uncommitted population within adult BM. They exhibit both hematopoietic and vasculogenic potential, making them valuable candidates for regenerative therapy. Their incorporation can activate pathways that promote angiogenesis. ²¹ On the other hand, NPCs and NSCs have both great potential for the treatment of neurological disorders. Thus, this combination offers a multifaceted approach to neural repair by harnessing the strengths of both cell types. ²² This strategy aims to improve cell survival, integration, and functional recovery, making it a promising avenue.

3. Autism spectrum disorder

ASD is a complex neurodevelopmental disorder that manifests in early childhood and is characterized by deficits in social interaction and communication, alongside repetitive behaviors and restricted interests. ²³ Its causes are not fully understood but a combination of genetic predisposition and environmental factors, such as immune dysregulation, encephalitis, and viral infections, is known to increase susceptibility. ²³ ASD presents with wide‐ranging symptoms and comorbidities, making treatment complex. Despite behavioral and pharmacological interventions, many individuals see limited improvement, driving the search for more effective therapies. ²⁴ ASD has become a prevalent disorder that significantly impacts individuals, their families, and society, highlighting the urgency for developing novel therapeutic approaches. Among emerging options, stem cell therapy, particularly using MSCs, shows promise due to their immunomodulatory and neuroprotective properties, which may address key aspects of ASD pathology. ²⁵

Preclinical studies suggest that stem cell therapy may hold therapeutic promise for ASD through various mechanisms, though findings remain difficult to generalize due to the heterogeneity of the disorder and variability in experimental models. Rodent models of ASD have shown that UC‐derived stem cells can suppress neuroinflammation and enhance brain connectivity via paracrine signaling. These cells secrete neurotrophic factors that promote neurogenesis, angiogenesis, synaptic formation, and remyelination of damaged axons. ²⁶ Therefore, a comprehensive synthesis of the available clinical trial data is essential to provide a balanced assessment of the potential of stem cell therapy for pediatric ASD and to guide future research endeavors.

Adult stem cells, particularly those derived from UCB, and BM‐derived stem cells have been the focus of multiple clinical investigations in pediatric ASD. Table 1 provides an overview of the key characteristics and outcomes of these trials, highlighting the therapeutic potential and current limitations of stem cell‐based interventions in this population.

Table 1.

Baseline characteristics of clinical trials on stem cell therapy for autism spectrum disorder.

Author (year)	Disease	Sample size (n)	Age (years)	Type of stem cell	Origin	Outcome	Ref.
Dawson et al. (2017)	ASD	Treated: 25⁎	2–5	UCB (single dose, IV)	Autologous	Improved sociability, communication, adaptive behavior, symptoms, illness severity, and expressive vocabulary after 6 M. Improved overall illness and eye gaze tracking after 6 and 12 M.	[27]
Chez et al. (2018)	ASD	Treated: 15, Placebo: 15	2–6	UCB (single dose, peripheral IV)	Autologous	Minimal efficacy. No significant improvements after 6 and 12 M.	[28]
Wong et al. (2024)	ASD	Treated: 19	4.15 ± 0.62	UCB (single dose, IV)	Autologous	Minimal efficacy. No change in adaptive behavior and cognition Improvement in language, sameness behavior after 12 M. Improvement in compulsive behavior and externalizing problems after 6 M. Improvement in social behavior at 6 and 12 M.	[29]
Nguyen Thanh et al. (2021)	ASD	Treated: 30⁎	3–7	BM‐MNCs (2 doses, IT) + Educational intervention	Autologous	Improvements in many aspects: severity, sociability, adaptive behavior, repetitive behavior, communication, eye contact, expressive. language, sleeping, sensory abnormality, and daily living skills.	[30]
Sharifzadeh et al. (2021)	ASD	Treated: 14 Control: 18	5–15	BM‐MSCs (2 doses, IT) + Rehabilitation therapy + Risperidone (low dose)	Autologous	Limited efficacy after 6 and 12 M. Decrease in illness severity based on CGI scale.	[31]
Lv et al. (2013)	ASD	Treated: 22†, Control: 14	3–12	UCB‐MNC (first doses, IV 3 other doses, IT) + UC‐MSCs Rehabilitation therapy	Allogeneic	Improvement in autistic behavior (CARS score), aberrant behavior, and severity of illness in combination therapy. No changes in hyperactivity, irritability, and inappropriate speech.	[32]

Abbreviations: ASD, autism spectrum disorder; BM‐MNCs, bone marrow‐derived mononuclear cells; BM‐MSCs, bone marrow‐derived mesenchymal stem cells; CARS, childhood autism rating scale; CGI, Clinical Global Impression; IT, intrathecal; IV, intravenous; M, month; UCB, umbilical cord blood; UCB‐MNC, umbilical cord blood‐derived mononuclear cells; UC‐MSCs, umbilical cord‐derived mesenchymal stem cells.

^⁎Uncontrolled clinical trials.

^†Among the 22 patients, 14 were treated with cord blood‐mononuclear and rehabilitation therapy, while the other 9 with a combination of cord blood‐derived mononuclear cells and umbilical cord blood‐derived mononuclear cells.

3.1. Umbilical cord blood cells

Dawson et al. ²⁷ conducted a phase I open‐label trial showing that a single infusion of autologous cord blood cells was safe and led to improvements in socialization, communication, adaptive behavior, and eye gaze tracking. However, a placebo‐controlled crossover trial by Chez et al. ²⁸ found no statistically significant differences, despite confirming safety and feasibility. Similarly, Wong et al. ²⁹ reported inconsistent improvements in autism symptoms, language, and cognitive skills, despite global symptom and sociability improvements. Notably, follow‐up analyses linked observed social and communication improvements to increased cortical connectivity between several areas, such as the left thalamus and the hippocampus through the fornix. ³³ In addition, electrophysiological recordings deciphered a normalization of the electroencephalogram (EEG) spectral characteristics, which was described as a U‐shaped power profile in ASD patients, a profile characterized by excessive power in low‐frequency and high‐frequency bands and reduced power in a midrange‐frequency band. ³⁴ These inconsistencies may stem from differences in sample size, patient characteristics, and outcome measures, highlighting the need for more targeted and larger‐scale studies.

3.2. Bone marrow‐derived cells

Nguyen Thanh et al. ³⁰ demonstrated that transplantation of BM‐MNCs combined with educational interventions led to significant improvements in adaptive capacity, social communication, repetitive behavior, hyperactivity, language, and daily living skills over 18 months. In contrast, Sharifzadeh et al. ³¹ found that BM‐MSCs alone produced modest improvements when combined with Risperidone and rehabilitation therapy. In the context of heart failure, BM‐MNCs demonstrated a slight advantage over BM‐MSCs as well. ³⁵ These differences may be attributed to the broader cellular composition of BM‐MNCs, which support neurogenesis, angiogenesis, and immunomodulation more effectively than MSCs alone. Additionally, MSCs may lose functionality over time, and preconditioning or genetic modification could enhance their overall therapeutic efficacy. ³⁶

3.3. Combination therapies

Lv et al. ³² reported that combining cord blood MNCs (CBMNCs) with UC‐derived MSCs (UC‐MSCs) and rehabilitation therapy yielded superior outcomes compared to CBMNCs alone. This suggests that multimodal approaches integrating stem cell therapy with behavioral interventions may amplify therapeutic effects.

Despite promising results, current clinical evidence for stem cell therapy in ASD is limited by methodological flaws. Trials like Dawson et al. ²⁷ and Chez et al. ²⁸ suffer from small sample sizes, while others vary in injection protocols and rely on caregiver reports or non‐standardized assessments. Long‐term follow‐up is rare, and diagnostic tools remain limited. A comprehensive synthesis of available data is needed, and future research must prioritize rigorously designed randomized controlled trials with standardized protocols and validated outcome measures to establish the safety and efficacy of stem cell therapy for pediatric ASD (Table 1).

4. Cerebral palsy

CP is a nonprogressive neurodevelopmental disorder resulting from early brain injury or abnormal brain development, typically occurring before, during, or shortly after birth. It manifests as motor impairments, spasticity, and postural dysfunction, often accompanied by secondary consequences such as frequent seizures, cognitive impairment, speech difficulties, and trouble swallowing. ³⁷ The severity of CP can be classified using the Gross Motor Function Classification System, which divides motor function into five levels ranging from mild (Level I) to severe impairment (Level V). Higher levels reflect increasing difficulty with mobility, posture, and independence, often indicating more complex symptoms and a greater need for assistive support. ³⁸ Pediatric stem cell therapy has been a primary focus for CP. Numerous trials were conducted over the years, incorporating different sources of stem cells, including cord blood cells, BM‐derived nucleated cells, MSCs, and NSCs, as summarized in Table 2. Although conventional therapies such as rehabilitation are being integrated, their effectiveness in improving motor functions is limited in more advanced cases. ⁵⁰

Table 2.

Baseline characteristics of clinical trials on stem cell therapy for cerebral palsy.

Author (year)	Disease	Sample size (n)	Age (years)	Type of stem cell	Origin	Outcome	Ref.
Sun et al. (2017)	CP	Treated: 31 Placebo: 32	1–7	UCB nucleated cells (single, low, or high dose, IV)	Autologous	No significant difference between the placebo and the treated group. Gross motor function improvement in the group with high dose infusion compared with the low dose after 1Y. Improved brain connectivity.	[39]
Kang et al. (2015)	CP	Treated: 17 Placebo: 17	6–20	UCB (single dose, IV or IA)	Allogeneic	Improvements in muscle strength at 1 and 3 M. Improvements in gross motor performance at 6 M. Decreased periventricular inflammation.	[40]
Sun et al. (2021)	Severe CP	Treated: 15⁎	1–6	HLA fully/partially matched sibling UCB cells (single dose, IV)	Allogeneic	No adverse events were associated with UCB infusion. Improved motor functions after 6 M.	[41]
Crompton et al. (2022)	CP	Treated: 12⁎	2–11	HLA fully matched sibling UCB cells (single dose, IV)	Allogeneic	Three adverse events related to the intervention, but overall safe. No meaningful changes in gross motor function.	[42]
Gu et al. (2020)	CP	Treated: 20 Placebo: 20	4.29 ± 0.39	UC‐MSCs (four doses, IV)	Allogeneic	Improvement in gross motor and cognitive functions after 12 M. Metabolic activity increased by over 50% in all cerebral regions of 3 patients.	[43]
Amanat et al. (2021)	CP	Treated: 36 Control: 36	4–14	UC‐MSCs (single dose, IT)	Allogeneic	Improvement in gross motor functions, self‐care, mobility, quality of life, and spasticity after 12 M. Improvement in white matter structure.	[44]
Zarrabi et al. (2022)	CP	Treated: 36 Placebo: 36	4–14	HLA fully‑matched UCB‐MNC (single dose, IT)	Allogeneic	Improvement in gross motor functions, spasticity, self‐care, and quality of life after 12 M. Improvements in white matter connectivity.	[45]
Sun et al. (2022)	CP	Treated: 31⁎	2–5	UCB‐nucleated cells (single dose, IV)	Allogeneic	Improvements in gross motor functions after 12 M.	[46]
Sharma et al. (2012)	CP	Treated: 20⁎	Mean 8.6	BM‐MNCs (single dose, IT) + Neurorehabilitation	Autologous	Improvements in symptoms such as muscle tone (75%), leg/hand movements (55%), speech (50%) and neck holding (45%).	[47]
Zali et al. (2015)	CP	Treated: 12⁎	4–10	Bone marrow‐derived CD133+ progenitor cells (single dose, IT)	Autologous	Significant improvements after 6 M in motor functions, the severity of spasticity, cognition, abnormal posture, and contracture.	[48]
Lv et al. (2023)	CP	Treated: 15 Control: 10	3–12	NSCs (three doses, IN) + Rehabilitation therapy	Allogeneic	IN administration is tolerated. Improvements at the level of gross and fine motor functions, self‐care, expression, social skills, and sleep quality. Brain structural and functional improvements.	[49]
Chen et al. (2013)	Moderate to severe CP	Treated: 30 Control: 30	5.53 ± 1.2	NSCs‐like cells derived from BM‐MSCs (two doses, IT)	Autologous	Motor function improvements. No language function recovery.	[50]

Abbreviations: BM‐MNCs, bone marrow‐derived mononuclear cells; BM‐MSCs, bone marrow‐derived mesenchymal stem cells; CP, cerebral palsy; HLA, human leukocyte antigen; IA, intra‐arterial; IN, intranasal; IT, intrathecal; IV, intravenous; M, month; NSCs, neural stem cells; UCB, umbilical cord blood; UC‐MSCs, umbilical cord‐derived mesenchymal stem cells; Y, year.

^⁎Uncontrolled clinical trials.

Preclinical studies have demonstrated the potential of stem cells to restore motor function and modulate neuroinflammation. For instance, the transplantation of NSCs in a CP rat model restored motor functions and improved gait parameters and symmetry ⁵¹ while human UC‐MSCs enhanced behavioral and physiological outcomes by downregulating the NogoA/NgR/Rho pathway—a major molecular mechanism that inhibits axonal regeneration and neural plasticity. These effects are thought to be mediated through secretion of growth factors, immunomodulation, activation of endogenous stem cells, and antiapoptotic effects. ⁵²

Stem cell therapy for CP has primarily focused on UCB and its derivatives. Sun et al. ³⁹ reported improvements in gross motor function following autologous UCB infusion, with higher cell doses correlating with enhanced outcomes. This increase corresponded with improved brain connectivity in the sensorimotor network, aligning with previous analyses that associated enhanced white matter connectivity with motor skills attributed to the paracrine signaling of UCB stem cells. ⁵³ Similarly, Kang et al. ⁴⁰ observed motor improvements linked to transient increases in pentraxin‐3 and toll‐like receptor 4, suggesting a role for innate immune modulation. In fact, pentraxin 3 has been shown to have a neuroprotective effect and promote blood flow and angiogenesis. ⁵⁴ While autologous stem cells are preferred for their safety and compatibility, not all children have preserved their UCB. Sibling and allogeneic UCB infusions have shown safety and potential efficacy, ⁴¹ , ⁴² warranting future randomized controlled trials to assess the potential efficacy of partially matched siblings and unrelated UCB donors. Gu et al. ⁴³ demonstrated improvements in motor and cognitive function following UC‐MSCs infusion combined with rehabilitation, with increased cerebral metabolic activity. Likewise, intrathecal MSCs injections have also shown promise in enhancing motor functions and white matter integrity, ⁴⁴ and the transplantation of a heterogenous population of UC‐derived cells also showed significant improvement. ⁴⁵ , ⁴⁶ However, allogeneic stem cell procedures require close monitoring, as some patients experience manageable adverse effects like fever. Therefore, clinical trials have explored BM as an alternative stem cell source. Sharma et al. ⁴⁷ showed that BM‐MNCs have yielded functional gains in musculoskeletal symptoms. Zali et al. ⁴⁸ demonstrated the safety of intrathecal administration of CD133⁺ enriched progenitor cells, noting potential short‐term benefits on neurological functions due to their enhanced regenerative capacity. Lastly, NSCs offer a promising autologous alternative, with early evidence of recovery following intranasal transplantation, including alleviation of symptoms related to sociability, fine motor functions, sleep quality, and daily activities, along with functional and structural brain improvement. ⁴⁹ Children tolerated well NPCs, with no documented allogeneic immune responses, despite some manageable adverse events. Given ethical concerns over using NPCs from aborted fetuses, Chen et al. ⁵⁰ examined induced pluripotent stem cells, successfully inducing NSCs‐like cells from autologous MSCs and achieving better short‐term recovery of motor function through intraspinal transplantation.

The CP literature included several well‐designed randomized controlled trial alongside many uncontrolled or open‐label studies, with risk of bias ranging from low in double‐blind sham or placebo‐controlled trials to serious or critical in uncontrolled designs. Stronger trials, such as Zarrabi et al., ⁴⁵ Kang et al., ⁴⁰ Sun et al., ³⁹ Amanat et al., ⁴⁴ and Gu et al. ⁴³ used objective motor function scales, though sample sizes were modest, and heterogeneity in cell type, dose, and delivery route complicated interpretation. While randomized controlled trials provide encouraging safety and efficacy signals, the evidence base still requires replication in larger, multicenter trials before firm conclusions can be drawn. Outcome measures vary widely, ranging from caregiver reports to non‐standardized behavioral assessments, complicating cross‐study comparisons. Yet, uncontrolled trials provide encouraging results as well (Table 2).

5. EPILEPSY

Epilepsy is a chronic neurological disorder characterized by the recurrence of unprovoked seizures due to abnormal electrical activity in the brain. Pediatric epilepsy can be classified into several types based on seizure characteristics and their causes. Idiopathic epilepsies typically have genetic origins without an identifiable cause, whereas symptomatic epilepsies are associated with identifiable brain abnormalities or injuries. Furthermore, generalized seizures involve the entire brain, while focal seizures originate from specific regions of the brain. It is estimated that 20%–40% of epileptic children develop drug‐resistant epilepsy (DRE) in which seizures persist even after the administration of at least two tolerable and adequate antiseizure medications. ⁵⁵

The hallmark of epilepsy is an imbalance between excitatory and inhibitory neurotransmission in the brain. Prolonged or chronic seizures can result in neuronal damage and death, activation of astrocytes, production of reactive oxygen species, and mitochondrial dysfunction. Therefore, the rationale behind stem cell therapy includes replacing damaged cells, promoting neurogenesis, secreting neuroprotective factors, and reducing neuroinflammation. These mechanisms could potentially restore normal brain function and alter the disease process in epilepsy. ⁵⁶ Experimental evidence on epileptic rodents showed promising results. The grafting of GABAergic interneuron progenitors into the brain of mice effectively controlled seizures and abnormal behavior. ⁵⁷ Despite the heterogeneity of epilepsy, stem cells have only been transplanted in pediatric DRE [Table 3]. In fact, some DRE cases involve impairment in cellular and humoral functions, which may contribute to seizure development and drug resistance.

Table 3.

Baseline characteristics of studies on stem cell therapy for epilepsy.

Author (year)	Disease	Sample size (n)	Age	Type of stem cell	Origin	Outcome	Ref.
Szczepanik et al. (2020)	AR‐E	Treated: 6⁎	7–16Y	ADRCs (3 doses, IT)	Autologous	No serious adverse events. Improvements in seizure frequency in 5/6 patients. Improvements in some cognitive functions and daily functioning.	[58]
Milczarek et al. (2018)	DRE	Treated: 4⁎	11M–6Y	BMNC (single dose, IV, and IT) + BM‐MSCs CD271+ population (4 doses, IT) + Neurorehabilitation therapy + Pharmacological therapy	Autologous	Clinical and quality of life ameliorations. Neurological improvements: reduction in epileptic seizures and SE episodes. Improvement in neuropsychological symptoms. Partial normalization of the bioelectrical activity of the brain.	[59]

Abbreviations: ADRCs, adipose‐derived regenerative cells; AR‐E, autoimmune refractory epilepsy; BM‐MSCs, bone marrow–derived mesenchymal stem cells; BMNC, bone marrow nucleated cells; CP, cerebral palsy; D, days; DRE, drug‐resistant epilepsy; IT, intrathecal; M, month; Y, year.

^⁎Uncontrolled clinical trials.

Szczepanik et al. ⁵⁸ studied the intrathecal infusion of autologous ADRCs in children with autoimmune conditions. The results showed some improvements in daily functioning, with one of six patients achieving full remission for 3 years. Three patients had reduced seizure frequency, while two were unresponsive. A temporary decrease in inflammation was noted, but returned to abnormal levels after 12 months. ⁵⁸ Additionally, administering BM‐MSCs yielded better outcomes in four patients. Milczarek's ⁵⁹ trial involved delivering BM nucleated cells followed by multiple injections of CD271⁺ cells, a unique population of MSCs. After the second transplantation, a gradual reduction in seizure frequency was reported, with a complete cessation of life‐threatening status epilepticus episodes in three patients and a shift to less polymorphic epilepsy. ⁵⁹ This population is associated with higher proliferation, cytokine secretion, immunosuppression, and vascularization abilities, ⁶⁰ which may explain its enhanced protective effects on DRE.

The current field of clinical trials for stem cell therapy in pediatric epilepsy is still in an early stage of development. Epilepsy studies were uniformly small, uncontrolled, and exploratory, with a critical risk of bias for efficacy interpretation. None were randomized, and most relied on seizure frequency reports without blinded verification, making them vulnerable to placebo effects and reporting bias, particularly when outcomes were caregiver‐reported. Patient populations and interventions were heterogeneous, and while feasibility and safety data are emerging, the evidence is insufficient to establish efficacy at this stage. These trials indicate that stem cell therapies may be a promising option for alleviating epileptic episodes. However, further research is necessary to determine the optimal regimens, microenvironments, and timing for stem cell differentiation and implantation. To prove its effectiveness and safety, advanced preclinical studies along with larger clinical trials must be conducted (Table 3).

6. CENTRAL NERVOUS SYSTEM INJURIES

Central nervous system (CNS) injuries in children—including TBI, hypoxie‐ischemic encephalopathy (HIE), and spinal cord injury (SCI)—can result in long‐term neurological deficits due to limited regenerative capacity. These injuries often lead to motor dysfunction, cognitive impairment, and behavioral disturbances, with few effective restorative treatments currently available (Table 4).

Table 4.

Baseline characteristics of studies on stem cell therapy for central nervous system injuries in newborns.

Author (year)	Disease	Sample size (n)	Gestational age or age	Type of stem cell	Origin	Outcome	Ref.
Cotten et al. (2014)	HIE	Treated: 23 Control: 83	34–40 W,‡ First postnatal hours§	UCB cells in neonates (4 doses, IV) + Hypothermia therapy	Autologous	Fresh autologous UCB infusion is feasible.	[61]
Cotten et al. (2023)	HIE	Treated: 6⁎	36–41 W,‡ First postnatal hours§	Cord tissue mesenchymal stromal cells in neonates (single dose, a second dose for 2/6, IV)	Allogeneic	All babies survived. Developmental assessment showed average to below average scores at 12 M and 17 M.	[62]
Ahn et al. (2018)	IVH	Treated: 9⁎	26.1 ± 2.1 W,‡ 11.6 ± 0.9 days§	CB‐MSCs (single low dose for 3 and single high dose for 6 patients, ICV)	Allogeneic	Safe and feasible treatment when administered 7–15D after birth. No mortality. Improvements in the cytokines and growth factor profiles in some patients.	[63]
Baak et al. (2022)	PAIS	Treated: 10⁎	40.3 W,‡ 3–5 days§	Bone marrow‐derived mesenchymal stromal cells (single dose, IN)	Allogeneic	The trial was feasible and safe on neonates until the endpoint, which was 3 M.	[64]
Luan et al. (2013)	CVI	Treated: 25 Control: 27	Median 18 M§	Neural Stem/Progenitor cells (single dose, ICV)	Allogeneic	Significant increase in visual recovery. Increased signaling within the occipital lobe and the visual pathways.	[65]
Cox et al. (2024)	Severe TBI	Treated: 27 Placebo: 19	5–17 Y§	BM‐MNCs (single low dose or single high dose, IV)	Autologous	Preservation of white matter and corpus callosum structure and connectivity. Clinically, there was a 3D reduction in the need for mechanical ventilation and a decrease in intracranial pressure monitoring days.	[66]
Sharma et al. (2020)	SCI	Treated: 11⁎	<18§, ¶	BM‐MNCs (single dose, IT) + Neurorehabilitation	Autologous	Symptom improvements. Early intervention (before 18Y) and multiple doses of BM‐MNCs have a better functional outcome.	[67]
Sharma et al. (2012)	SCI	Treated: 4⁎	Mean 8.8 Y¶	BM‐MNCs (single dose, IT) + Neurorehabilitation	Autologous	Improvements were reported regarding muscle strength, spasticity, sensation, urine control, and sitting balance.	[47]

Abbreviations: BM‐MNCs, bone marrow‐derived mononuclear cells; CB‐MSCs, cord blood‐derived mesenchymal stem cells; CVI, cortical visual impairment (neonatally induced); HIE, hypoxic‐ischemic encephalopathy; ICV, intra‐cerebro‐ventricular; IN, intranasal; IT, intrathecal; IV, intravenous; IVH, intraventricular hemorrhage; M, month; PAIS, perinatal arterial ischemic stroke; SCI, spinal cord injury; TBI, traumatic brain injury; UCB, umbilical cord blood; W, week; Y, year.

^⁎Uncontrolled clinical trial.

^‡Gestational age.

^§Age at the beginning of the trial.

^¶This trial encompassed 180 patients from all ages, of which 11 were below 18 years. A sub‐analysis examined the factor of age.

6.1. Perinatal brain injuries

Perinatal brain injuries refer to a variety of conditions that arise around the time of birth, a period when the brain is particularly vulnerable and susceptible to external insults. These injuries are major contributors to lifelong neurodevelopmental disabilities and result from various perinatal occurrences. Among the most researched are HIE, intraventricular hemorrhage (IVH), and perinatal arterial ischemic stroke (PAIS). While each condition has its unique causes and biological mechanisms, they all share a common characteristic: An interruption of normal brain development during a crucial stage. This interruption establishes conditions for lasting cognitive, motor, and sensory impairments. Increasingly, researchers and clinicians are concentrating on regenerative methods, particularly stem cell therapy, as a promising strategy to enhance existing treatments and utilize the brain's potential for recovery.

6.1.1. Hypoxie‐ischemic encephalopathy

HIE is a serious neonatal condition caused by insufficient oxygen and blood flow to the brain, often resulting in long‐term neurological impairments. Estimates indicate that 20%–40% of affected infants either die or develop profound disabilities by the age of two. ⁶⁸ Cooling therapy is the conventional treatment, offering partial neuroprotection. Yet around 30% of cooled infants either die or survive with significant impairments. ⁶¹ Accordingly, stem cell therapy may rather be an add‐on to cooling therapy.

Preclinical studies have demonstrated that stem cells, particularly NSCs, can restore motor function, reduce lesion volume, and improve behavioral outcomes in HIE animal models. Although endogenous NSCs possess the ability to self‐repair following brain injury, their response is often insufficient and requires time to proliferate and migrate to the affected area. Therefore, the transplantation of exogenous NSCs may be a more effective approach to enhance brain recovery after injury. ⁶⁹

Clinically, a 2014 study demonstrated the feasibility of intravenous infusions of fresh autologous UCB cells in neonates with HIE. The outcomes aligned with preclinical findings, showing improved neurological recovery when infusions were administered shortly after the hypoxic insult. ⁶¹ However, the logistical challenge of collecting, processing, and delivering stem cells within the first few hours after birth remains a significant barrier to widespread implementation. To address this, Cotten et al. ⁶² shifted focus to allogeneic mesenchymal stromal cells from UC tissue, which offer greater availability and logistical flexibility. In their study, six neonates with moderate to severe HIE received infusions, all of whom survived. Developmental assessments revealed age‐appropriate to low‐average scores, suggesting potential neuroprotective effects. ⁶²

Although UC‐derived cell therapy shows promise, it remains in the early stages of clinical evaluation. Larger, controlled trials are essential to establish statistical significance and long‐term efficacy. An ongoing trial is currently investigating the safety and feasibility of autologous UCB stem cell therapy in neonatal HIE, with completion expected in 2028. ⁷⁰

6.1.2. Intraventricular hemorrhage

Prematurely born infants are at increased risk of developing neurological complications later in life, largely due to the high incidence of IVH. This condition is particularly prevalent among neonates born before 29 weeks of gestation. In these cases, bleeding typically occurs within the ventricular system due to the rupture of fragile vessels in the highly vascularized subependymal germinal matrix. ⁷¹

Studies indicate that over half of preterm infants with severe IVH either succumb to the condition or develop posthemorrhagic hydrocephalus (PHH), often necessitating shunt placement. In the absence of effective treatments to mitigate brain injury or halt PHH progression, Ahn et al. ⁶³ investigated the safety and feasibility of intraventricular transplantation of allogeneic human UCB‐derived MSCs transplantation into infants with severe IVH. The administered dose was well tolerated; however, further randomized controlled trials are essential to determine the optimal dosage and timing of intervention. Long‐term follow‐up is also needed to assess whether stem cell therapy can effectively reduce IVH‐related neurological sequelae—such as developmental delays, CP, and cognitive impairments—despite observed improvements in hemorrhage resolution and cytokine and growth factor profiles in some patients.

6.1.3. Perinatal arterial ischemic stroke

PAIS is a common form of IS occurring during the perinatal period, often leading to a range of comorbidities and persistent neurodevelopmental disabilities throughout childhood.

Preclinical studies have demonstrated that MSCs can promote neurogenesis and repair ischemic brain damage by modulating the neurovascular environment. In rodent models of ischemic stroke (IS), MSCs were shown to induce regenerative changes that support functional recovery, offering a compelling rationale for their application in neonatal brain injury settings. ⁷²

Given the limited efficacy of current treatments, Baak et al. ⁶⁴ investigated the potential of stem cell therapy by transplanting BM‐MSCs into neonates with PAIS. This study represents a significant milestone as the first to administer stem cells via the intranasal route. No serious adverse effects or unexpected brain abnormalities were observed during the 3‐month follow‐up. ⁶⁴ However, further studies are needed to evaluate both short‐ and long‐term efficacy.

A key innovation in this trial is the use of a noninvasive intranasal delivery technique, which, if proven therapeutically effective, could transform the landscape of stem cell therapy. The blood‐brain barrier (BBB) presents a major obstacle to delivering drugs to the CNS via conventional routes such as intravenous injection, often limiting their clinical utility. Intranasal administration, first introduced by William Frey in 1989, offers a promising alternative by enabling the transport of both small molecules and macromolecular proteins directly to the brain, bypassing the BBB. ⁷³

6.2. Postnatal brain injury

Pediatric postnatal brain injuries can lead to enduring motor, cognitive, and behavioral impairments. These injuries may arise directly from external mechanical trauma or as a consequence of perinatal complications, including HIE, preterm birth, neonatal asphyxiation, and intracranial hemorrhage. Such events disrupt normal neurodevelopment and may initiate secondary cascades of inflammation, excitotoxicity, and cell death.

Multiple neurological functions may be affected, including vision; brain injuries are recognized as the third leading cause of cortical visual impairment (CVI) in children. In a controlled randomized trial, Luan et al. ⁶⁵ explored the potential of intracerebroventricularly administered NSCs and NPCs to restore or enhance visual acuity in patients with severe neonatally‐induced CVI. The intervention yielded significantly greater improvements than conventional rehabilitation training, irrespective of the underlying etiology of CVI. Patients demonstrated a faster and more pronounced recovery trajectory, with one previously blind individual regaining light perception. Furthermore, functional magnetic resonance imaging (MRI) revealed increased activity within the occipital lobe and associated visual pathways, suggesting that the observed benefits may be attributed to the neuroprotective, anti‐inflammatory, and regenerative properties of the transplanted cells. ⁶⁵

Conversely, brain injury frequently occurs during postnatal life, with pediatric TBI representing a leading cause of mortality and long‐term disability in children. Moderate to severe TBI is typically characterized by diffuse axonal injury, disruption of cortical and subcortical networks, and microstructural alterations in white matter, manifesting as cognitive, behavioral, and functional impairments. ⁷⁴ In a phase II randomized controlled trial, autologous BM‐MNCs were administered 48 h following severe TBI. The intervention was associated with sustained structural preservation in cerebral white matter, a correlate of improved neurocognitive outcomes. At 1‐year follow‐up, treated patients exhibited 50.9% less volumetric loss compared to controls, reflecting significant white matter preservation. ⁶⁶ These findings suggest that stem cell therapy may confer neuroprotective benefits even in older pediatric populations, potentially mitigating the progressive damage associated with diffuse injury. Additionally, the immunomodulatory properties of BM‐MNCs may help attenuate secondary injury cascades commonly observed in TBI.

6.3. Spinal cord injuries

Although relatively rare, SCIs in children can lead to profound and lasting neurological deficits. Following the initial mechanical insult, a cascade of secondary events, including inflammation, gliosis, formation of inhibitory extracellular matrices, and scar tissue—further exacerbates the injury and impedes axonal regeneration. These processes create a hostile microenvironment that limits the efficacy of conventional therapeutic interventions. ⁷⁵

Preclinical studies in animal models of SCIs have shown promising results, with stem cell transplantation leading to improved locomotor function, reduced lesion volume, and enhanced neural regeneration, highlighting the potential of stem cell therapy to yield meaningful clinical benefits in SCI. ⁷⁶

To translate these findings into clinical practice, Sharma et al. ⁶⁷ conducted a clinical trial evaluating the safety and effect of autologous BM‐MNCs combined with neurorehabilitation across a broad age range. The intervention was deemed safe and contributed to improved recovery and quality of life in patients with sub‐acute and chronic SCI. Notably, age‐stratified analysis revealed that individuals under 18 years of age experienced superior outcomes, suggesting that enhanced neuroplasticity in younger patients may facilitate a more robust therapeutic response. Furthermore, administering two doses of BM‐MNCs proved more effective than a single dose. ⁶⁷ These findings align with earlier reports involving pediatric patients, where improvements were observed in muscle strength, urinary control, sitting balance, spasticity, and sensory function following similar cell‐based interventions. ⁴⁷

Most of the studies focusing on pediatric CNS injuries are early‐phase safety or feasibility trials at serious risk of bias. Many were open‐label without control groups, limiting causal inference, and acute injury settings introduced variability in standard care that could confound results. Evidence is preliminary and encouraging, but requires confirmation in larger, blinded, controlled studies. Key concerns include optimal timing of intervention, the potential for tumorigenesis, and the risk of immune rejection. Pediatric SCIs also present unique anatomical and physiological considerations; children's spinal cords are more elastic and structurally distinct from those of adults, resulting in different injury patterns and healing responses that complicate clinical management ⁷⁷ (Table 4).

7. NEUROMUSCULAR DISEASES

Neuromuscular diseases in pediatric populations, particularly Duchenne muscular dystrophy (DMD) and spinal muscular atrophy type 1 (SMA‐1), are characterized by progressive muscle degeneration, motor impairment, and high morbidity. Despite advances in gene and molecular therapies, these conditions remain difficult to manage, prompting growing interest in stem cell‐based interventions. Stem cells offer potential regenerative, anti‐inflammatory, and neuroprotective benefits, but their clinical translation requires careful evaluation of both biological efficacy and methodological rigor (Table 5).

Table 5.

Baseline characteristics of studies on stem cell therapy for neuromuscular diseases.

Author (year)	Disease	Sample size (n)	Age	Type of stem cell	Origin	Outcome	Ref.
Sharma et al. (2012)	MD⁎	Treated: 38†	Mean 9 Y	BM‐MNCs (single dose, IM)	Autologous	Symptom‐wise improvements include gait and the strength of the trunk and limbs. MRI showed muscle regeneration.	[47]
Rajput et al. (2015)	DMD	Treated: 11 Control: 5	5–18 Y	UC‐MSCs (IV, IM)	Allogeneic	Stabilization of muscle power. No GVHD or any deleterious effects.	[78]
Mohseni et al. (2022)	SMA‐I	Treated: 5 Control: 5	2–10 M	SPAD‐MSCs (3 doses, IT)	Allogeneic	Significant improvement in the motor amplitude response of the tibial nerve.	[79]

Abbreviations: BM‐MNCs, bone marrow‐derived mononuclear cells; CMD, congenital muscular dystrophy; DMD, Duchenne muscular dystrophy; GVHD, graft‐versus‐host disease; IM, intramuscular; IT, intrathecal; IV, intravenous; M, month; MD, muscular dystrophy; MRI, magnetic resonance imaging; SMA‐1, spinal muscular atrophy type 1; SPAD‐MSCs, side population adipose‐derived mesenchymal stem cells; UC‐MSCs, umbilical cord‐derived mesenchymal stem cells; Y, year.

^⁎Uncontrolled clinical trial.

^†Muscular dystrophy patients, of which 36 are Duchenne muscular dystrophy and 2 are congenital muscular dystrophy.

7.1. Duchenne muscular dystrophy

DMD is caused by mutations in the dystrophin gene, resulting in a deficiency or absence of dystrophin protein, essential for maintaining muscle cell membrane integrity. The disease typically manifests in early childhood and leads to progressive muscle weakness and degeneration. While satellite cells possess regenerative capacity, their therapeutic use is limited due to delivery challenges and poor migration. Myoblasts, derived from satellite cells, were initially considered for therapy but yielded disappointing outcomes due to low engraftment and limited regenerative potential.

Based on preclinical findings, stem cells derived from BM and peripheral blood are more accessible but have shown limited ability to form functional muscle fibers, often lacking dystrophin expression. MSCs from tissues such as the synovial membrane may support muscle regeneration indirectly by secreting extracellular matrix‐supporting and anti‐inflammatory molecules, though their direct contribution to muscle fiber formation remains inefficient. These findings suggest that while stem cells may not fully restore muscle architecture, they could serve as adjunctive therapies to modulate the disease environment. ⁸⁰

In clinical trials, children with DMD and congenital muscular dystrophy received autologous BM‐MNCs transplants. Remarkably, 97% of patients demonstrated functional improvements, particularly in trunk and lower limb strength, with some regaining gait and upper limb function. MRI scans revealed muscle regeneration at injection sites, and electromyography showed increased amplitude and frequency of motor unit potentials, with some previously myopathic muscles returning to normal. ⁴⁷ Additional studies in adults have explored various cell types, including myoblasts, mesoangioblasts, CD133⁺ cells, MSCs, and cardiosphere‐derived cells, but pediatric applications remain limited. While there have been some positive indications regarding safety and histological recovery, these treatment options are still considered preliminary. A major challenge is that cells isolated from diseased muscle often lose regenerative potential during ex vivo expansion. To address this, bioengineering strategies are being developed to preserve stemness by modulating specific signaling pathways and recreate supportive microenvironments. ⁸¹

Despite promising outcomes, the clinical studies lack rigorous methodological design. Most trials were non‐randomized and uncontrolled, limiting the ability to attribute observed improvements solely to the intervention. Sample sizes were small, and statistical power calculations were not reported, raising concerns about reproducibility and generalizability. Blinding and placebo controls were absent, which may introduce bias in functional assessments. Future studies should incorporate randomized controlled designs with clearly defined endpoints and adequate statistical planning to validate therapeutic efficacy.

7.2. Spinal muscular atrophy type 1

SMA‐1, also known as Werdnig–Hoffmann disease, is a severe lower motor neuron disorder caused by biallelic pathogenic variants in the SMN1 gene. It primarily affects anterior horn cells in the spinal cord and motor nuclei in the brainstem, leading to profound muscle atrophy and respiratory failure. Type I is the most common and lethal form, typically manifesting in infancy with a life expectancy under 2 years. ⁸²

Stem cell therapy for SMA‐1 aims to provide neuroprotection and replace damaged motor neurons. Based on preclinical findings, ESCs have demonstrated the ability to differentiate into motoneurons, yielding modest improvements in motor function and survival in mouse models. Genetically modified induced pluripotent stem cells mimicking SMN1 have shown enhanced motor neuron connectivity, increased muscle strength, and extended lifespan—up to 40% longer in treated mice. ⁸³ While these results are encouraging, they remain modest compared to the transformative effects of gene therapies. Combining stem cell approaches with molecular treatments may offer synergistic benefits, especially for symptomatic patients. Nevertheless, additional preclinical studies are necessary to confirm the safety and effectiveness of stem cell‐based therapies for clinical application.

At the clinical level, Mohseni et al. ⁷⁹ conducted a clinical trial using side population adipose‐derived MSCs, a primitive stem cell subset with enhanced regenerative capacity. Five infants with SMA‐1 were treated, and although only one survived the study period, the intervention was deemed feasible and safe. It is critical to note that SMA‐1 is a fatal condition, with a median life expectancy of under 2 years in the absence of effective intervention. Electromyography revealed a significant increase in tibial nerve motor response amplitude following the third injection, suggesting potential neurotrophic effects. However, the high mortality rate underscores the aggressive nature of the disease and the need for early intervention. ⁷⁹ Early treatment initiation could improve clinical outcomes.

The SMA‐1 trial was exploratory and lacked key methodological safeguards. The sample size was extremely limited, and no randomization or control group was used beyond observational comparison. Statistical power was not addressed, and survival outcomes were confounded by disease severity and timing of intervention. Current findings therefore inform feasibility and safety rather than efficacy, underscoring the need for rigorously controlled future trials (Table 5).

8. Lysosomal storage diseases

LSDs are a heterogeneous group of rare, inherited metabolic disorders caused by deficiencies in lysosomal enzymes or transport proteins. These defects lead to the accumulation of undegraded or partially degraded substrates within lysosomes, disrupting cellular homeostasis and triggering multisystem pathology. Neurological involvement is common across many LSDs, manifesting as cognitive decline, motor dysfunction, seizures, and psychiatric symptoms. Progressive neuronal damage and apoptosis further exacerbate these impairments. ⁸⁴ Stem cell therapy, particularly HSC transplantation (HSCT), has emerged as a potential strategy to address the underlying metabolic defects through cross‐correction, wherein donor‐derived cells deliver functional enzymes to affected tissues. While promising, most stem cell modalities remain experimental, and clinical translation is hindered by methodological limitations, ethical constraints, and the rarity of these conditions. ⁸⁵ Table 6 summarizes stem cell therapy application on various LSDs with neurological impairments.

Table 6.

Baseline characteristics of clinical trials on stem cell therapy for the treatment of lysosomal storage diseases.

Author (year)	Disease	Sample size (n)	Age	Type of stem cell	Origin	Outcome	Ref.
Selden et al. (2013)	I‐NCL or LI‐NCL	Treated: 6†	2–9 Y	NSCs (single low dose for 3 and single high dose for 3 other patients, ICV) + Immunosuppressive therapy	Allogeneic	No severe adverse events.	[7]
Lönnqvist et al. (2001)	I‐NCL	Treated: 3⁎	4–11 M	HSCT (single dose, IV)	Allogeneic	PPT1 enzyme activity was normalized in peripheral leukocytes but not in CSF. Mild and transient amelioration.	[86]
Escolar et al. (2005)	Krabbe's disease (AS)	Treated: 11⁎	12–44 D	Partial HLA‐match UCB after myeloablative chemotherapy (‐)	Allogeneic	100% survival with progressive central myelination and continued gains in developmental skills, cognitive function, and receptive language skills. Few had delays in expressive language and gross motor function.	[87]
	Krabbe's disease (S)	Treated: 14⁎	142–352 D	Partial HLA‐match UCB after myeloablative chemotherapy (‐)	Allogeneic	43% survival with minimal neurologic improvements.	[87]
Yagasaki et al. (2011)	Krabbe's disease (AS)	Treated: 1⁎, †	42 D	Partial HLA‐matched UCB (‐)	Allogeneic	After 14 M, gross motor and psychomotor development were somehow normal. The galactosylceramidase enzyme activity was increased but there was a mild focal demyelination.	[88]
Grewal et al. (2004)	α‐ manno‐ sidosis	Treated: 4‡	3–23 Y	HSCT (‐)	Allogeneic	Improvement of hearing, adaptive and verbal memory functions, and stabilization of intellectual functions. There was normalization of leukocyte α‐mannosidase activity.	[89]
Sauer et al. (2009)	MPS‐I	Treated: 12⁎	6–32 M	HSCT (‐)	Allogeneic	Children had either stabilized or improved neurological function. One patient developed acute GVHD and two others had regimen‐related toxicity.	[90]

Abbreviations: AS, asymptomatic; CSF, cerebrospinal fluid; D, days; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; ICV, intra‐cerebro‐ventricular; I‐NCL, infantile neuronal ceroid lipofuscinosis; LI‐NCL, late infantile neuronal ceroid lipofuscinosis; M, month; MPS‐1, mucopolysaccharidosis type 1 (Hurler syndrome); NSCs, neural stem cells; PPT1, palmitoyl‐protein thioesterase 1; S, symptomatic; Y, year; (‐), information not available.

^⁎Uncontrolled clinical trials.

^†Case study.

^‡Three of the four patients had type I (age between 3 and 6 Y) while the remaining one had type II (age: 23).

8.1. Neuronal ceroid lipofuscinosis

NCL, also known as Batten disease, is a fatal neurodegenerative disorder characterized by the accumulation of autofluorescent lipopigments (ceroid and lipofuscin) within lysosomes of neurons and other cell types. This accumulation leads to progressive neurological deterioration, including seizures, vision loss, and cognitive decline. ⁹¹

In infantile NCL mouse models, transplantation of human CNS stem cells demonstrated successful engraftment, migration, and production of palmitoyl‐protein thioesterase 1 (PPT1), the deficient enzyme in certain NCL subtypes. These interventions reduced lipofuscin accumulation, conferred neuroprotection, and delayed motor decline. ⁹² While these results are encouraging, translating them into consistent clinical outcomes remains a challenge.

Early clinical studies explored transplantation of human NSCs ⁷ and HSCs ⁸⁶ in a small patient cohort. Lönnqvist et al. ⁸⁶ reported transient biochemical improvement, with normalization of PPT1 activity in peripheral leukocytes but not in CSF. The trial was conducted in children at advanced disease stages, which likely limited therapeutic efficacy. Hence, intervening at earlier stages could prevent fatal neurodegeneration. Although the procedures were feasible and safe, further studies are needed to determine optimal cell sources, injection routes, and timing of intervention.

The referenced clinical trial lacked randomization, control groups, and statistical power calculations. The small sample size and late‐stage inclusion due to its rarity reduced the ability to detect meaningful neurological improvements.

8.2. Globoid cell leukodystrophy

Globoid cell leukodystrophy, commonly known as Krabbe's disease, is a rare and fatal genetic disorder caused by mutations in the GALC gene, resulting in deficient galactocerebrosidase activity. This leads to the accumulation of psychosine, a neurotoxic metabolite that disrupts myelination and causes progressive neurological decline. Preclinical data are limited, but the therapeutic rationale centers on cross‐correction, where donor‐derived macrophages deliver functional GALC enzyme to host myelinating cells, mitigating neuroinflammation and partially restoring myelination.

Escolar et al. ⁸⁷ demonstrated that UCB transplantation in presymptomatic infants altered disease trajectory, restoring GALC levels, promoting myelination, and supporting age‐appropriate cognitive development. In contrast, post‐symptomatic transplantation yielded minimal neurological improvement. ⁸⁷ A case study involving a 42‐day‐old infant showed partial benefit, though mild focal demyelination persisted after 14 months. ⁸⁸ However, despite its promise, HSCT is not curative and fails to prevent long‐term neurological deterioration. Consequently, many patients continue to experience progressive peripheral neuropathy, along with persistent motor and expressive language impairments. While the study provided compelling evidence for early intervention, it lacked randomization and control groups. Sample sizes were small, and statistical power was not explicitly addressed. Long‐term follow‐up was limited, and outcome measures were not standardized across patients. These factors constrain generalizability and underscore the need for multicenter, controlled trials with stratified enrollment based on disease stage.

8.3. Alpha‐mannosidosis

Alpha‐mannosidosis is a rare LSD caused by mutations in the alpha‐mannosidase gene, leading to impaired degradation of mannose‐rich oligosaccharides. Clinical manifestations include intellectual disability, hearing loss, motor coordination deficits, and progressive neurological deterioration. In a small, uncontrolled trial involving four patients, HSCT was associated with stabilization of cognitive function, attenuation of cognitive decline, and improved auditory outcomes. ⁸⁹

8.4. Mucopolysaccharidosis

MPS is an inherited metabolic disorder caused by lysosomal enzyme deficiencies that impair glycosaminoglycan (GAG) degradation. MPS‐I (Hurler syndrome) and MPS‐II (Hunter syndrome) are associated with severe somatic and neurological symptoms, often leading to early mortality.

MPS‐I (Hurler syndrome) leads to early childhood mortality. Sauer et al. ⁹⁰ reported that HSCT using peripheral blood‐derived cells led to neurological stability, low GVHD incidence, and improved survival. Retrospective analysis showed increased life expectancy and clinical improvement, despite residual disease burden. ⁹³ When therapy was initiated early and noncarrier donors were used, the outcome was better.

MPS‐II (Hunter's syndrome), caused by iduronate‐2‐sulfatase deficiency, may involve neuropathic features. Kubaski et al. ⁹⁴ found that HSCT recipients exhibited better long‐term somatic outcomes, joint mobility, and daily functioning compared to those receiving enzyme replacement therapy (ERT). HSCT was also associated with lower GAG levels and improved or stable brain MRI findings, whereas ERT patients showed persistent abnormalities. ⁹⁴

The LSDs discussed remain critically underexplored, with stem cell therapy offering encouraging—yet still preliminary—potential for symptom relief. However, their complex multisystem pathology and early onset present formidable barriers to developing standardized treatments. The rarity of these conditions severely limits patient recruitment for controlled trials, undermining statistical power and generalizability. Ethical constraints and the lack of validated biomarkers further complicate trial design and outcome assessment. Notably, the referenced studies were retrospective and lacked prospective randomization, control groups, and power calculations, rendering their findings vulnerable to selection bias and interpretive limitations. Outcome measures were inconsistently applied, and long‐term follow‐up was insufficient, highlighting the urgent need for rigorously designed, multicenter trials with standardized protocols and stratified patient cohorts (Table 6).

9. DISCUSSION

This review summarizes clinical applications of stem cell therapies in PNDs, and surveys preliminary and descriptive studies to provide up‑to‑date insights while highlighting the need for low‑bias, well‑controlled research to enable robust conclusions.

Stem cell‐based therapy holds promise for treating various PNDs, but clinical translation faces significant hurdles. HSCs and MSCs are most frequently used, with UCB and BM serving as major sources. MSCs, in particular, are valued for their ethical acceptability, low tumorigenic risk, ability to differentiate into multiple cell types, and secretion of neurotrophic factors that support neuronal repair. ⁹⁵ They also exhibit in vitro mechanisms similar to leukocytes, which may enable migration across the BBB, though in vivo relevance remains uncertain. ⁹⁶

Despite encouraging preclinical data, several translational barriers limit the therapeutic impact of stem cell approaches in PNDs. Principal limitations include restricted cell availability, suboptimal engraftment and integration into host tissue, and the absence of harmonized protocols for delivery routes, dosing regimens, and diagnostic or outcome measurement tools. ⁹⁷ Many clinical studies to date are small, uncontrolled, and brief in follow‐up, which constrains the interpretation of safety and efficacy signals. Reported clinical outcomes are heterogeneous: while most adverse events are mild, serious risks such as ectopic tissue growth and tumorigenicity remain a concern. ⁹⁸ Ethical issues, especially salient in pediatric populations, include criteria for patient selection, risks associated with surgical delivery, and regulatory compliance. ⁹⁹

Optimization of dose, administration frequency, and route is a major unresolved challenge. Evidence suggests higher MSC doses can sometimes be associated with improved outcomes, yet dose escalation may increase risks such as embolic events. ¹⁰⁰ Repeated dosing is biologically plausible and may be necessary: MSCs generally persist for only 2 to 3 months post‐transplantation ⁵⁸ and therefore single administrations may not provide a durable benefit. At the same time, cumulative cell exposure could increase safety risks. Taken together, these observations indicate the need for systematic, translational dose–response and repeat‐administration studies that measure biodistribution, retention, functional integration, and embolic risk in relevant preclinical models before larger clinical application.

Patient age and disease stage strongly influence therapeutic responsiveness. Clinical reports show better outcomes when cell therapy is instituted at earlier stages of disease. For example, earlier intervention may mitigate cumulative neurodegenerative damage that accrues with prolonged seizures in epilepsy, possibly explaining superior results in early‐stage cases. ⁵⁸ Inherited leukodystrophies such as Krabbe disease likewise demonstrate this principle: asymptomatic neonates treated with UCB show marked improvement and prolonged survival compared with symptomatic patients. ⁸⁷ , ⁸⁸ Conversely, disorders in which trials enrolled patients with advanced neuronal, axonal, and glial loss, such as NCL, have shown limited progress, likely reflecting irreversible pathology in late‐stage disease. ⁷ , ¹⁰¹ Gupta et al. ¹⁰² similarly reported poor outcomes when HSCT was given late in childhood‐onset adrenoleukodystrophy. These findings emphasize the importance of early diagnosis (including neonatal screening where appropriate) to maximize the potential benefit of cell‐based interventions. ¹⁰³

Tumorigenicity and GVHD are persistent safety concerns with certain stem cell types. GVHD after allogeneic HSCT can be attenuated by immunosuppression or cotransplantation of BM‐derived MSCs, ¹⁰⁴ but residual risks justify exploration of alternatives. Cell‐free approaches, notably the stem cell secretome and extracellular vesicles, offer a potentially safer therapeutic modality that can modulate the CNS microenvironment and influence neuronal function at a distance. For instance, UCB‐derived exosomes have shown neuroprotective effects in animal models of Parkinson's disease, ¹⁰⁵ and NSC‐derived extracellular vesicles have been proposed as a translational strategy to reduce tumorigenic risk while harnessing paracrine benefits. ¹⁰⁶ Focused preclinical work comparing cell versus cell‐free therapies on potency, durability, biodistribution, and safety will be informative.

Moreover, monotherapy has dominated clinical studies in LSDs, often with limited benefit. Preclinical and limited clinical evidence suggest that combining modalities may improve outcomes. In Krabbe models, superficial radiation therapy combined with NSCs infusion or bone marrow (BM) transplantation doubled lifespan relative to radiation alone, ¹⁰⁷ and in a small clinical series, combining ERT with HSCT reduced morbidity in Hurler syndrome. ¹⁰⁸ These data support further investigation of rational combination therapies. Similarly, conventional cell delivery faces challenges of poor targeting, low survival, and immune clearance. Nanoparticle‐based carriers (e.g., liposomes or biomimetic scaffolds) and other engineered delivery systems warrant investigation in preclinical PND models to protect cells or deliver secreted factors, improve CNS targeting, and extend therapeutic half‐life.

A pervasive limitation in pediatric studies is the frequent absence of randomized, controlled designs and adequate control groups, which undermines causal inference about treatment effects and safety. Many published reports are descriptive, uncontrolled case series that nevertheless provide useful real‐world information about feasibility and adverse events. Future efforts should prioritize multicenter, placebo‐controlled randomized trials with standardized outcome measures, prespecified endpoints, and sufficiently long follow‐up to capture late adverse events and durable functional change.

To accelerate safe and effective translation, we recommend the following: (1) rigorous preclinical studies to define dose–response, biodistribution, tumorigenicity and immunogenicity in relevant models; (2) development and adoption of standardized clinical protocols (delivery, potency assays, endpoints, and follow‐up duration); These protocols should also encompass Good Manufacturing Practice production standards, validated potency assays, and clear batch‑release criteria to ensure product consistency and regulatory readiness; (3) Early‐disease enrollment strategies, supported by expanded newborn screening where evidence supports benefit; (4) comparative studies of cell‐based versus cell‐free secretome therapeutics; (5) exploration of combinatory regimens (e.g., ERT + HSCT or radiation + cell therapies) where mechanistic rationale exists; and (6) application of advanced delivery platforms (nanoparticles, scaffolds) to enhance targeting and survival. We further recommend establishing centralized registries and minimum long‑term follow‑up durations (e.g., ≥5 years) to capture late adverse events and assess durability of therapeutic effects.

AUTHOR CONTRIBUTIONS

Daniel Bou Najm: Investigation (lead); methodology (lead); writing—original draft (lead); writing—review and editing (equal). Saada Alame: Conceptualization (lead); methodology (supporting); supervision (lead); writing—review and editing (equal).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

Not available.

Bou Najm D, Alame S. Therapeutic potential of stem cells in pediatric neurology: insights from clinical trials. Neuroprotection. 2025;3:303‐321. 10.1002/nep3.70022

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.