Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders that are mainly characterized by deficits in social communication and interactions. Repetitive behaviors and/or interests and sensory sensitivities are also common. Many individuals also have comorbidities, including intellectual disability, adaptive skill deficits, anxiety, and aggressive behaviors. The prevalence of ASD is reported to be 1:68 (Centers for Disease Control and Prevention, 2016) with boys affected at a higher rate than girls (4.5:1).

ASDs are present in children from a very young age and with modern diagnostics can be diagnosed by <24 months of age. While autism is not a fatal disease, it causes lifelong morbidity in many affected individuals and their families. Those diagnosed with ASD who also have intellectual disability are unlikely to be able to live independently and may be dependent on parental/societal care for their entire life. There are currently no approved therapies that address the core symptoms of autism. Thus, there is a keen interest in exploring novel therapeutic approaches to the condition.

ASDs are a heterogeneous group of disorders, and it is likely that the etiology of disease is not the same in all cases. Broadly, there is evidence that genetic mutations may be responsible for the disorder in <10% of cases. There also is evidence that neuroinflammation, either in utero or postnatally, may play a role. Furthermore, as named, ASD is a spectrum of disorders that vary in severity, impact on the individual and their family, and selection of and efficacy of interventions and treatments.

Cellular-based therapy is undergoing testing in clinical trials for many neurological diseases including, but not limited to, cerebral palsy, hypoxic ischemic encephalopathy, severe traumatic brain injury, spinal cord injury, stroke, and ASD.^1-3 Mesenchymal stromal cells (MSCs) derived from bone marrow or cord or other birthing tissues, cord blood cells, and bone marrow cells are all undergoing testing in early phase clinical trials. In most studies, cells are delivered intravenously, but in a few, cells are given intrathecally. There are claims identifying modulation of neuroinflammation as the mechanism of action of these various cells, but none are fully substantiated at this time. In addition to formal clinical trials, there are many unproven stem cell interventions, offered without regulatory oversight by clinics with varying qualifications, which are available on a fee-for-service (also known as “pay to participate”) basis that can be classified as “medical tourism,” risky, and/or unproven treatments.

The identification and use of objective and validated outcome measures in clinical trials in children with ASD is very challenging. Measures generally involve, at least in part, parent-reported behavioral outcomes that are difficult to administer and standardize. It is critical before claiming a benefit of a particular intervention, to conduct one or more phase III randomized, blinded, placebo-controlled clinical trial(s) to confirm true responses and to differentiate placebo/expectancy effects from true responses. In addition, studies in children, who are developing, growing physically, and changing, are more difficult because of the need to differentiate a change from expected development to an effect of the intervention undergoing testing. Of note, to date there have not been any therapeutic interventions that have demonstrated efficacy in formal phase III clinical trials in children with ASD.

Over the past few years, SCTM has published eight manuscripts reporting results of small early phase clinical trials of cord blood (n = 4), induced pluripotent stem cells (n = 1), cord tissue MSCs (n = 2), or bone marrow cells (n = 1) in children with ASD. Highlights of some of these studies are described here.

Dawson and colleagues conducted a phase I, open-label study, determining that autologous cord blood infusions were safe and feasible.⁴ The authors hypothesized that the treatment reduced symptoms in children with ASD because cord blood cells modulate inflammatory processes in the brain. Twenty-five children, aged 2-5 years (median age 4.6), were enrolled. Patients had to have stored a qualified banked autologous cord blood unit. There were no serious adverse events related to infusion. Improvements in parent-reported outcomes of social communication skills improved in children with a nonverbal IQ >70 in the first 6 months post-treatment. Assessments using the Vineland Adaptive Behavior Scales-II (VABS-II), a caregiver questionnaire that assesses socialization, communication, daily living skills, and motor skills, showed a significant improvement in the socialization and adaptive behavior domains, but not in the communication domains, in the first 6 months after treatment. There was no further improvement from 6 to 12 months. Eye tracking and electroencephalogram (EEG) results correlated with the responses seen on the VABS-II.

Another cord blood study used a randomized, placebo-controlled, crossover design.⁵ Twenty-nine children with ASD, aged 2-6 years, were enrolled. Patients received autologous cord blood or placebo, were evaluated at 12 and 24 weeks, and then crossed over to the opposite treatment. There were no serious adverse events. Multiple endpoints were evaluated, and although there were trends toward improvement on the VABS and other socialization scales, there were no statistically significant differences for any endpoints.

A phase II randomized, placebo-controlled, double-blind clinical trial was recently published in the Journal of Pediatrics; 180 children with ASD, aged 2-7 years, were randomized to either autologous (n = 56) or unrelated donor partially HLA-matched allogeneic (n = 63) vs placebo (n = 61).⁶ The study was modeled to enroll a minimum of 143 children with a nonverbal IQ >70 to be powered to answer the primary study question, but due to a flaw in study design, only 101 of the 280 enrolled children met this criteria. Nonetheless, the study was analyzed as enrolled. The cord blood infusions were well tolerated. Analysis of the entire cohort showed no evidence for improvement in the primary endpoint, which was the VABS-III Socialization Domain in the treatment arms. A large expectancy effect was observed in the placebo arm in many of the behavior measures. A subset analysis of children without intellectual disability, the intended study population, showed significant improvements in the VABS Communication Domain, eye-tracking, EEG, and the Clinical Global Impression-Improvement scale in children treated with cord blood.

In another small, open-labeled study, allogeneic MSCs derived from umbilical cord tissue were administered to 20 children with ASD.⁷ Efficacy was evaluated with the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS). Patients received four intravenous treatments over a 9 month period, and were followed at 3 and 12 months. There were no serious adverse events. Both the CARS and ATEC scores of eight subjects decreased over the course of treatment, placing these children in a lower ASD symptom category when compared with baseline. Inflammatory cytokine levels also decreased. In this report, the benefit was mild, but hypothesis generating for future investigation.

Earlier this year, the Duke group published their experience with 12 children with ASD, aged 2 to 11 years, treated on an open-label phase I study investigating MSCs derived from allogeneic cord tissue MSCs.⁸ Children were treated with 1, 2, or 3 infusions of 2 × 10e6 cells/kg separated by 2 months each. All of the infusions were well tolerated. Low titer, anti-class I HLA antibodies targeted against HLA loci on the MSC donor cells and not on the patients' cells, developed in half of patients. Fifty-eight percent of the patients showed improvement in two of three behavior endpoints that were described in the results. The authors concluded that infusions of cord tissue MSC are safe and that further randomized studies are needed to determine efficacy.

The study by Thanh et al,⁹ “Outcomes of bone marrow mononuclear cell transplantation combined with interventional education for autism spectrum disorder,” published in a recent edition of the journal has stimulated conversations and controversy. The article described an early phase open-label, nonrandomized study of intrathecal autologous bone marrow mononuclear cells combined with educational intervention for children with ASD. The authors inaccurately described the therapy as “transplantation,” which was misleading. The therapy was comprised of two intrathecal doses of bone marrow cells, one at baseline followed by 8 weeks of behavioral therapy and a second repeated 6 months later. The primary outcome measure was the CARS score. The authors reported improvements in multiple behavioral endpoints within 18 months of treatment and concluded that the therapy was safe and that further randomized placebo-controlled studies are needed.

In response to this paper, Dr. Heather Finlay-Morreale wrote a passionate letter to the editor questioning the ethics of performing this trial in children with ASD.¹⁰ Specific criticisms included the fact that the risk of toxicity of the intrathecal route of administration of cells was not justified, particularly in vulnerable children who could not consent for themselves. In response to Dr. Finlay-Morealle's letter, the authors of the manuscript wrote a rebuttal, which is published in this issue of the journal. In addition, the journal's editorial staff felt compelled to address her concerns in a broader sense. Some children with autism can have mild deviations from neurotypical behaviors with normal intelligence and can navigate their world with accommodations from others. More often, though, children with more severe manifestations of autism, especially with comorbidities that cause intellectual disabilities, cannot navigate their world and create seemingly insurmountable challenges for their families, siblings, teachers, therapists, and others. Frankly, there are no therapies that effectively modify the core symptoms of autism and new treatments are needed. Thus, the justification of the need for effective and safe interventions is evident.

Dr. Finlay-Morreale makes some valid points in her letter, particularly that Thanh and colleagues did not treat the children in their series with stem cells. Bone marrow-derived mononuclear cells were used. In addition, the cells were not transplanted; rather they were administered via intrathecal injection with no preparative therapy or intent of engraftment. As both authors of this position piece are experienced in administering intrathecal chemotherapy in patients with hematological malignancies and Dr. Kurtzberg also has limited experience giving cell therapy intrathecally to children with leukodystrophies, we do not agree that performing spinal taps on children will result in “lifelong pain or bleeding into the spinal cord causing paralysis.” Having said this, we do agree that intrathecal administration of cells would have likely undergone additional scrutiny in the United States before it could be incorporated into a clinical trial in children with ASD. Furthermore, the manufacturing of the cells and final formulation for administration could significantly increase (or decrease) the safety of the intrathecal dose. Specifically, red blood cells should be eliminated from an intrathecal formulation. Furthermore, only certain solutions are safe for intrathecal administration (Ringer's lactate, Elliot's B solution) and the authors did not specify these details about their cellular product.

At SCTM, we feel that it is important to publish manuscripts describing early phase clinical trials in this new and emerging area. The early studies will not be perfect, but with transparent and constructive discussion among the stakeholders, in peer-reviewed medical journals—not through social networks or blogs—accurate information will be disseminated and subsequent studies will be improved. These scientific publications will also be vetted by review teams and critiqued in a way that improves the overall quality of their manuscripts. This practice should also encourage the “bad actors” to present their results in a legitimate scientific journal rather than in the lay press or through testimonials or on blogs. The scientific community, parents, and medical professionals caring for children with autism need to work together to better understand the various forms and etiologies of this heterogeneous disease, to identify the children who are in need of therapy, and to evaluate the safety of various approaches. We look forward to learning about more advances in this complex disease.

自闭症谱系障碍（ASD）是一组神经发育障碍，主要特征是社交沟通和互动缺陷。重复的行为和/或兴趣和感官敏感性也很常见。许多人还患有合并症，包括智力障碍、适应技能缺陷、焦虑和攻击性行为。据报道，自闭症谱系障碍的患病率为 1:68（美国疾病控制与预防中心，2016 年），其中男孩的患病率高于女孩（4.5:1）。

自闭症谱系障碍（ASD）在儿童很小的时候就存在，通过现代诊断方法可以在 24 个月以下的时候诊断出来。虽然自闭症不是一种致命的疾病，但它会导致许多受影响的个人及其家人终生发病。那些被诊断患有自闭症谱系障碍并患有智力障碍的人不太可能能够独立生活，并且可能一生都依赖父母/社会的照顾。目前还没有批准的疗法可以解决自闭症的核心症状。因此，人们对探索这种疾病的新治疗方法产生了浓厚的兴趣。

自闭症谱系障碍 (ASD) 是一组异质性疾病，所有病例的病因可能并不相同。总体而言，有证据表明，不到 10% 的病例中，基因突变可能是导致该疾病的原因。还有证据表明，子宫内或产后的神经炎症可能发挥了作用。此外，顾名思义，自闭症谱系障碍是一系列疾病，其严重程度、对个人及其家庭的影响以及干预和治疗的选择和效果各不相同。

基于细胞的疗法正在针对许多神经系统疾病进行临床试验，包括但不限于脑瘫、缺氧缺血性脑病、严重创伤性脑损伤、脊髓损伤、中风和自闭症谱系障碍。^1-3源自骨髓或脐带或其他分娩组织的间充质基质细胞 (MSC)、脐带血细胞和骨髓细胞都在早期临床试验中进行测试。在大多数研究中，细胞通过静脉注射，但在少数研究中，细胞通过鞘内注射。有人声称神经炎症的调节是这些不同细胞的作用机制，但目前还没有得到充分证实。除了正式的临床试验外，还有许多未经证实的干细胞干预措施，由具有不同资质的诊所在没有监管监督的情况下提供，这些干预措施是按服务收费（也称为“付费参与”）提供的，可分为作为“医疗旅游”、有风险和/或未经证实的治疗方法。

在自闭症儿童临床试验中确定和使用客观且经过验证的结果测量非常具有挑战性。衡量标准通常至少部分涉及家长报告的难以管理和标准化的行为结果。在声称特定干预措施的益处之前，进行一项或多项随机、盲法、安慰剂对照的 III 期临床试验以确认真实反应并区分安慰剂/预期效果与真实反应至关重要。此外，对正在发育、身体成长和变化的儿童进行研究更加困难，因为需要区分预期发育的变化和正在测试的干预措施的效果。值得注意的是，迄今为止，还没有任何治疗干预措施在自闭症儿童的正式 III 期临床试验中证明有效。

在过去的几年中，SCTM发表了八篇手稿，报告了脐带血 (n = 4)、诱导多能干细胞 (n = 1)、脐带组织间充质干细胞 (n = 2) 或骨髓的小型早期临床试验的结果患有自闭症谱系障碍 (ASD) 儿童的细胞 (n = 1)。这里描述了其中一些研究的要点。

道森和同事进行了一项第一阶段开放标签研究，确定自体脐带血输注是安全可行的。⁴作者推测，这种治疗可以减轻自闭症儿童的症状，因为脐带血细胞可以调节大脑中的炎症过程。共有 25 名年龄在 2-5 岁（中位年龄 4.6 岁）的儿童参加。患者必须储存合格的自体脐带血。没有与输注相关的严重不良事件。在治疗后的前 6 个月内，非语言智商 >70 的儿童的家长报告的社交沟通技巧结果有所改善。使用 Vineland 适应性行为量表 II (VABS-II)（一种评估社交、沟通、日常生活技能和运动技能的看护者问卷）进行的评估显示，社交和适应性行为领域有显着改善，但沟通领域没有改善，在治疗后的前 6 个月内。6 至 12 个月后没有进一步改善。眼动追踪和脑电图 (EEG) 结果与 VABS-II 上看到的反应相关。

另一项脐带血研究采用了随机、安慰剂对照、交叉设计。⁵ 29 名年龄为 2-6 岁的自闭症谱系障碍 (ASD) 儿童被纳入研究。患者接受自体脐带血或安慰剂，在第 12 周和第 24 周时进行评估，然后交叉接受相反的治疗。没有发生严重的不良事件。对多个终点进行了评估，尽管 VABS 和其他社会化量表有改善的趋势，但任何终点均没有统计学上的显着差异。

一项 II 期随机、安慰剂对照、双盲临床试验最近发表在《儿科学杂志》上；180 名 2-7 岁的 ASD 儿童被随机分配到自体供体 (n = 56) 或无关的 HLA 部分匹配的同种异体供体 (n = 63) 与安慰剂 (n = 61) 组。⁶该研究的模型是至少招募 143 名非语言智商 >70 的儿童来回答主要研究问题，但由于研究设计存在缺陷，280 名招募的儿童中只有 101 人符合这一标准。尽管如此，该研究还是在入组时进行了分析。脐带血输注耐受性良好。对整个队列的分析显示，没有证据表明主要终点（即治疗组中的 VABS-III 社会化领域）有所改善。在安慰剂组的许多行为测量中观察到了很大的预期效应。对无智力障碍儿童（目标研究人群）的子集分析显示，接受脐带血治疗的儿童在 VABS 沟通领域、眼动追踪、脑电图和临床整体印象改善量表方面有显着改善。

在另一项小型开放标记研究中，将来自脐带组织的同种异体 MSC 给予 20 名患有自闭症谱系障碍 (ASD) 的儿童。⁷使用自闭症治疗评估清单 (ATEC) 和儿童自闭症评定量表 (CARS) 评估疗效。患者在 9 个月内接受了 4 次静脉注射治疗，并在 3 个月和 12 个月时进行了随访。没有发生严重的不良事件。八名受试者的 CARS 和 ATEC 评分在治疗过程中均有所下降，与基线相比，这些儿童处于较低的 ASD 症状类别。炎症细胞因子水平也下降。在这份报告中，好处是轻微的，但为未来的研究提供了假设。

今年早些时候，杜克大学研究小组发表了他们对 12 名 2 至 11 岁 ASD 儿童进行开放标签 I 期研究的治疗经验，该研究调查了源自同种异体脐带组织 MSC 的 MSC。^{8 名}儿童接受 1、2 或 3 次 2 × 10e6 细胞/kg 输注治疗，每次间隔 2 个月。所有输注均耐受良好。半数患者体内产生了针对 MSC 供体细胞而非患者细胞上的 HLA 基因座的低滴度抗 I 类 HLA 抗体。58% 的患者在结果中描述的三个行为终点中的两个表现出改善。作者得出结论，输注脐带组织间充质干细胞是安全的，需要进一步的随机研究来确定疗效。

Thanh 等人⁹的研究“骨髓单核细胞移植与自闭症谱系障碍介入教育相结合的结果”发表在该杂志最近一期上，引发了讨论和争议。该文章描述了一项针对自闭症谱系障碍儿童鞘内自体骨髓单核细胞结合教育干预的早期开放标签、非随机研究。作者错误地将这种疗法描述为“移植”，这是一种误导。该疗法包括两次鞘内注射骨髓细胞，一次在基线时进行，随后进行 8 周的行为治疗，第二次在 6 个月后重复。主要结果指标是 CARS 评分。作者报告了治疗 18 个月内多个行为终点的改善，并得出结论认为该疗法是安全的，需要进一步的随机安慰剂对照研究。

作为对这篇论文的回应，Heather Finlay-Morreale 博士给编辑写了一封热情洋溢的信，质疑在自闭症谱系障碍儿童中进行这项试验的伦理道德。¹⁰具体的批评包括这样一个事实，即鞘内注射细胞途径的毒性风险是不合理的，特别是对于无法自己同意的弱势儿童。针对 Finlay-Morealle 博士的信函，该手稿的作者撰写了反驳文章，并发表在本期杂志上。此外，该杂志的编辑人员感到有必要从更广泛的意义上解决她的担忧。一些患有自闭症的儿童可能与智力正常的神经典型行为有轻微偏差，并且可以通过他人的适应来驾驭自己的世界。然而，更常见的是，患有更严重自闭症的儿童，尤其是患有导致智力障碍的合并症的儿童，无法驾驭他们的世界，并给他们的家人、兄弟姐妹、老师、治疗师和其他人带来看似难以克服的挑战。坦率地说，没有任何疗法可以有效改变自闭症的核心症状，因此需要新的治疗方法。因此，有效和安全干预措施的必要性是显而易见的。

Finlay-Morreale 博士在信中提出了一些有效的观点，特别是 Thanh 和同事没有用干细胞治疗他们系列中的孩子。使用骨髓来源的单核细胞。此外，细胞并未进行移植；相反，它们是通过鞘内注射进行给药，没有准备治疗或植入意图。由于本立场文章的两位作者在对血液恶性肿瘤患者进行鞘内化疗方面经验丰富，而 Kurtzberg 博士对脑白质营养不良儿童进行鞘内细胞治疗的经验也有限，因此我们不认为对儿童进行脊椎穿刺会导致“终生”。疼痛或脊髓出血导致瘫痪。” 话虽如此，我们确实同意，在将细胞鞘内给药纳入自闭症谱系障碍儿童的临床试验之前，在美国可能会接受额外的审查。此外，细胞的制造和最终给药制剂可以显着增加（或降低）鞘内剂量的安全性。具体而言，应从鞘内制剂中消除红细胞。此外，只有某些溶液对于鞘内给药是安全的（林格氏乳酸盐、埃利奥特 B 溶液），并且作者没有具体说明有关其细胞产品的这些细节。

在SCTM，我们认为发表描述这一新兴领域早期临床试验的手稿非常重要。早期的研究不会是完美的，但通过利益相关者之间在同行评审的医学期刊上（而不是通过社交网络或博客）进行透明和建设性的讨论，准确的信息将被传播，后续的研究将得到改进。这些科学出版物还将接受评审小组的审查，并以提高稿件整体质量的方式进行批评。这种做法还应该鼓励“不良行为者”在合法的科学期刊上展示他们的结果，而不是在普通媒体或通过推荐或博客上展示他们的结果。科学界、家长和照顾自闭症儿童的医疗专业人员需要共同努力，更好地了解这种异质性疾病的各种形式和病因，识别需要治疗的儿童，并评估各种方法的安全性。我们期待了解这种复杂疾病的更多进展。