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Abstract
Aim
There is inadequate evidence concerning the efficacy and safety of stem cell therapy for autism spectrum disorders. We carried out the primary meta-evaluation of stem cell therapy for autism spectrum disorders in kids to supply evidence for clinical rehabilitation.
The information supply contains PubMed/Medline, Web of Science, EMBASE, Cochrane Library and China Academic Journal, from inception to twenty fourth JULY 2021. After sifting via the literature, the Cochrane software was utilized to assess the chance of bias. Finally, we extracted data from these research and calculated pooled efficacy and safety.
5 studies that met the inclusion standards have been included in current analysis. Meta-evaluation was carried out utilizing rehabilitation therapy because the reference customary. Data showed that the Childhood Autism Rating Scale rating of stem cell group was hanging decrease than the control 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-analysis suggested that stem cell therapy for children with autism is likely to be safe and efficient. However, the evidence was compromised by the limitations in current study size, missing standardized injection routes and doses of stem cells, in addition to shortages in diagnostic instruments and lengthy interval observe-up studies. Hence, it requires more studies to systematically confirm the efficacy and security of stem cell therapy for children with autism spectrum disorders.
Keywords: autism spectrum disorders (ASD), stem cell therapy, meta-evaluation, efficacy, security
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 kids, in accordance with the U.S. Centers for Disease Control and Prevention (2). Despite its rising prevalence (3, 4), the etiology of ASD shouldn’t be totally understood but, which can be interpreted as together with each genetic and environmental factors (5). The processes of inflammation and immune activation might act to switch the danger of ASD gene expression or destruct strategy of typical neural growth in ASD (6). ASD patients are a heterogeneous group with completely different symptom traits (7), thus there isn’t a definitive therapy for ASD patients (8).
Given the potential results of sustained immune disorders and inflammation in ASD and recognized paracrine (9), homing (10, 11), immunomodulatory (12) and multi-directional differentiation capacity (13, 14) of stem cells, they are receiving consideration as a potential therapeutic strategy. Growing numbers of research reviews have confirmed the efficacy and security of stem cell therapy with different methods including 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 reviews or case sequence research are limited to some geographical areas, thus fail to provide ample guidelines for clinical decisions. Moreover, these research have several shortcomings, equivalent to small pattern measurement, non-commonplace control teams, non-standard assessment scale and brief-time period comply with-up. Most importantly, after we started this study, there was no systematic proof-primarily based medical evaluate demonstrating the efficacy and security of stem cell therapy for ASD.
Collectively, we goal to rigorously screen and extract all preclinical trial information on stem cell therapy for autism, objectively consider and summarize proof regarding the effectiveness of stem cell therapy for autism signs by means of systematic review and meta-analysis.
The examine design was developed by the steering group, adopted by the standard Cochrane Neonatal Review Group strategies and PRISMA reporting guidelines. We have now already submitted a registration utility at Prospero (CRD42021285384, https://www.crd.york.ac.uk/prospero/).
Population
Children and adolescents (age 0-18 years) have been diagnosed with autism, no matter area, gender, or race.
Intervention
Multiple kinds of stem cells interventions on youngsters with autism had been investigated inside the current systematic overview and meta-analysis, with no limitations on injection times, administration route and dose. Studies of stem cells in combination with other therapies, reminiscent of antipsychotic medicine, are also being thought-about.
Comparisons
Rehabilitation therapy contains 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 another evaluation tools appropriate for ASD in the corresponding research.
Study Types
Randomized managed trials (RCTs) and managed clinical trials (CCTs) have been included in this examine, each paralleled or crossover. For trials that had a crossover design, we included all the data earlier than and after the crossover.
Data Sources
The following English and Chinese databases had been searched from their inception to 24th JULY 2021: PubMed/Medline, Web of Science, EMBASE, Cochrane library, China Academic Journal (by way of China National Knowledge Infrastructure [CNKI], [WanfangData], [Cqvip], [SinoMed]) and Clinicaltrials.gov. An in depth illustration of search strategies is obtainable in Supporting info 1 (S1. Search Strategy). No date restrictions or language restrictions are used for retrieval. Finally, references have been tracked and included in the examine to ensure that no RCTs and CCTs had been missed by the search technique.
Study Selection
All prospective managed clinical studies of stem cell therapy on autism patients were included, as were trials through which stem cells have been part of a complex intervention. We excluded qualitative research, uncontrolled trials, case studies and case sequence, in addition to trials that developed between totally different cell types, and research that failed to offer detailed results.
Data Extraction and Quality and Validity Assessment
Two independent reviewers evaluated the retrieved studies for inclusion and assessed the methodological high quality of included research. Elements extracted included study characteristics (creator, country, publication 12 months and experimental design), participant traits (intercourse, age range and diagnostic standards), intervention particulars (forms of cells, dose ranges, administration and frequency), consequence measurement, follow-up time and opposed reactions. The chance 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 were performed utilizing Review Manager 5.Three software. The information required for meta-analysis were obtained by direct input or oblique calculation primarily based on the original knowledge (The info of Cars could be obtained directly, and the effective enchancment number of CGI must be calculated primarily based on the overall effectivity provided in the unique text multiplied by the number of each group, like Dawson et al.’s examine). When studies of a number of intervention teams are in contrast, the „shared“ control group is cut up equally in each comparison (21) and the weighted average distinction (WMD) and threat ratio (RR) were used to match continuous variables (CGI and Cars) and dichotomous variables (Adverse events) respectively. All outcomes obtained were reported with 95% confidence intervals (CI). Heterogeneity among research was decided by Q check 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 selection of eligible trials is introduced in Figure 1. A complete 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 also included 1 latest analysis stories by means of quotation searching to ensure that the retrieved literature includes all of the studies within the revealed meta-analysis (26). Finally, 5 studies have been included within our meta-analysis.
Figure 1.
The inclusion flow chart of the literature was retrieved.
Characteristics of the Studies
The characteristics of the included studies are listed in Table 1. Diagnosis standards have been carried out primarily 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%) criteria. The 5 studies comprised 3 RCTs and a pair of CCTs, pattern sizes ranged from 36 to 180. A total of 325 topics had been included in the systematic evaluation and meta-analysis, 319 of whom had been analyzed for security, including 265 males and fifty four females. However, in Dawson’s research (27), two pilot individuals and a pair of contributors had been found to be ineligible [bipolar disorder (n = 1), the primary caregiver doesn’t speak English (n = 1)] after randomization, thus had been excluded from the efficacy analysis. Collectively, only 315 topics have been included within the efficacy analysis.
Table 1.
Summary of clinical studies of stem cells therapy for autism spectrum disorders.
RCT, randomized controlled trial; CCT, managed clinical trail; 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 rating 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 phrase image vocabulary take a look at; M, month; W, week.
Methodological Quality
The Figures 2, three showed the assessment outcomes of bias danger and methodological suitability of the included studies. Studie by Dawson et al was considered prime quality and low threat of bias. Lv et al. ’s study was excessive threat in the sector of random sequence era and have „Some concerns“ in a number of domains that considerably lowers confidence within the end result. The other three studies must be thought-about „Some concerns“ based on Cochrane’s e book of their one or two domains.
Figure 2.
Figure 3.
Risk of bias and applicability considerations.
Meta-Analysis
Five eligible articles have been meta-analyzed using a random results model, with Cars (Figure 4) and CGI (Figure 5) as main and secondary indicators to evaluate the effectiveness of stem cell therapy for autism, and adversarial reactions as security indicator (Figure 6).
Figure 4.
Cars forest plot included within the examine.
Figure 5.
CGI forest plot included within the research.
Figure 6.
Forest plot of antagonistic occasions.
As could be seen from the forest diagram in Figure 4, heterogeneity take a look at p = 0.14; I2 = 42%, indicating moderate heterogeneity. Data confirmed that the Cars rating of the stem cell group was significantly lower 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 reflects the incidence events of antagonistic reactions in every group [RR = 1.55; 95%CI = (0.60, 3.98); p = 0.36; Figure 6], there was no vital distinction within 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, we’ve got visual outliers. The sensitivity analysis discovered 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 were extra stable [RR = 4.70; 95%CI = (0.90, 24.63); p = 0.07; Heterogeneity test p = 0.95; I2 = 0%].
Stem cells are outlined as tissue items of biological programs which is accountable for the regeneration and development of organs and tissues. Stem cells are capable of self-renew and differentiate into multiple cell line ages, subsequently, these cells will also be units that evolve by way of pure choice (28, 29). Hematopoietic stem cells were primarily found and used for the treatment of blood-system failure induced by nuclear radiation (30). Lately, the clinical outcomes present that stem cells have proven promising results in quite a lot of chronic and troublesome diseases, comparable to spinal cord harm (31-34), graft-vs. -host illness (GVHD) (35, 36), diabetes and complications (37-39), stroke (40, 41), and so forth. As anticipated, more and more researchers are making an attempt to find out the efficacy of stem cell therapy for ASD.
Martínez (26) printed the first systematic evaluation and meta-analysis of stem cell therapy for autism in September 2021, however they included uncontrolled studies in the analysis to compensate for the insufficient variety of research. Especially within the research inside the control group, they only extracted information from the intervention group, which could scale back the clinical guiding significance of the conclusion that stem cell therapy considerably improves scales in patients with ASD. Our examine demonstrates that stem cell therapy for children with autism seems to be secure and effective. Cars – the first final result measurement confirmed the efficacy, whereas, the secondary final result measurement-CGI, showed no distinction between stem cells and control treatment. Furthermore, Bieleninik, Ł (42) discovered whole prices of ASD together with well being services prices and societal costs, were estimated to be around 2834 EUR in 2 months by evaluation with 5 European countries and 4 non-European nations. However, the median total prices and costs for stem-cell transplant hospitalization were $270,198 and $92,717 from 2002 to 2015 (43). Given the persistence of autism, the hospitalization cost also elevated dramatically. Therefore, this can be very essential to make the costly stem cell therapy to realize tremendously therapeutic impact. Currently, stem cell therapies for autism is mostly considered a new mean of clinical trials and have simply been performed in only a few places. It’s urgent to type the standardized remedy methods and enhance the curative impact earlier than that they are popularized in clinical observe.
We are able to glimpse from the included research where future autism stem cell therapy needs to be standardized. Firstly, we famous that the doses of cell injections in the included research had been diverse. In Sharifzadeh’s examine (22), subjects received a complete of 0.5-1 × 108 cells in the first injection and 0.3-0.5 × 108 cells within the second injection. In different research (19, 24, 25, 44), subjects obtained injections starting from 2 × 106/kg to 2.5 × 107/kg cells at a time. Different doses of cell injection may account for the inconsistent efficacy. Owing to those restricted studies, we could not analyze the affect of dosage on the efficacy and safety of stem cell injections. Secondly, there are two methods of cell injection: intravenous injection and intrathecal injection. Intravenous infusion of cells could restrict the homing effect, cells may very well be trapped in organs resembling lungs, heart, liver or kidney and get blocked by the blood-brain barrier, which might reduce the therapeutic impact on ASD (45, 46). Furthermore, solely two studies were adopted up for 12 months, such a short period just isn’t conducive to observing progress in the development of core signs of autism. Previous studies have suggested enhancements noticed after 12-month and 18-month observe-up, significantly within the Clinical Global Impression Scale (17, 27, 46). The CGI ranking scale has been extensively utilized in psychiatry to evaluate the degree of symptom and therapeutic efficacy, and the improvement (CGI-I) scale is used to assess the extent a patient has improved or worsened following an intervention, however they are non-ASD particular (47), which could explain why there was no vital distinction within the CGI scores between the two teams. Additionally, ASD is a complex neuropsychiatric disorder with substantial phenotypic and genetic heterogeneity (48), reducing the affect of heterogeneity on therapy and analysis studies is kind of essential. Moreover, there are multiple sources of stem cells, and the therapeutic effects of stem cells from totally different sources could fluctuate. Lv (19) and Liu (44) recommend that in contrast with the management group, the impact of cord blood mononuclear cells (CBMNC) transplantation was vital, however, the combination of CBMNC and umbilical cord mesenchymal stem cells (UCMSCs) had a better therapeutic effect than CBMNC alone. The small pattern dimension of included studies can also be an issue that cannot be ignored. As talked about above, there are numerous studies in the sector of stem cell therapy for autism that have directly or indirectly demonstrated its effectiveness. However, they did not meet the standards for inclusion in our analysis and were not meta-analyzed, but their results had been equally vital.
Overall, the key limitations of the included research had been small pattern measurement, non-specific final result measures, therapy regimens were not uniform, and missing enough follow-up.
In conclusion, the usage of stem cells to deal with children with autism may be effective and secure, but we consider that the current evidence is in-enough, the conclusions are based mostly on research that wouldn’t have a uniform therapy protocol. Besides, because of the high value of stem cell therapy and the lack of widespread clinical utility, guardians of youngsters with autism should be discreetly about enrolling in clinical trials of stem cell remedies for autism. It is pressing to determine a standardized therapy protocol by means of numerous trials, such as the most fitted stem cell type, administration method and dose should be screened; the publish-remedy evaluation of stem cell therapy should be improved. These might lead to the invention of stem cell therapy for autism and its pathogenesis, thus additional improving the therapeutic effect. We anticipate stem cell therapy to be used in the clinical therapy of autism and have significant therapeutic effects, but it remains to be lots of labor to be finished before this could occur.
The original contributions presented in the study are included within the article/Supplementary Material, further inquiries could be directed to the corresponding creator.
JQ: conceptualization, writing-reviewing and modifying, information extraction, and assessing the chance of bias. ZL: conceptualization, writing-reviewing and enhancing, knowledge extraction, and assessing the danger of bias. JY: writing-authentic draft, study selection, research retrieval, and statistical analysis. MZ: research choice, research retrieval, and statistical analysis. LL: study selection, and information extraction. ZZ: writing-reviewing and knowledge extraction. ZH: assessing the standard of studies. LZ: article revision and grammar revision. YL: writing-authentic draft and statistical analysis. All authors contributed to the article and authorized the submitted model.
The authors are grateful for the financial support acquired from the muse 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 therapy of cardiovascular and cerebrovascular diseases, Ministry of Education (XN201913). The foundation 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 article can be discovered on-line at: https://www.frontiersin.org/articles/10.3389/fped.2022.897398/full#supplementary-materials
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