自体脐带血输注在患有自闭症谱系障碍的幼儿中是安全可行的: 单中心 I 期开放标签试验的结果

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尽管在早期诊断和行为疗法方面取得了进展, 自闭症谱系障碍儿童更有效的治疗方法 (自闭症谱系障碍) 需要. 我们假设脐带血来源的细胞疗法可能通过调节大脑中的炎症过程来缓解 ASD 症状. 因此, 我们进行了第一阶段, 评估单次静脉输注自体脐带血的安全性和可行性的开放标签试验, 以及对几种 ASD 评估工具变化的敏感性, 为未来的试验确定合适的终点. 二十五个孩子, 中年的 4.6 年 (范围 2.26–5.97), 确诊为 ASD 并拥有合格的自体脐带血库, 被录取. 在脐带血输注前立即对儿童进行一系列行为和功能测试 (基线) 和 6 和 12 几个月后.

对 12 个月期间的不良事件的评估表明该治疗是安全且耐受性良好的. 在家长报告的社交沟通技巧和自闭症症状测量中观察到儿童行为的显着改善, 临床医生对整体自闭症症状严重程度和改善程度的评分, 表达词汇的标准化测量, 儿童对社会刺激的注意力的客观眼动追踪测量, 表明这些措施可能是未来研究中有用的终点.

stem cell ukraine在第一次观察到行为改善 6 输注后数月,并且在基线非语言智商较高的儿童中更大. 这些数据将作为未来研究的基础,以确定脐带血输注对 ASD 儿童的疗效. 干细胞转化医学 2017;6:1332–1339

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意义声明
This phase I study demonstrates that it is safe and feasible to perform autologous umbilical cord blood infusions in young children with autism spectrum disorder and identifies several promising outcome measures for use in future trials.

介绍
Autism spectrum disorder (自闭症谱系障碍) is a neurodevelopmental disorder characterized by impairments in social communication and the presence of repetitive behaviors and a restricted range of activities, with onset early in life. ASD is estimated to affect approximately 1 在 68 children in the U.S. 1. The majority of individuals with ASD are not able to live independently and require lifelong support or accommodations. 因此, the lifetime cost of supporting an individual with ASD is estimated to be $1.4 百万. The cost is $2.4 million for those who also have an intellectual disability 2.

ASD 的治疗方法包括药物治疗, 行为疗法, 职业和言语治疗, 和专业的教育和职业支持. 早期强化行为干预与显着改善的结果相关 3, 但即使有这样的干预, 许多患有 ASD 的人仍然严重受损. 目前所有可用的医疗方法, 比如精神药物, 旨在改善相关的共病症状, 比如烦躁, 但不要解决核心自闭症症状. 有鉴于此, 对针对 ASD 核心症状的更有效治疗的巨大需求尚未得到满足.

遗传和环境因素都有助于 ASD 的病因 4-6. 虽然确切的病理生理学尚不清楚, 观察结果包括大脑区域的突触功能异常 7, 8, 白质异常 9, 和神经炎症 10. 自闭症患者大脑中免疫病理学的发病机制可能是由于免疫相关基因网络的过度表达 11, 存在针对胎儿脑组织的母体抗体 12, 非典型水平的促炎细胞因子 (IL-6, 肿瘤坏死因子-α) 在脑脊液中 13, 和过度的小胶质细胞激活导致异常的神经连接通路 14, 15. 像这样, 影响免疫调节或神经连接调节的治疗方法是该人群新疗法的合理目标. 临床前模型表明,脐带血含有效应细胞, 通过旁分泌信号, 改变大脑连接并抑制炎症 16, 17. 脑瘫和其他后天性脑损伤患者输注自体脐血细胞已被证明是安全的 18-20. 我们假设输注自体脐带血细胞可能在 ASD 的治疗中发挥重要作用,并在单一中心进行了, 开放标签, 在年轻儿科参与者中进行的 I 期安全性和可行性试验. 该研究侧重于 (一种) 单次静脉输注自体脐带血的安全性和 (乙) 对患有 ASD 的幼儿使用几种不同评估工具的变化的敏感性和可行性.

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材料和方法
研究设计和概述
本研究为 I 期, 单中心, 单次静脉输注自体脐带血的开放标签试验 25 自闭症儿童. 所有儿童最初都参加了一项筛查方案,以获取有关他们储存的脐带血单位的医疗记录和信息. 所有参与者的护理人员都通过电话完成了研究前筛查访谈,并提供了医疗记录和视频供研究团队审查以确定是否有资格参加试验. 确诊为 ASD 且拥有合格的自体脐带血单位的儿童有资格参加. 就试验的筛选和治疗阶段获得了书面知情同意书. 该试验得到杜克医院机构审查委员会的批准,并在 IND 下进行 #15949.

作为参与研究的一部分,参与者及其护理人员三次前往杜克大学. 在他们的基线访问中, 他们进行了评估并接受了单次静脉自体脐带血输注. 在已知 HLA 差异的情况下,软骨生长并治愈了兔子的骨关节炎 6 和 12 输液后几个月, 参与者返回进行后续临床评估. 额外的照顾者访谈和问卷收集于 3 和 9 输液后几个月.

参与者
参与者之间 2 和 5 根据《精神疾病诊断和统计手册》,符合 ASD 临床诊断标准的年龄, 第五版 (帝斯曼-5) 21 有资格被纳入研究. ASD 的 DSM-5 诊断由临床专家建立,并根据自闭症诊断观察计划提供信息 (好的), 第二版 22 和自闭症诊断访谈, 修改 (阿迪) 23. 包括其他纳入标准 (一种) 非语言智商 (智商)  ≥ 35 的斯坦福-比奈幼儿智力量表, 第五版 24 或马伦早期学习量表 25, (乙) 合格的自体脐带血单位的可用性, (C) 参与者至少在目前的药物治疗上保持稳定 2 输液前几个月, (组内患者接受不同的治疗) 3次前往杜克大学的能力 (基线和 6 和 12 基线后几个月), 和 (在临床基础上或在有合作协议的情况下使用其他机构的资源进行必要检查的能力) 父母会说英语. 包括排除标准 (一种) 既往细胞治疗史, (乙) 使用静脉注射免疫球蛋白或其他抗炎药物 (非甾体抗炎药除外), (C) 已知遗传 (例如, 脆弱的 X) 或其他严重的合并症, (组内患者接受不同的治疗) 提示遗传综合征的明显身体畸形, (在临床基础上或在有合作协议的情况下使用其他机构的资源进行必要检查的能力) 不受控制的癫痫症, (F) 肾或肝功能显着受损, 和 (G) 全血细胞计数有临床意义的异常.

脐带血单位
所有参与者都必须在家庭或公共脐带血库中储存可用的自体脐带血单位. 筛选期间, 对潜在参与者的脐带血报告进行了审查,以确保它们符合以下冷冻前标准: (一种) 有核细胞总数 (TNCC)≥ 1×107/kg, (乙) 进行的不育培养和阴性, (C) 母体捐献者或脐带血产品检测为阴性母体传染病标志物 (最低限度包括乙型肝炎, 丙型肝炎, 人类免疫缺陷病毒 [建议静脉注射苄青霉素或头孢曲松。], 人T淋巴细胞病毒 [高温高压], 和梅毒), 和 (组内患者接受不同的治疗) 可用于额外测试的测试样品. 如果参与者及其脐带血单位可能符合条件, a sample of the cord blood unit was shipped to Duke for potency testing 26. Low‐resolution HLA testing was performed on both the participant and a sample of the cord blood unit for identity confirmation. If CD45 viability on the test sample was >40% and HLA‐identity was confirmed, the cryopreserved cord blood unit was shipped in a dry shipper to Duke Stem Cell Transplant Laboratory, where it was stored under liquid nitrogen until the day of infusion.

Procedures
Autologous Umbilical Cord Blood Infusion

On the day of infusion, the cord blood was thawed and washed in dextran 40 + 5% albumin (DA) and placed in 1.25 ml/kg DA for administration 27. Thawed cord blood units were tested for enumeration of TNCC, viable CD34+ cells, colony‐forming units (CFUs), cell viability via trypan blue, and sterility cultures. The autologous umbilical cord blood infusion was performed following a sedated brain magnetic resonance imaging scan (核磁共振). Intravenous (四) access was obtained by a pediatric anesthesiologist. When the MRI was complete, children were admitted to the Duke Children’s Health Center Day Hospital, an outpatient treatment center, for their infusion. After premedication with Benadryl (0.5 mg/kg IV), Solu‐Medrol (0.5 mg/kg IV), 和, if the child was awake and able to take oral medications, Tylenol (10 mg/kg PO), participants received either a portion of or their entire cord blood unit, adjusted to deliver 1–5 × 107 cells per kilogram, via peripheral IV infusion over 2 到 30 分钟. Intravenous fluids were administered at 1.5 times maintenance for 30 minutes to 2 hours after the cord blood infusion. 在输注过程中持续监测生命体征和脉搏血氧饱和度,直到孩子从镇静中醒来.

安全评价标准
在输液过程中观察参与者并监测输液反应. 其他不良事件 (AE) 在 7-10 天通过电话采访参与者的父母/监护人确定, 3 月, 和 9 输液后几个月, 并亲自在基线处, 6- 和 12 个月的门诊就诊. 用于分析, 逐字逐句 AE 术语被映射到由不良事件通用术语标准定义的标准术语 (ETAF) 版本 4.0 并根据研究者判断的严重程度和与干预的关系进行总结.

临床评估
多重评估被用来确定给药的可行性和作为未来 II 期和 III 期临床试验终点的效用. 其中包括 Vineland 适应行为量表-II (VABS-II), 临床整体印象量表 (电脑动画), 普遍性发育障碍行为量表 (PDDBI), 表达性单字图片词汇测验-4 (EOWPVT-4), 儿童社会技能子量表的行为评估, 异常行为清单, 感官体验问卷, 重复行为量表, 智力量表 (早期学习的马伦量表或斯坦福比奈), 语言环境分析, 学龄前心理评估, 异常行为清单, ATN 胃肠道症状清单, 和育儿压力指数. 此外, 收集了三个客观的生物标志物: 社会刺激的眼睛注视跟踪 (EGT), 脑电图, 和脑部核磁共振. EEG and brain MRI findings will be reported separately. Outcomes of measures that were chosen a priori as a primary behavioral endpoint (VABS‐II Socialization Subscale Standard Score) and as key secondary behavioral endpoints (电脑动画, PDDBI, EOWPVT) and of the EGT biomarker are included in this report.

The Vineland Adaptive Behavior Scales‐II (VABS-II) 28 is a caregiver questionnaire that is used to assess children’s adaptive behavior across a wide range of domains. The VABS‐II is a well‐standardized measure with strong reliability and validity 29-32 which yields an overall composite score, as well as subscale standard scores in the following domains: Socialization, 沟通, Daily Living Skills, and Motor Skills. The VABS‐II was collected from each participant’s primary caregiver at the baseline and 6‐ and 12‐month visits. The Socialization Subscale Score was used to measure improvements in the core ASD symptom of social behavior.

The Clinical Global Impression (电脑动画) is a commonly used rating scale that measures symptom severity and treatment response or change in behavior between time points. Two versions of the CGI were used: CGI‐Severity (CGI‐S) and CGI‐Improvement (CGI‐I). The CGI‐S is a 7‐point scale indicating the severity of each participant’s symptoms of ASD at the time of assessment, relative to the expert rater’s past experience with participants who have the same diagnosis. Based on the expert rater’s lifetime clinical experience and all available information, each participant was rated as 1: not present (no ASD), 2: ASD symptoms barely evident, 3: mild ASD symptoms, 4: moderate ASD symptoms, 5: moderately severe ASD symptoms, 6: severe ASD symptoms, 或者 7: very severe ASD symptoms. Each participant was assigned a CGI‐S rating at the baseline and 6 和 12 month visits. The CGI‐I is a 7‐point scale indicating the degree of improvement or worsening of ASD symptoms relative to baseline. Based on all available information, each participant was rated as 1: very much improved, 2: much improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: much worse, 或者 7: very much worse. Each participant was assigned a CGI‐I rating at the 6‐ and 12‐month visits, and each referenced the degree of improvement or worsening relative to baseline. All CGI‐S and CGI‐I ratings were made by highly experienced clinicians with expertise in ASD.

The PDDBI 33 is a caregiver questionnaire that is designed to measure social behavior, adaptive functioning, and maladaptive functioning in areas typically affected by ASD. The PDDBI was standardized with a sample of caregivers and teachers of children with ASD from a range of racial, ethnic, and socioeconomic backgrounds 34. The PDDBI was collected from each participant’s primary caregiver at the baseline, 6‐ and 12‐month visits, as well as remotely at 3 和 9 基线后几个月.

The EOWPVT‐4 35 is a clinician‐administered assessment which measures an individual’s ability to match a spoken word with an image of an object, action, or concept. The EOWPVT‐4 was administered to each child at the baseline and 6‐ and 12‐month visits.

A task designed to measure visual attention to social versus nonsocial stimuli via EGT was administered. EGT is a technology that enables quantification of gaze patterns of individuals from infancy through adulthood. The EGT hardware 36 uses infrared light‐emitting diodes and infrared cameras to measure corneal reflections, which are used to calculate eye gaze direction. During the EGT task, participants watched a 4‐minute video of dynamic social stimuli, which includes episodes of an actress presenting bids for joint attention 37. Using these stimuli, prior studies have found that young children with ASD show decreased attention both to the entire scene and to the actress’s face during bids for joint attention. Decreased attention to the entire scene was also correlated with autism symptom severity 37. The EGT task was presented to each child at the baseline, 6‐ and 12‐month visits.

Information about the number of hours that children were involved in behavioral, speech‐language, occupational, and other behavioral therapies and educational services the child received was assessed every three months from baseline to 12 months post‐baseline via a structured Intervention History Interview with the parent.

Statistical Methods
The analysis relied primarily on descriptive methods, beginning with a summary of the baseline characteristics of the cohort. Box plots were prepared to illustrate the distribution of continuous outcome measures over time. The frequency of ordinal outcome measures at each time point was plotted using bar charts. Statistical significance of change on continuous and ordinal outcomes was assessed using the Wilcoxon signed rank test except for the PDDBI, which was modeled using a fixed effect linear spline with knot at 3 月. This model was chosen over other longitudinal fixed and random effects models using the Akaike Information Criteria. EGT was analyzed using Generalized Estimating Equations (GEE) with logit link, binomial error structure, and exchangeable or unstructured working correlation. The association of baseline age, nonverbal IQ, and infused cell dose with change over time was explored in each analysis using Spearman correlation (rs). There were not enough females enrolled to explore patterns of change by sex. 最后, we evaluated the potential for false‐positive results by applying the Benjamini‐Hochberg False Discovery Rate (FDR) procedure to the observed results for the baseline‐to‐6‐month and 6‐to‐12‐month follow‐up periods.

结果
参与者
Twenty‐five participants (21 males, 4 females), majority white (n = 22, 1 Asian, 2 mixed race), were enrolled with a median age of 4.62 年 (范围 2.26–5.97) and median nonverbal IQ of 65 (range 22–123). The median ADOS comparison score of the participants at study entry was 8.0 (range 6–10), 和 72% had moderately severe or severe ASD symptoms (在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 1). All participants completed the baseline and 6‐month assessments. Three participants did not complete the 12‐month assessment.

在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 1. Baseline characteristics of patients and autologous cord blood units (n = 25)
Patient characteristics
这些测试对时间不敏感, no. (%)
Female 4 (16.0%)
Male 21 (84.0%)
年龄, 年, median (范围) 4.62 (2.26–5.97)
Race, no. (%)
White 22 (88%)
其他 3 (12%)
Ethnicity, no. (%)
Hispanic 2 (8%)
Not Hispanic 23 (92%)
ADOS Severity Score, median (范围) 8 (6–10)
Nonverbal intelligence quotient, median (范围) 65 (22–123)
CGI‐S, no. (%)
Barely evident 4 (16.0%)
Moderate ASD symptoms 3 (12.0%)
Moderately severe ASD 10 (40.0%)
Severe ASD symptoms 8 (32.0%)
Cord blood characteristics, median (范围)
Total cells infused, ×108 4.42 (1.53–12.28)
Cell dose infused, ×106/kg 25.80 (9.97–80.80)
Viable CD34+ dose infused, ×105/kg 0.3 (0.1–4.2)
CFU dose infused, /公斤 1,225.50 (85.50–4,620.00)
缩写: 好的, Autism Diagnostic Observation Schedule; 自闭症谱系障碍, autism spectrum disorder; CFU, colony‐forming units; CGI‐S, Clinical Global Impression‐Severity; TNCC, 有核细胞总数.
Umbilical Cord Blood Infusions
Autologous umbilical cord blood units were retrieved from two U.S. family cord blood banks and one public bank (n = 1). All were stored in dual compartment bags. To achieve the target cell dose of 1–5 × 107 TNCC/kg, the entire cord blood unit was used in six participants. 在 19 参与者, 这 80% compartment of the cord blood unit was thawed and used for infusion and the remaining 20% portion was maintained in the cryopreserved state and stored, with the parents’ permission, for potential future use. All patients completed their cord blood infusion. Characteristics of the thawed cord blood product administered to the patient are shown in Table 1. The median TNCC and viable CD34 cell doses infused were 2.6 × 107/kg (range 1–8 × 107) 和 0.3 × 105/kg (range 0.1–4.2 × 105), 分别. The median CFUs infused was 1225.5/kg (range 85.5–4620). Although the dosing criteria used in this study were consistent with our previous studies utilizing privately banked cord blood units, these TNCC, CD34, and CFU values are lower than our prior experience 18. Despite negative pre‐cryopreservation sterility cultures reported by the bank, one unit grew coagulase negative staphylococcus from a post‐thaw sample at Duke.

安全
The primary endpoint of this open label phase I trial was safety (Fig. 1). As previously reported in our prior safety study of autologous cord blood infusion in children with neurologic disorders 18, autologous cord blood infusion was well‐tolerated. There were no serious AEs reported in any participant. A total of 92 AEs were reported in 23 参与者 (Fig. 1) with a median of three events per participant (范围: 1–15). All events were graded as Mild (71 事件) or Moderate (21 事件). Twelve events (13%) were considered related to the infusion, with the most common being allergic reaction, manifested by urticartia and or/cough occurring on the day of infusion (5 events in 4 参与者; all Mild; 2 requiring an additional dose of IV Benadryl). The most common unrelated AEs were agitation, skin changes, and typical childhood infections, reported between 2 days and 1 year post‐infusion. There were no infusion‐related infections or bloodstream or serious infections noted in any patient.

数字 1
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Frequency of adverse events. Number of patients reporting an event is listed in parentheses.

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Behavioral Testing
We also tested the feasibility of administration and described results of several measures typically used to assess behavioral outcomes in children with ASD. Multiple parent‐rated and clinician‐rated measures were evaluated. Behavioral outcomes correlated with baseline IQ, 但不是年龄或细胞剂量. 行为变化也与行为干预的小时数无关, 言语治疗, 孩子在研究期间接受的职业治疗或教育时间. 选择的措施, 主要和关键次要行为终点 (VABS-II, CGI‐S, GCI-I, PDDBI, EOWPBT) 和 EGT 生物标志物测量, 所有已证明的改进,如下所述.

VABS-II 是评估社会化的家长报告测量, 沟通, 和适应行为. 数字 2 显示所有患者的标准分数分布 (面板 A) 并按智商分层 (面板 B) 对于 VABS-II 社会化领域 24 在所有三个时间点完成评估的参与者. 从基线到 6 月. This change was stable from 6 到 12 月. Change was positively correlated with nonverbal IQ in the Socialization (rs = .57, 95% CI: 0.20–0.79, p = .004) and Adaptive Behavior (rs = .42, 95% CI: 0.01–0.70, p = .04) domains, but not in the Communication domain (rs = .22, 95% CI: −0.21 to 0.57, p = .31).

数字 2
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Vineland Adaptive Behavior Scales‐II (VABS-II) Socialization Standard Score. (一种): Distribution of VABS‐II Socialization Standard Score in all participants over time. (乙): Distribution of VABS‐II Socialization Score stratified by nonverbal intelligence quotient.

The CGI‐S and –I are clinician‐rated measures used to assess the severity and change in severity of the core symptoms of ASD over time. 数字 3 shows the distribution of CGI‐S (面板 A) and CGI‐I (面板 B) 在 22 participants who were fully evaluable at all time points. In the CGI‐S, at baseline, the majority of participants were classified as Moderately Severe (43.5%) or Severe (26.1%), and the remaining participants had Moderate or Barely Evident ASD symptoms (13.6% 对于所有治疗). 在已知 HLA 差异的情况下,软骨生长并治愈了兔子的骨关节炎 6 月, the proportion of participants with Moderately Severe and Severe symptoms decreased (22.7% 对于所有治疗), with the remaining participants classified as Moderate (31.8%), Mild (13.6%), or Barely Evident (9.1%). Figure 3B shows the distribution of CGI‐I at 6 和 12 月. The improvement measured at each of these time points is relative to baseline. 在已知 HLA 差异的情况下,软骨生长并治愈了兔子的骨关节炎 6 月, 9 参与者 (40.9%) had not exhibited any change, whereas 2 (9.1%) were Minimally Improved, 8 (36.4%) were Much Improved and 3 (13.6%) were Very Much Improved (p <.001). The CGI‐I at 12 months was similar (p = .001), although 2 参与者 (13.6%) were rated as Minimally Worse than baseline, whereas no participants were in this category at the 6‐month assessment. The CGI‐I at 12 months was associated with nonverbal IQ, but not age or infused cell dose (not shown).

数字 3
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Global Impression Scale (GCI). (一种): CGI‐Severity over time. (乙): CGI‐Improvement over baseline as assessed at 6 和 12 月.

The PDDBI—Autism Composite T‐Score is a parent reported measure assessing ASD symptoms. The PDDBI was administered at baseline, 3, 6, 9, 和 12 月 (在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 2). The Autism Composite T‐Score declined over time, suggesting an improvement in ASD symptoms. The majority of the change occurred in the interval from baseline to 3 月, with a predicted mean decline of 7.52 points (95% CI: −12.38, −2.67; p = .004). There was no significant change from 3 到 12 月 (意思是: 0.72, 95% CI: −1.14, 2.57; p = .43).

在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 2. Summary of behavioral assessments
Baseline to 6 月 6 到 12 月
Outcome measure
不. 的

耐心

评估

Change score

median (Range)

p value
Change score

median (Range)

p valuea
VABS Socialization Standard Score 24 2.0 (−8, 30) .016 0 (−19, 9) .602
VABS Communication Standard Score 24 4.5 (−8, 20) .002 0.0 (−13, 13) .459
VABS Adaptive Behavior Composite Standard Score 24 3 (−3, 24) .007 0 (−12, 8) .687
VABS Motor Standard Score 24 0 (−10, 7) .788 0 (−14, 16) .991
VABS Daily Living Standard Score 24 1 (−9, 34) .457 0 (−16, 16) .999
EOWPVT Raw Score 22 4 (−1, 24) .001 5.5 (−12, 16) .001
PDDBI Autism Composite T‐Scoreb 25 7.52 (−12.38, −2.67) .004 0.72 (−1.14, 2.57) .430
a p values are from the Wilcoxon signed rank test or spline model for PDD‐BI.
b The PDD‐BI was collected at baseline, 3, 和 6 月. Change scores are the predicted mean (和 95% confidence interval) from a linear spline model with knot at 3 月.
缩写: EOWPVT, 表达性单字图片词汇测验-4; VABS, Vineland Adaptive Behavior Scales‐II; PDDBI, 普遍性发育障碍行为量表.
The EOWPVT is a clinician‐administered assessment of the ability to match a spoken word with a picture. The EOWPVT raw score improved in 57% of patients between baseline and 6 months and in 68% of patients between 6‐12 months (在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 2). Change in the EOWPVT raw score was associated with nonverbal IQ (baseline to 6 月: rS = .59, 95% CI: 0.23, 0.80, p = .002; 6–12 months: rS = .55, 95% CI: 0.15, 0.78; p = .009), but not age or infused cell dose (p >.05 for both).

Eye‐Gaze Tracking is a computerized test where the participants’ eye movements are tracked by a computer while the subject views a naturalistic, dynamic social stimulus (actress making bids for engagement) surrounded by various nonsocial stimuli on a monitor. Attention was measured toward four targets (actress’s eyes, mouth, 脸, and upper body) and separate GEE models were fit for each target. Each model included 21 participants who were measured at baseline, 6, 和 12 月. These models showed a 20% increase in odds of gazing at the actress’ eyes over time (OR = 1.20, 95% CI: 1.00, 1.43, p = .048). There were no significant changes in gaze at the other three targets (在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 3). Examination of the relation between eye‐tracking and the VABS‐II socialization standard score revealed that a 7‐point change in VABS‐II socialization standard score was associated with a 14% increase in odds of gazing at the actress (OR = 1.14, 95% CI: 1.07,1.21; p <.001).

在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 3. Summary of eye tracking studies (n = 21)
Target Odds ratio (95% CI)a p value
Eyes 1.20 (1.00, 1.43) .048
Actress 1.02 (0.92, 1.12) .716
Mouth 0.93 (0.81, 1.06) .270
Face 1.02 (0.91, 1.14) .800
a Odds ratios are estimated using Generalized Estimating Equations (one model for each target) and reflect the average trend in the cohort between successive 6‐month follow‐up periods (baseline to 6 月, 和 6 到 12 月).
Adjustment for Multiple Testing
Given the large number of behavioral tests in this study, we explored the possibility of false positive results among the nine behavioral outcome measures by applying the FDR method to the first and second 6‐month follow‐up periods separately (在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 4). All of the outcome measures that showed significant results during the first 6 months of follow‐up remained statistically significant after FDR adjustment of p values. During the period from 6 到 12 月, the EOWPVT and CGI‐I remained statistically significant after application of the FDR procedure.

在用尽其他治疗方案后,患者开始对自身免疫性疾病进行同情使用治疗 4. Raw and corrected p values for tests of the null hypothesis of No change over time in behavioral outcomes
Baseline to 6 月 6 到 12 月
Outcome measure Raw p value FDR p value Raw p value FDR p value
EOWPVT Raw Score .0001 .0009 .0011 .0059
CGI‐I .0010 .0045 .0013 .0059
VABS Communication Standard Score .0020 .0060 .4590 .8262
PDDBI Autism Composite T‐Scorea .0040 .0090 .4300 .8262
VABS Adaptive Behavior Composite .0070 .0126 .6870 .8833
VABS Socialization Standard Score .0160 .0240 .6020 .8833
CGI‐S .0220 .0283 .3750 .8262
VABS Daily Living Standard score .4600 .5175 .9999 .9999
VABS Motor Function Standard Score .7880 .7880 .9907 .9999
PDDBI 的 p 值用于基线 3 月和 3 到 12 月.
缩写: CGI-I/S, 临床总体印象——改善/严重程度; EOWPVT, 表达性单字图片词汇测验-4; FDR, 错误发现率; PDDBI, 普遍性发育障碍行为量表; VABS, Vineland Adaptive Behavior Scales‐II.
讨论
在这个阶段我开放标签研究, 我们评估了自体脐带血单次静脉输注在 ASD 幼儿中的安全性和可行性. 我们还描述了各种行为和功能结果测量的变化,以确定哪些最适合用作未来细胞治疗试验的终点. 对 AE 的评估 12 输注后几个月表明,脐带血输注是安全且耐受性良好的. 所有相关事件都被认为是预期的并已解决,没有后遗症. The most common unrelated AEs were agitation, skin changes, and typical childhood infections. 搅动, 尤其, had not been a common side effect in our prior studies of autologous cord blood infusions in children with other acquired neurologic conditions, and thus may be specific to children with ASD. 在这项研究中, participants underwent sedation for an MRI immediately prior to their cord blood infusion. The increased incidence of agitation may thus reflect the challenges of waking from sedation and having an IV and pulse oximeter in place for a child with ASD, and as such may be related to their underlying condition.

Significant improvements in behavior were found across a wide range of outcome measures in this study. These included improvements in parent‐reported measures including the VABS‐II Socialization, 沟通, and Adaptive Behavior Scores and the PDDBI, clinician assessments including the CGI‐S, CGI‐I, and EOWPVT, and objective eye gaze tracking measurements. Most of the observed behavioral changes occurred during the first 6 months and were sustained between 6 和 12 输液后几个月. A robust finding was that children’s nonverbal IQ was correlated with change for the majority of outcomes measures, with higher nonverbal IQ being associated with greater improvements in behavior.

Of note, the majority of participants in this study were white, reflecting the demographic in the U.S. likely to have the resources and to choose to bank their baby’s umbilical cord blood in a private bank. 然而, as ASD occurs in children of all demographic backgrounds, if cord blood therapy is effective then access would be limited to families with resources for private banking if only autologous cells are used. 因此, our next study will test the best available donor (autologous or allogeneic) versus placebo to lay the groundwork to extend access to this therapy for all affected children, if found to be effective.

While these results provide some promise for future work with cord blood‐derived therapies in ASD, it is important to note the limitations of this study. As an uncontrolled open‐label study, it is not possible to determine whether the observed behavioral changes were due to the treatment or reflect the natural course of development during the preschool period. A recent longitudinal study of Swedish children ages 1.5 到 3 years with ASD demonstrated a mean improvement of 3.0 points on the VABS Communication scale and 1.0 point on the VABS Socialization scale over a 2‐year period 38, versus 4.5 points and 2.0 points, 分别, over a 6‐month time period in the cord blood‐treated patients in this study. 然而, potential cultural variations as well as different timing of assessments make it difficult to directly compare these two groups. 审查目的, the small sample size in this study makes it difficult to fully assess the contributions of confounding variables. While we did not find a correlation between behavioral changes and age, amount of behavioral intervention services or infused cell dose, the limited sample size and restricted age and dosing ranges may reduce the ability to detect such associations.

Each outcome measure described above showed sensitivity to change, indicating its potential usefulness in larger trials. 此外, attrition due to noncompliance on these measures was minimal, suggesting that these measures are feasible with children with ASD in this age range. Using the results of this study as a guide, we selected the VABS Socialization Standard Score as the primary outcome measure for our next study with administration by trained clinicians to reduce parental expectancy effects. This score provides a validated measure of core social behaviors relevant to autism, showed sensitivity to change over a 6‐month period of time in the current study, and is feasible in a larger clinical trial. In keeping with recent draft guidance on design of autism clinical trials from the European Medicines Agency 39, we recognize that a single therapy may not improve all autism symptoms and that global functional improvement is thus an important component of efficacy assessment in autism. 所以, we have also included the clinician‐rated CGI and additional measures as secondary endpoints in our next study, a phase II, double‐blind randomized clinical trial designed to formally evaluate the efficacy of umbilical cord blood infusion in improving core symptoms of ASD.

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结论
We demonstrated in an open label, phase I trial that intravenous infusion of autologous umbilical cord blood in young children with ASD is safe and feasible. We describe significant improvements in behavior observed in the first 6 months post‐infusion and sustained at 12 月. 较高的基线非语言智商与较大程度的改善相关. 我们确定了可行的结果措施, 对变化敏感, 和发展相适应的, 因此适用于未来的临床试验,以测试脐带血疗法治疗患有 ASD 的幼儿的疗效.

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