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That is an open-access article distributed beneath the phrases of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in different boards is permitted, provided the original author(s) and the copyright proprietor(s) are credited and that the unique publication in this journal is cited, in accordance with accepted educational apply. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Aim

There is insufficient proof relating to the efficacy and security of stem cell therapy for autism spectrum disorders. We carried out the primary meta-analysis of stem cell therapy for autism spectrum disorders in children to provide evidence for clinical rehabilitation.

The info supply consists of PubMed/Medline, Web of Science, EMBASE, Cochrane Library and China Academic Journal, from inception to 24th JULY 2021. After sifting through the literature, the Cochrane device was applied to evaluate the chance of bias. Finally, we extracted information from these research and calculated pooled efficacy and security.

5 studies that met the inclusion criteria were included in present evaluation. Meta-analysis was performed using rehabilitation therapy because the reference commonplace. Data showed that the Childhood Autism Rating Scale rating of stem cell group was striking lower than the management group (WMD: −5.96; 95%CI [−8.87, −3.06]; p < 0.0001). The Clinical Global Impression score consolidated effect size RR = 1.01, 95%CI [0.87, 1.18], Z = 0.14 (p = 0.89), the effective rate for The Clinical Global Impression was 62% and 60% in the stem cell group and the control group, respectively. The occurrence events of adverse reactions in each group (RR = 1.55; 95%CI = 0.60 to 3.98; p = 0.36), there was no significant difference in the incidence of adverse reactions between the stem cell group and the control group.

The outcomes of this meta-evaluation suggested that stem cell therapy for children with autism is perhaps protected and effective. However, the proof was compromised by the constraints in current research measurement, missing standardized injection routes and doses of stem cells, as well as shortages in diagnostic instruments and long period follow-up research. Hence, it requires extra studies to systematically confirm the efficacy and safety of stem cell therapy for youngsters with autism spectrum disorders.

Keywords: autism spectrum disorders (ASD), stem cell therapy, meta-evaluation, efficacy, safety

Introduction

Autism spectrum disorder (ASD) is a bunch of neurodevelopmental disorders characterized by social deficits, communication inabilities and stereotypic behaviors (1). The incidence is estimated to be 1-2% of all youngsters, in response to the U.S. Centers for Disease Control and Prevention (2). Despite its rising prevalence (3, 4), the etiology of ASD just isn't totally understood but, which can be interpreted as together with both genetic and environmental components (5). The processes of inflammation and immune activation may act to switch the risk of ASD gene expression or destruct technique of typical neural growth in ASD (6). ASD patients are a heterogeneous group with completely different symptom traits (7), thus there is no such thing as a definitive remedy for ASD patients (8).

Given the potential effects of sustained immune disorders and inflammation in ASD and known paracrine (9), homing (10, 11), immunomodulatory (12) and multi-directional differentiation capability (13, 14) of stem cells, they are receiving attention as a possible therapeutic method. Growing numbers of analysis stories have confirmed the efficacy and safety of stem cell therapy with totally different strategies together with autologous bone marrow mononuclear cells (15-17), fetal stem cells (18), human cord blood mononuclear cells (19) and umbilical cord mesenchymal stem cells (20) in patients with autism. However, the great mass of these case studies or case series research are restricted to some geographical areas, thus fail to provide sufficient guidelines for clinical selections. Moreover, these research have a number of shortcomings, comparable to small sample measurement, non-customary management teams, non-customary evaluation scale and short-term comply with-up. Most significantly, when we started this research, there was no systematic proof-based medical assessment demonstrating the efficacy and security of stem cell therapy for ASD.

Collectively, we intention to rigorously display and extract all preclinical trial information on stem cell therapy for autism, objectively evaluate and summarize evidence concerning the effectiveness of stem cell therapy for autism signs by systematic evaluation and meta-analysis.

The study design was developed by the steering group, followed by the usual Cochrane Neonatal Review Group methods and PRISMA reporting pointers. We now have already submitted a registration software at Prospero (CRD42021285384, https://www.crd.york.ac.uk/prospero/).

Population

Children and adolescents (age 0-18 years) were diagnosed with autism, no matter area, gender, or race.

Intervention

Multiple sorts of stem cells interventions on kids with autism were investigated within the current systematic review and meta-analysis, with no limitations on injection times, administration route and dose. Studies of stem cells together with other remedies, such as antipsychotic medicine, are additionally being thought-about.

Comparisons

Rehabilitation therapy includes sensory integration therapy, auditory training, behavioral intervention, occupational therapy, speech therapy and music therapy.

Outcomes

The primary indicators are the scores of Clinical Global Impression (CGI) and Childhood Autism Rating Scale (Cars) or every other analysis tools suitable for ASD in the corresponding studies.

Study Types

Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) had been included on this examine, each paralleled or crossover. For trials that had a crossover design, we included all the information before and after the crossover.

Data Sources

The next English and Chinese databases were searched from their inception to twenty fourth JULY 2021: PubMed/Medline, Web of Science, EMBASE, Cochrane library, China Academic Journal (by means of China National Knowledge Infrastructure [CNKI], [WanfangData], [Cqvip], [SinoMed]) and Clinicaltrials.gov. An in depth illustration of search methods is obtainable in Supporting information 1 (S1. Search Strategy). No date restrictions or language restrictions are used for retrieval. Finally, references have been tracked and included within the study to make sure that no RCTs and CCTs had been missed by the search strategy.

Study Selection

All prospective managed clinical studies of stem cell therapy on autism patients were included, as were trials through which stem cells had been a part of a posh intervention. We excluded qualitative studies, uncontrolled trials, case research and case series, in addition to trials that developed between totally different cell types, and studies that failed to provide detailed results.

Data Extraction and Quality and Validity Assessment

Two independent reviewers evaluated the retrieved research for inclusion and assessed the methodological high quality of included studies. Elements extracted included research characteristics (writer, country, publication yr and experimental design), participant traits (intercourse, age vary and diagnostic criteria), intervention details (types of cells, dose ranges, administration and frequency), end result measurement, follow-up time and antagonistic reactions. The risk of bias was assessed using the Review Manager 5.3. The disagreements were thrashed out by the two reviewers.

Data Analysis

Data entry and evaluation had been performed utilizing Review Manager 5.Three software. The information required for meta-analysis were obtained by direct input or oblique calculation based on the unique information (The info of Cars might be obtained directly, and the effective enchancment number of CGI must be calculated based mostly on the whole efficiency provided in the unique textual content multiplied by the quantity of each group, like Dawson et al.'s examine). When studies of a number of intervention groups are in contrast, the "shared" control group is break up equally in every comparability (21) and the weighted average difference (WMD) and risk ratio (RR) had been used to check steady variables (CGI and Cars) and dichotomous variables (Adverse events) respectively. All results obtained were reported with 95% confidence intervals (CI). Heterogeneity among research was determined by Q test and I2 statistics (I2 equals or exceeds 50%, p < 0.05 is considered to have greater heterogeneity). The random effect model or mixed effect model was selected according to the size of heterogeneity. With high heterogeneity, sensitivity analysis or subgroup analysis was used to detect the source of heterogeneity; if the source of heterogeneity cannot be found, a descriptive analysis was conducted.

Results of the Search

A flowchart describing the collection of eligible trials is introduced in Figure 1. A total of 137 articles from 9 databases were retrieved: Web of Science (n = 15) databases, PubMed/MEDLINE (n = 12), Cochrane (n = 7), Embase (n = 36), CNKI (n = 11), Wan fang Data (n = 30), Cqvip (n = 19), Sino Med (n = 4), Clinicaltrials.gov (n = 3). We additionally included 1 newest analysis studies by quotation looking to ensure that the retrieved literature consists of all the studies in the published meta-analysis (26). Finally, 5 research had been included within our meta-analysis.

Figure 1.

The inclusion circulation chart of the literature was retrieved.

Characteristics of the Studies

The traits of the included research are listed in Table 1. Diagnosis standards have been performed mainly by the Diagnostic and Statistical Manual of Mental Disorders-four (DSM-4) (60.0%) or Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (40.0%) standards. The 5 research comprised three RCTs and a pair of CCTs, pattern sizes ranged from 36 to 180. A complete of 325 topics had been included within the systematic evaluation and meta-evaluation, 319 of whom have been analyzed for security, including 265 males and 54 females. However, in Dawson's study (27), two pilot participants and a pair of members have been discovered to be ineligible [bipolar disorder (n = 1), the primary caregiver does not converse English (n = 1)] after randomization, thus were excluded from the efficacy analysis. Collectively, only 315 topics were included within the efficacy evaluation.

Table 1.

Summary of clinical research of stem cells therapy for autism spectrum disorders.

RCT, randomized controlled trial; CCT, controlled clinical path; DSM,Diagnostic and Statistical Manual of Mental Disorders; BMMSC, bone marrow mesenchymal stem cell; MNCs, mononuclear cells; MSCs, mesenchymal stem cells; CB, cord blood; UCMSCs, umbilical cord mesenchymal stem cells; AUCB,autologous umbilical cord blood; DMSO, Dimethyl sulfoxide; Cars, childhood autism ranking scale; CGI, Clinical Global Impression; VABS, Vineland Adaptive Behavior Scales; PDDBI, The PDD Behavior Inventory; EOWPVT, Expressive One-Word Picture Vocabulary Test; ABC, Autism Behavior Checklist; ROWPVT, receptive one word picture vocabulary test; M, month; W, week.

Methodological Quality

The Figures 2, three confirmed the assessment results of bias danger and methodological suitability of the included research. Studie by Dawson et al was considered top quality and low threat of bias. Lv et al. 's examine was high threat in the sector of random sequence generation and have "Some concerns" in multiple domains that substantially lowers confidence within the end result. The opposite three studies should be considered "Some concerns" in keeping with Cochrane's e book in their one or two domains.

Figure 2.

Figure 3.

Risk of bias and applicability considerations.

Meta-Analysis

Five eligible articles were meta-analyzed utilizing a random effects model, with Cars (Figure 4) and CGI (Figure 5) as major and secondary indicators to evaluate the effectiveness of stem cell therapy for autism, and antagonistic reactions as safety indicator (Figure 6).

Figure 4.

Cars forest plot included in the study.

Figure 5.

CGI forest plot included in the study.

Figure 6.

Forest plot of antagonistic occasions.

As may be seen from the forest diagram in Figure 4, heterogeneity check p = 0.14; I2 = 42%, indicating average heterogeneity. Data showed that the Cars score of the stem cell group was considerably decrease than the control group [WMD: −5.96; 95% CI (−8.87, −3.06); p < 0.0001] (Figure 4). A higher score of CARS refers to severe disease. Overall, our results showed that the stem cell group had better efficacy in ASD treatment than the control group. In addition, sensitivity analysis was conducted to eliminate outliers in another intervention group (Lv 2013b) of Lv et al.'s study and the results were found to be stable (WMD: −7.08; 95%CI [−9.46, −4.70]; p < 0.0001; heterogeneity test p = 0.53; I2 = 0%).

We found that the forest plot of CARS had moderate heterogeneity. According to the results of the methodological quality assessment, we concluded that the research quality of Lv et al.'s study was low. Afterward, we conducted a subgroup analysis based on the methodological quality, and found that the combined results of CARS in the high-quality group were stable [WMD: −6.37; 95%CI (−9.11, −3.63); p < 0.00001, heterogeneity test p = 0.55; I2 = 0] (Figure 7). The results of Lv et al. 's study showed high heterogeneity and instability in the low-quality group [WMD:−4.83; 95% CI (−13.78, 4.12); p = 0.29; heterogeneity test p = 0.02; I2 = 82%] (Figure 7). Therefore, Lv et al.'s study might be the source of heterogeneity. The results in Figure 5 show no significant difference in CGI. Consolidated effect size RR = 1.01, 95%CI [0.87, 1.18], Z = 0.14 (p = 0.89), the effective rate for CGI was 62 and 60% in the stem cell group and the control group, respectively. Heterogeneity test I2 = 0%, p = 0.72, indicating no heterogeneity.

Figure 7.

Cars Forest plot of subgroup evaluation.

The forest plot in Figure 6 displays the occurrence occasions of adverse reactions in every group [RR = 1.55; 95%CI = (0.60, 3.98); p = 0.36; Figure 6], there was no important difference in the incidence of adverse reactions between the stem cell group and the management group, with heterogeneity test p = 0.28; I2 = 22%. Based on the forest map, now we have visual outliers. The sensitivity evaluation found that the research of Dawson et al was an outlier and the cause of heterogeneity. Whereas, after Dawson et al's study was excluded, the outcomes had been extra stable [RR = 4.70; 95%CI = (0.90, 24.63); p = 0.07; Heterogeneity test p = 0.95; I2 = 0%].

Stem cells are defined as tissue items of biological techniques which is liable for the regeneration and improvement of organs and tissues. Stem cells are able to self-renew and differentiate into multiple cell line ages, therefore, these cells can also be units that evolve through pure selection (28, 29). Hematopoietic stem cells were primarily found and used for the therapy of blood-system failure induced by nuclear radiation (30). Lately, the clinical results present that stem cells have shown promising results in a variety of chronic and troublesome diseases, similar to spinal cord injury (31-34), graft-vs. -host illness (GVHD) (35, 36), diabetes and complications (37-39), stroke (40, 41), etc. As expected, increasingly researchers are attempting to find out the efficacy of stem cell therapy for ASD.

Martínez (26) published the first systematic evaluate and meta-evaluation of stem cell therapy for autism in September 2021, however they included uncontrolled studies within the evaluation to compensate for the inadequate variety of research. Especially within the research inside the management group, they solely extracted knowledge from the intervention group, which could cut back the clinical guiding significance of the conclusion that stem cell therapy considerably improves scales in patients with ASD. Our research demonstrates that stem cell therapy for children with autism appears to be protected and efficient. Cars - the primary end result measurement confirmed the efficacy, whereas, the secondary end result measurement-CGI, confirmed no difference between stem cells and control remedy. Furthermore, Bieleninik, Ł (42) found total costs of ASD including well being services prices and societal costs, had been estimated to be around 2834 EUR in 2 months by evaluation with 5 European international locations and 4 non-European international locations. However, the median total fees and costs for stem-cell transplant hospitalization have been $270,198 and $92,717 from 2002 to 2015 (43). Given the persistence of autism, the hospitalization cost also elevated dramatically. Therefore, it is extremely essential to make the expensive stem cell therapy to achieve enormously therapeutic effect. Currently, stem cell remedies for autism is mostly considered a brand new mean of clinical trials and have simply been conducted in just a few locations. It is pressing to form the standardized remedy strategies and enhance the curative effect earlier than that they're popularized in clinical observe.

We can glimpse from the included research the place future autism stem cell therapy must be standardized. Firstly, we famous that the doses of cell injections in the included studies had been diverse. In Sharifzadeh's examine (22), topics received a complete of 0.5-1 × 108 cells in the primary injection and 0.3-0.5 × 108 cells within the second injection. In other research (19, 24, 25, 44), subjects obtained injections ranging from 2 × 106/kg to 2.5 × 107/kg cells at a time. Different doses of cell injection could account for the inconsistent efficacy. Owing to these limited research, we could not analyze the influence of dosage on the efficacy and security of stem cell injections. Secondly, there are two ways of cell injection: intravenous injection and intrathecal injection. Intravenous infusion of cells may restrict the homing impact, cells could be trapped in organs comparable to lungs, coronary heart, liver or kidney and get blocked by the blood-mind barrier, which could reduce the therapeutic impact on ASD (45, 46). Furthermore, solely two research have been followed up for 12 months, such a brief period isn't conducive to observing progress in the improvement of core symptoms of autism. Previous research have instructed enhancements observed after 12-month and 18-month follow-up, significantly in the Clinical Global Impression Scale (17, 27, 46). The CGI score scale has been extensively utilized in psychiatry to judge the degree of symptom and therapeutic efficacy, and the development (CGI-I) scale is used to evaluate the extent a affected person has improved or worsened following an intervention, but they are non-ASD particular (47), which might clarify why there was no significant distinction within the CGI scores between the two teams. Additionally, ASD is a fancy neuropsychiatric disorder with substantial phenotypic and genetic heterogeneity (48), lowering the affect of heterogeneity on therapy and analysis studies is sort of important. Moreover, there are multiple sources of stem cells, and the therapeutic effects of stem cells from completely different sources could range. Lv (19) and Liu (44) counsel that in contrast with the control group, the effect of cord blood mononuclear cells (CBMNC) transplantation was vital, nevertheless, the mix of CBMNC and umbilical cord mesenchymal stem cells (UCMSCs) had a greater therapeutic effect than CBMNC alone. The small pattern measurement of included research can also be an issue that can not be ignored. As mentioned above, there are a lot of research in the sector of stem cell therapy for autism that have immediately or indirectly demonstrated its effectiveness. However, they did not meet the factors for inclusion in our analysis and were not meta-analyzed, however their results have been equally important.

Overall, the main limitations of the included studies have been small pattern dimension, non-particular consequence measures, therapy regimens weren't uniform, and missing satisfactory comply with-up.

In conclusion, the use of stem cells to deal with youngsters with autism could also be effective and protected, however we believe that the current proof is in-enough, the conclusions are based on research that would not have a uniform therapy protocol. Besides, because of the high price of stem cell therapy and the lack of widespread clinical software, guardians of kids with autism have to be discreetly about enrolling in clinical trials of stem cell therapies for autism. It's urgent to determine a standardized remedy protocol by means of a lot of trials, such as the best suited stem cell sort, administration methodology and dose must be screened; the put up-therapy analysis of stem cell therapy have to be improved. These may result in the invention of stem cell therapy for autism and its pathogenesis, thus further bettering the therapeutic impact. We expect stem cell therapy to be used in the clinical therapy of autism and have important therapeutic effects, nevertheless it continues to be quite a bit of work to be completed earlier than this could happen.

The original contributions presented within the examine are included in the article/Supplementary Material, further inquiries might be directed to the corresponding writer.

JQ: conceptualization, writing-reviewing and editing, information extraction, and assessing the risk of bias. ZL: conceptualization, writing-reviewing and modifying, data extraction, and assessing the danger of bias. JY: writing-unique draft, study selection, analysis retrieval, and statistical analysis. MZ: examine choice, research retrieval, and statistical evaluation. LL: study choice, and knowledge extraction. ZZ: writing-reviewing and data extraction. ZH: assessing the quality of research. LZ: article revision and grammar revision. YL: writing-unique draft and statistical evaluation. All authors contributed to the article and authorised the submitted model.

The authors are grateful for the financial support received from the inspiration of Jiangxi Educational Committee (GJJ180791). The Science and Technology Project of Jiangxi Provincial Health Commission (20191079). The Open Project of Key Laboratory of Prevention and remedy of cardiovascular and cerebrovascular diseases, Ministry of Education (XN201913). The muse of Technology Innovation Team of Gannan Medical University (TD201806). Key Project Foundation of Gannan Medical University (ZD201831). First Affiliated Hospital of Gannan Medical University, Doctor Start-up Fund (QD076), and Jiangxi Provincial Natural Science Foundation (20212BAB206075).

We thank the 2 colleagues who put ahead advices for this study, Junming Chen and Dongmiao Han.

Supplementary Material

The Supplementary Material for this text will be discovered on-line at: https://www.frontiersin.org/articles/10.3389/fped.2022.897398/full#supplementary-material

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