Progress in clinical trials of stem cell therapy for cerebral palsy

Abstract

Introduction

Cerebral palsy (CP) is a group of permanent disorders of the development of movement and posture, often accompanied by disturbances of sensation, perception, cognition, communication and behavior, by epilepsy, and by secondary musculoskeletal problems (Rosenbaum et al., 2007). The prevalence rate is approximately 3 per 1000 births globally, and is much higher in some developing countries (Graham et al., 2016; Van Naarden Braun et al., 2016; Korzeniewski et al., 2018). The causes of CP are complex, and include perinatal stroke, low birth weight, birth complications, gestational age, multiple births, and infection (Korzeniewski et al., 2018). Recent studies show that 14% of patients may have causative single-gene mutations (MacLennan et al., 2015), and the apolipoprotein E (APOE) genotype is correlated with the risk and severity of CP (Korzeniewski et al., 2018). Because of the complex etiology of CP, the pathological changes in the brain are highly variable (Brandenburg et al., 2019). Furthermore, a small proportion of patients may have completely normal magnetic resonance imaging (MRI) findings. A European study (Bax et al., 2006) found that 42.5% of children with CP have white matter damage. In addition, basal ganglia lesions, cortical/subcortical lesions, malformations, focal infarcts, and miscellaneous lesions are also shown in MRI. The treatment of CP has continuously evolved. Traditional rehabilitation treatments (Reid et al., 2015) such as physiotherapy, occupational and speech therapy, assistive devices, pharmacological intervention, and surgery such as neurectomy and rhizotomy (Koman et al., 2004; Graham et al., 2016; Jindal et al., 2019) have little efficacy for CP.

Recent studies show that stem cell therapy might effectively cure CP owing to the multi-directional differentiation potential and migration capabilities of stem cells (Fan et al., 2015; Jantzie et al., 2018; Jiao et al., 2019). Several studies have investigated the mechanisms underlying the effectiveness of stem cells in CP animal models (Zheng et al., 2012). These studies suggest that trophic factor secretion (Bennet et al., 2012), neurogenesis (Carroll and Mays, 2011; Jantzie et al., 2018), immunomodulation (Bennet et al., 2012; Jantzie et al., 2018), angiogenesis (Kiasatdolatabadi et al., 2017) and neuroplasticity (Daadi et al., 2010) are key to their therapeutic effectiveness. An increasing number of studies of stem cell therapy have been carried out for various diseases, including stroke (Bernstock et al., 2017; Liao et al., 2019), amyotrophic lateral sclerosis (Mazzini et al., 2016), Alzheimer’s disease (Duncan and Valenzuela, 2017; Reza-Zaldivar et al., 2019), spinal cord injury (Assinck et al., 2017; Mukhamedshina et al., 2019) and Parkinson’s disease (Han et al., 2015). Accordingly, transplantation of stem cells is considered a promising and effective treatment for CP as well (Novak et al., 2016).

Children with CP show improvements in gross motor function (Wang et al., 2013; Thanh et al., 2019), fine motor function (Luan et al., 2012), cognition and other symptoms such as salivation, emotional changes and language competence (Dong et al., 2018; Huang et al., 2018) after receiving stem cell infusion. Some of these improvements could be evaluated with rating scales, while others could not. Furthermore, the design of these clinical trials differed substantially, such as in cell subtype, dose and delivery method of the stem cells, and patient background. These differences make it difficult to evaluate and compare the outcomes among the clinical trials. Thus, much more research is needed before stem cells can be used as cell preparations in clinical practice. Here, we summarize recent clinical trials of stem cell therapies for CP, with the aim of allowing researchers to recognize the progress and shortcomings of current clinical trials, and so that future clinical trials of stem cell therapies for CP can be more effectively carried out.

Clinical Trial Data Retrieval of Stem Cell Therapy for Cerebral Palsy

An electronic search of the PubMed and ClinicalTrials databases for studies and clinical trials of cerebral palsy from 1971 to 2020 was performed using the following criteria: ((“stem cells”[MeSH Terms]) OR (“umbilical cord blood”[MeSH Terms])) AND (“cerebral palsy”[MeSH Terms]). The results were further screened by title, abstract or project information. As of April 28, 2020, there were only 39 clinical trials of stem cell therapy for CP registered on clinicaltrials.gov (Additional Tables ​Tables11 and ​and22), of which 18 have been completed. At the same time, some clinical trials not registered on clinicaltrials.gov were also completed and provided some referential results. We performed a literature search with the keywords “cerebral palsy”, “umbilical cord blood” and “stem cell” in PubMed, and the article type was limited to “clinical trials”. A total of 20 articles were retrieved (Additional Table 3). The retrieved trials differed in study design, the age and type of the included population, subtype and dose of stem cells, administration method and course of treatment. The trials also varied in assessment tools. Most of these clinical trials are single-arm studies with a small sample size, and are difficult to comparatively evaluate because of the lack of parallel controls. Large-sample randomized controlled trials are needed to obtain more clinically robust data.

Types of Stem Cells Transplanted for the Treatment of Cerebral Palsy

Despite the abundance of stem cell sources, the stem cells used in these clinical trials were mainly derived from the following five tissues: bone marrow (Sharma et al., 2015; Nguyen et al., 2017, 2018), human umbilical cord blood (hUCB)/umbilical cord (UC) (Huang et al., 2018; Okur et al., 2018), fetal brain (Chen et al., 2010; Luan et al., 2012), adipose and peripheral blood (Ruff et al., 2013; Rah et al., 2017) (Figure 1). Stem cells produced by these tissues include mesenchymal stromal cells (MSCs) (Wang et al., 2013), total nucleated cells (Mancías-Guerra et al., 2014), neural stem cell-like cells (Chen et al., 2013), CD133-positive enriched bone marrow progenitor cells (Zali et al., 2015) and mononuclear cells (Sharma et al., 2015; Nguyen et al., 2017; Nguyen et al., 2018). In some clinical trials, patients did not exclusively receive stem cells, but cord blood containing stem cell components, and these treatments have also shown therapeutic effectiveness (Min et al., 2013; Sun et al., 2017). Among these, hUCB/UC is the most common source of stem cells, while bone marrow is the second most common. Both of these sources are comparatively abundant, the collection methods are simple, and ethical concerns are fewer. In some studies, the sources are of autologous origin, while in others, they are of allogeneic origin. Because harvesting the tissues can cause great physical and psychological trauma to children, autologous bone marrow stem cells are not a good choice for children with CP. In fact, stem cells of allogeneic origin all exhibit low immunogenicity, which is effective at avoiding immune rejection (Forraz and McGuckin, 2011). Stem cells from different sources have different efficacies, but even stem cells from the same source vary in efficacy during treatment. Liu et al. (2017) compared the efficacy of bone marrow mononuclear stem cells (BMMNCs) and bone marrow MSCs in the treatment of pediatric CP, and found that bone marrow MSCs were better than BMMNCs in the treatment of CP. While neural stem cells are considered ideal cells for the treatment of nerve injury, few studies have applied these cells in CP treatment (Trounson and McDonald, 2015). The fetal brain is considered the optimal source of neural stem cells, but their use is controversial because of ethical issues, and have only been allowed to be used in some clinical trials in China (Chen et al., 2010; Luan et al., 2012). Peripheral blood and adipose are the least common stem cell sources in these studies, although they have been increasingly used as a source of cells in other fields (Xue and Milano, 2020). Treatment with peripheral blood cells has also shown effectiveness (Rah et al., 2017), but whether adipose-derived stem cells can be effective for CP patients remains to be investigated. Together, the current clinical trials suggest that, regardless of the source and type of stem cells, they all show therapeutic effectiveness for CP. However, further clinical trials are needed to identify the most therapeutically effective stem cell type for CP.

Figure 1

The stem cell types used in clinical trials for cerebral palsy.

The various types of stem cells injected into the human body are not only functionally different, but are also very diverse in origin. Of these, peripheral blood, umbilical cord and adipose sources are relatively abundant, while bone marrow and fetal brain sources are less. Ad: Administration; De: derived.

Routes and Methods of Cell Delivery for Cerebral Palsy Patients

Administration routes

CP patients participating in stem cell clinical trials can receive stem cell transplantation in a variety of ways (Figure 2). Lumbar puncture and intravenous injection are the most common routes of administration, brain stereotactic surgery is relatively less used, while nasal administration has never been reported. A clinical trial is currently being conducted to assess the comparative effectiveness of the various administration routes (NCT03414697). Lumbar puncture administration allows drugs to reach the brain through the cerebrospinal fluid circulation, and similarly, researchers have found that stem cells can also reach the brain directly through this route (Kim et al., 2020). Although intrathecal administration is accompanied by some side effects, they can be improved by medical treatment or are spontaneously relieved (Mancías-Guerra et al., 2014; Sharma et al., 2015; Trounson and McDonald, 2015; Nguyen et al., 2017). Stereotactic brain surgery, which also allows stem cells to enter the brain directly, is much more invasive than lumbar puncture. The side effects of stereotactic surgery are relatively serious, such as lateral ventricular blood vessel injury (He et al., 2012), which may cause brain damage, thereby counteracting the therapeutic effect of stem cells. Intravenous injection is also a common route of stem cell administration, but because of the blood-brain barrier, only a small fraction of the stem cells can enter the brain parenchyma (Sherman et al., 2019). Thus, the regeneration and differentiation of exogenous stem cells in the brain is less efficient. Nonetheless, this administration method has been shown to have some therapeutic effectiveness (Mancías-Guerra et al., 2014; Zhang et al., 2015; McIntosh et al., 2016; Huang et al., 2018), which might be mediated by trophic factors secreted by the stem cells. Nasal administration has been used in clinical practice for many years, but it is a relatively novel method for stem cell therapy. Some investigators have employed this administration route in animal models (Donega et al., 2013). Preclinical studies indicate that stem cells enter the brain through the perineural space between the cribriform plate and the olfactory nerve (Danielyan et al., 2009; Galeano et al., 2018), thereby bypassing the blood-brain barrier (Lochhead and Thorne, 2012). Nasal administration can be said to be the least invasive of these administration methods, and if it also demonstrates better efficacy, it can be widely employed in the future.

Figure 2

The common administration routes for cerebral palsy patients in stem cell therapy.

Patients receive stem cell therapy usually through four routes—intrathecal injection, intravenous injection, intranasal injection and intracranial injection. Intranasal injection is noninvasive, while intrathecal and intravenous injection are moderately invasive, but might induce some adverse events. Intracranial is the most invasive, and has the most side effects.

Safety and Efficacy of Stem Cell Therapy for Cerebral Palsy

Mechanisms Underlying the Effectiveness of Stem Cell Therapy for Cerebral Palsy

It is well-known that stem cells have the ability to differentiate, and under appropriate conditions, become any type of cell in the human body. Stem cells also have the ability to proliferate indefinitely (Jin, 2017). Stem cells have been applied in the clinical study of a variety of neurological diseases (Duncan and Valenzuela, 2017; Burman et al., 2018), and have shown good therapeutic effectiveness and safety for many diseases that cannot be resolved by drugs. Preclinical studies indicate that stem cells also have immunomodulatory actions (Naji et al., 2019) and can secrete cytokines (Huang and Zhang, 2019). Thus, the mechanisms of the therapeutic effectiveness of stem cell therapy for CP likely involves the following: After entering, stem cells can differentiate into neurons and glial cells, such as astrocytes, and replace damaged cells, and then re-establish connections with other neural cells. Stem cells secrete a variety of cytokines that modulate the inflammatory response, and ensure the survival of neurons and promote angiogenesis. In addition, exogenous stem cells can also induce and accelerate endogenous repair (Huang and Zhang, 2019).

Challenges in the Future Application of Stem Cell Therapy for Cerebral Palsy

With the increase in the number of clinical studies, stem cells are expected to be marketed successively in the near future, bringing new options for the treatment of CP. However, many problems remain to be tackled. The follow-up observation period of current clinical trials is generally short, and the long-term safety and efficacy of stem cell therapy remain to be adequately assessed. It is clear that all types of stem cells have a therapeutic effect in CP. However, because the doses, sources and administration routes differ among the clinical trials, it is currently difficult to declare the best candidate for CP patients. Clinical trials of CP have to date been mainly carried out on younger children, but with the advancement of medical care, many children with CP survive, and it remains unknown whether stem cell therapy can also improve symptoms in older patients. Additionally, it is necessary to identify the optimal administration method to maximize efficacy and minimize side effects, although nasal administration shows promise. Further improvements are needed in efficacy assessment methods. Although scale assessment has been used for many years, the limitations in symptom assessment cannot be ignored. Currently, most scale assessments can only assess the improvement of a certain aspect of clinical symptoms. Furthermore, the scales are prone to human error. New assessment methods, such as positron emission tomography/CT and MRI, have been employed and have shown to be effective in some clinical trials (Eggenberger et al., 2019). However, the radiation exposure from positron emission tomography/CT cannot be ignored. The application of computer analysis of EEG data in other fields (Beaty et al., 2016; Avena-Koenigsberger et al., 2017) may also be applicable to the evaluation of CP. MRI and EEG, as objective examination methods, are sensitive to the changes in brain structure and function. The combination of MRI and EEG using computer data processing techniques may enhance the evaluation of CP.

Additional files:

Additional Table 1: Completed and recruiting clinical trials of stem cells therapy for CP.

Additional Table 2: Other clinical trials of stem cells therapy for CP.

Additional Table 3: Published clinical trials of stem cell therapy for CP.

Additional Figure 1: The type of CP patients enrolled in clinical trials.

Additional Figure 2: The administration routes of stem cell therapy for CP.

Footnotes

References

Source

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284300/