Otizm Spektrum Bozukluğu Olan Küçük Çocuklarda Otolog Kordon Kanı İnfüzyonları Güvenli ve Uygulanabilir: Results of a Single‐Center Phase I Open‐Label Trial
Despite advances in early diagnosis and behavioral therapies, otizm spektrum bozukluğu olan çocuklar için daha etkili tedaviler (OSB) ihtiyaç vardır. We hypothesized that umbilical cord blood‐derived cell therapies may have potential in alleviating ASD symptoms by modulating inflammatory processes in the brain. Buna göre, we conducted a phase I, open‐label trial to assess the safety and feasibility of a single intravenous infusion of autologous umbilical cord blood, as well as sensitivity to change in several ASD assessment tools, to determine suitable endpoints for future trials. Twenty‐five children, median age 4.6 yıllar (range 2.26–5.97), with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit, were enrolled. Children were evaluated with a battery of behavioral and functional tests immediately prior to cord blood infusion (baseline) Ve 6 Ve 12 aylar sonra.
Assessment of adverse events across the 12‐month period indicated that the treatment was safe and well tolerated. Significant improvements in children’s behavior were observed on parent‐report measures of social communication skills and autism symptoms, clinician ratings of overall autism symptom severity and degree of improvement, standardized measures of expressive vocabulary, and objective eye‐tracking measures of children’s attention to social stimuli, indicating that these measures may be useful endpoints in future studies.
Behavioral improvements were observed during the first 6 months after infusion and were greater in children with higher baseline nonverbal intelligence quotients. These data will serve as the basis for future studies to determine the efficacy of umbilical cord blood infusions in children with ASD. Stem Cells Translational Medicine 2017;6:1332–1339
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Significance Statement
Bu aşama I çalışması, otizm spektrum bozukluğu olan küçük çocuklarda otolog göbek kordon kanı infüzyonlarının gerçekleştirilmesinin güvenli ve uygulanabilir olduğunu göstermekte ve gelecekteki denemelerde kullanılmak üzere ümit verici birkaç sonuç ölçütünü tanımlamaktadır..
giriiş
Otizm spektrum bozukluğu (OSB) sosyal iletişimde bozulma, tekrarlayan davranışlar ve sınırlı aktivite aralığı ile karakterize nörogelişimsel bir bozukluktur., yaşamın erken dönemlerinde başlayan. ASD'nin yaklaşık olarak etkileyeceği tahmin edilmektedir. 1 içinde 68 ABD'deki çocuklar. 1. OSB'li bireylerin çoğunluğu bağımsız yaşayamaz ve yaşam boyu destek veya konaklamaya ihtiyaç duyar. Buna göre, OSB'li bir bireyi desteklemenin yaşam boyu maliyetinin şu şekilde olduğu tahmin edilmektedir: $1.4 milyon. Maliyeti $2.4 aynı zamanda zihinsel engelli olanlar için milyon 2.
Treatment approaches for ASD include medication, behavioral therapy, occupational and speech therapies, and specialized educational and vocational support. Erken yoğun davranışsal müdahale, önemli ölçüde iyileştirilmiş sonuçlarla ilişkilidir 3, ama böyle bir müdahaleye rağmen, OSB'li birçok kişi önemli ölçüde engelli olmaya devam ediyor. Şu anda mevcut olan tüm tıbbi tedaviler, psikotrop ilaçlar gibi, ilişkili eşlik eden semptomları iyileştirmeyi amaçlamaktadır, sinirlilik gibi, ancak temel otizm semptomlarına değinmeyin. Bunun ışığında, OSB'nin temel semptomlarını hedef alan daha etkili tedavilere karşı karşılanmamış büyük bir ihtiyaç var.
OSB etiyolojisine hem genetik hem de çevresel faktörler katkıda bulunmaktadır. 4-6. Patofizyolojisi kesin olarak bilinmemekle birlikte, gözlemler beyin bölgelerindeki anormal sinaptik işleyişi de içermektedir. 7, 8, beyaz madde anormallikleri 9, ve nöroinflamasyon 10. Pathogenesis of immune pathology in the brains of patients with ASD may be due to overexpression of immune‐related gene networks 11, presence of maternal antibodies to fetal brain tissue 12, atypical levels of proinflammatory cytokines (IL‐6, TNF‐α) in the cerebral spinal fluid 13, and excessive microglial activation leading to aberrant neural connectivity pathways 14, 15. Gibi, therapeutic approaches impacting immune modulation or regulation of neural connectivity are logical targets for novel treatments for this population. Preclinical models have shown that umbilical cord blood contains effector cells that, through paracrine signaling, alter brain connectivity and also suppress inflammation 16, 17. Infusions of autologous cord blood cells have been shown to be safe in patients with cerebral palsy and other acquired brain injuries 18-20. We hypothesized that infusions of autologous cord blood cells could play an important role in the treatment of ASD and conducted a single center, open‐labeled, phase I safety and feasibility trial in young pediatric participants. The study focused on (A) the safety of a single intravenous infusion of autologous umbilical cord blood and (B) the sensitivity to change and feasibility of administration of several different assessment tools in young children with ASD.
Materials and Methods
Study Design and Overview
This study was a phase I, single‐center, open‐label trial of a single intravenous infusion of autologous umbilical cord blood in 25 children with ASD. All children were initially enrolled on a screening protocol to obtain medical records and information about their banked cord blood unit. All participants’ caregivers completed a prestudy screening interview by phone and provided medical records and videos for review by the study team to determine eligibility for the trial. Children with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit were eligible to participate. Written informed consent was obtained for both the screening and the treatment phases of the trial. The trial was approved by the Duke Hospital Institutional Review Board and conducted under IND #15949.
Participants and their caregivers traveled to Duke University three times as part of their participation in the study. At their baseline visit, they were evaluated and received a single intravenous autologous cord blood infusion. At 6 Ve 12 months post‐infusion, participants returned for follow‐up clinical assessments. Additional caregiver interviews and questionnaires were collected at 3 Ve 9 months post‐infusion.
Participants
Participants between 2 Ve 5 years of age who met criteria for a clinical diagnosis of ASD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) 21 were eligible for study inclusion. The DSM‐5 diagnosis of ASD was established by expert clinicians and informed by the Autism Diagnostic Observation Schedule (ADOS), Second Edition 22 and the Autism Diagnostic Interview, Revised (ADI‐R) 23. Additional inclusion criteria included (A) a nonverbal intelligence quotient (IQ) of ≥ 35 on the Stanford‐Binet Intelligence Scales for Early Childhood, Fifth Edition 24 or Mullen Scales of Early Learning 25, (B) availability of a qualified autologous umbilical cord blood unit, (C) participant was stable on their current medications for at least 2 months prior to the infusion, (d) ability to travel to Duke University three times (baseline and 6 Ve 12 months post‐baseline), Ve (e) parents were English speaking. Exclusion criteria included (A) a history of prior cell therapy, (B) use of intravenous immunoglobulin or other anti‐inflammatory medications (with the exception of NSAIDs), (C) known genetic (e.g., fragile X) or other significant medical comorbidity, (d) obvious physical dysmorphology suggestive of a genetic syndrome, (e) an uncontrolled seizure disorder, (F) önemli ölçüde bozulmuş böbrek veya karaciğer fonksiyonu, Ve (G) Tam kan sayımında klinik olarak anlamlı anormallikler.
Göbek Kordon Kanı Üniteleri
Tüm katılımcıların bir ailede veya kamu kordon kanı bankasında hazır bir otolog göbek kordon kanı ünitesine sahip olması gerekiyordu.. Tarama sırasında, potansiyel katılımcıların kordon kanı raporları, aşağıdaki kriyoprezervasyon öncesi kriterleri karşıladıklarından emin olmak için gözden geçirildi: (A) toplam çekirdekli hücre sayısı (TNCC)≥ 1 × 107/kg, (B) önceden oluşturulmuş ve negatif olan kısırlık kültürleri, (C) Anne donöründe veya kordon kanı ürününde test edilen negatif anne bulaşıcı hastalık belirteçleri (minimal düzeyde hepatit B dahil, Hepatit C, insan bağışıklık eksikliği virüsü [HIV], insan T lenfotrofik virüsü [HTLV], ve frengi), Ve (d) ek testler için test örneği mevcuttur. If the participant and their cord blood unit were likely to be eligible, 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 (MR). Intravenous (IV) 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), Ve, 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 ile 30 minutes. Intravenous fluids were administered at 1.5 times maintenance for 30 minutes to 2 hours after the cord blood infusion. Vital signs and pulse oximetry were monitored continuously during the infusion and until the child awoke from sedation.
Safety Evaluation Criteria
Participants were observed during the infusion and monitored for infusion reactions. Additional adverse events (AE) were identified through phone interviews with participants’ parent/guardian at 7–10 days, 3 aylar, Ve 9 months after infusion, and in person at the baseline, 6‐ and 12‐month clinic visits. For analysis, verbatim AE terms were mapped onto standard terminology defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and summarized according to severity and relationship to the intervention as judged by the investigator.
Clinical Assessments
Multiple assessments were used to determine both feasibility of administration and utility as an endpoint for future phase II and III clinical trials. These included the Vineland Adaptive Behavior Scales‐II (VABS‐II), Clinical Global Impression Scale (CGI), Pervasive Developmental Disorder Behavior Inventory (PDDBI), Expressive One‐Word Picture Vocabulary Test‐4 (EOWPVT‐4), Behavior Assessment for Children‐Social Skills subscale, Aberrant Behavior Checklist, Sensory Experiences Questionnaire, Repetitive Behavior Scale, Intelligence Scales (Mullen Scales of Early Learning or Stanford‐Binet), Language Environment Analysis, Preschool Age Psychiatric Assessment, Aberrant Behavior Checklist, ATN GI Symptoms Inventory, and Parenting Stress Index. Ek olarak, three objective biomarkers were collected: Eye Gaze Tracking of Social Stimuli (EGT), EEG, and brain MRI. 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 (CGI, 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, Communication, 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 (CGI) 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. Uzman değerlendiricinin yaşam boyu klinik deneyimine ve mevcut tüm bilgilere dayanmaktadır, her katılımcı şu şekilde derecelendirildi: 1: mevcut değil (ASD yok), 2: ASD belirtileri zar zor belli oluyor, 3: hafif ASD semptomları, 4: orta dereceli ASD semptomları, 5: orta derecede şiddetli OSB belirtileri, 6: Şiddetli OSB belirtileri, veya 7: çok şiddetli OSB belirtileri. Her katılımcıya başlangıçta bir CGI-S derecelendirmesi verildi ve 6 Ve 12 aylık ziyaretler. CGI-I, OSB semptomlarının başlangıca göre iyileşme veya kötüleşme derecesini gösteren 7 puanlık bir ölçektir.. Mevcut tüm bilgilere dayanarak, her katılımcı şu şekilde derecelendirildi: 1: çok gelişti, 2: çok gelişmiş, 3: minimal düzeyde geliştirilmiş, 4: değişiklik yok, 5: minimum düzeyde daha kötü, 6: çok daha kötü, veya 7: çok daha kötü. Her katılımcıya 6 ve 12 aylık ziyaretlerde bir CGI-I derecelendirmesi verildi., ve her biri başlangıç noktasına göre iyileşme veya kötüleşme derecesine atıfta bulundu. 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 Ve 9 months post‐baseline.
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, Önceki araştırmalar, OSB'li küçük çocukların, ortak ilgi arayışı sırasında hem sahnenin tamamına hem de oyuncunun yüzüne karşı dikkatlerinin azaldığını ortaya çıkarmıştı.. Sahnenin tamamına olan ilginin azalması da otizm semptom şiddetiyle ilişkiliydi 37. EGT görevi başlangıçta her çocuğa sunuldu., 6‐ and 12‐month visits.
Çocukların davranışsal faaliyetlere dahil oldukları saat sayısı hakkında bilgi, konuşma dili, Mesleki, Çocuğun aldığı diğer davranışsal terapiler ve eğitim hizmetleri başlangıçtan itibaren her üç ayda bir değerlendirildi. 12 Başlangıç seviyesinden sonraki aylarda ebeveynle yapılandırılmış bir Müdahale Geçmişi Görüşmesi yoluyla.
İstatistiksel Yöntemler
Analiz öncelikle tanımlayıcı yöntemlere dayanıyordu, kohortun temel özelliklerinin bir özetiyle başlayarak. 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 aylar. 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. Nihayet, Benjamini-Hochberg Yanlış Keşif Oranını uygulayarak yanlış pozitif sonuç potansiyelini değerlendirdik (FDR) başlangıçtan 6 aya kadar ve 6 ila 12 ay arasındaki takip dönemleri için gözlemlenen sonuçlara ilişkin prosedür.
Sonuçlar
Participants
Yirmi beş katılımcı (21 erkekler, 4 dişiler), çoğunluk beyaz (n = 22, 1 Asya, 2 karışık ırk), ortalama yaşla kaydoldular 4.62 yıllar (range 2.26–5.97) ve ortalama sözel olmayan IQ'su 65 (aralık 22–123). Katılımcıların çalışmaya girişteki ortalama ADOS karşılaştırma puanı şuydu: 8.0 (aralık 6–10), Ve 72% orta derecede şiddetli veya şiddetli OSB semptomları vardı (Masa 1). Tüm katılımcılar temel ve 6 aylık değerlendirmeleri tamamladı. Üç katılımcı 12 aylık değerlendirmeyi tamamlamadı.
Masa 1. Hastaların ve otolog kordon kanı ünitelerinin temel özellikleri (n = 25)
Hasta özellikleri
Seks, HAYIR. (%)
Dişi 4 (16.0%)
Erkek 21 (84.0%)
Yaş, yıllar, medyan (range) 4.62 (2.26–5.97)
Race, HAYIR. (%)
White 22 (88%)
Other 3 (12%)
Ethnicity, HAYIR. (%)
Hispanic 2 (8%)
Not Hispanic 23 (92%)
ADOS Severity Score, medyan (range) 8 (6–10)
Nonverbal intelligence quotient, medyan (range) 65 (22–123)
CGI‐S, HAYIR. (%)
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, medyan (range)
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, /kg 1,225.50 (85.50–4,620.00)
Abbreviations: ADOS, Autism Diagnostic Observation Schedule; OSB, Otizm spektrum bozukluğu; CFU, colony‐forming units; CGI‐S, Clinical Global Impression‐Severity; TNCC, toplam çekirdekli hücre sayısı.
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. İçinde 19 katılımcılar, the 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) Ve 0.3 × 105/kg (range 0.1–4.2 × 105), sırasıyla. 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.
Emniyet
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 katılımcılar (Fig. 1) with a median of three events per participant (range: 1–15). All events were graded as Mild (71 events) or Moderate (21 events). 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 katılımcılar; 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.
Figür 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, but not age or cell dose. Changes in behavior were also not correlated with the number of hours of behavioral interventions, speech‐language therapy, occupational therapy or educational hours the child received during the tenure of the study. The measures chosen, a primary and key secondary behavioral endpoints (VABS‐II, CGI‐S, GCI‐I, PDDBI, EOWPBT) and the EGT biomarker measure, all demonstrated improvements and are described below.
The VABS‐II is parent‐report measure that assesses socialization, iletişim, and adaptive behaviors. Figür 2 shows the distribution of standard scores in all patients (Panel A) and stratified by IQ (Panel B) for the VABS‐II Socialization domain in the 24 participants who completed the assessments at all three time points. A statistically significant increase in standard score was observed from baseline to 6 aylar. This change was stable from 6 ile 12 aylar. 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).
Figür 2
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Vineland Adaptive Behavior Scales‐II (VABS‐II) Socialization Standard Score. (A): Distribution of VABS‐II Socialization Standard Score in all participants over time. (B): 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. Figür 3 shows the distribution of CGI‐S (Panel A) and CGI‐I (Panel B) içinde 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% each). At 6 aylar, the proportion of participants with Moderately Severe and Severe symptoms decreased (22.7% each), 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 Ve 12 aylar. The improvement measured at each of these time points is relative to baseline. At 6 aylar, 9 katılımcılar (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 katılımcılar (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).
Figür 3
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Global Impression Scale (GCI). (A): CGI‐Severity over time. (B): CGI‐Improvement over baseline as assessed at 6 Ve 12 aylar.
The PDDBI—Autism Composite T‐Score is a parent reported measure assessing ASD symptoms. The PDDBI was administered at baseline, 3, 6, 9, Ve 12 aylar (Masa 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 aylar, with a predicted mean decline of 7.52 points (95% CI: −12.38, −2.67; p = .004). There was no significant change from 3 ile 12 aylar (mean: 0.72, 95% CI: −1.14, 2.57; p = .43).
Masa 2. Summary of behavioral assessments
Baseline to 6 aylar 6 ile 12 aylar
Outcome measure
No. ile ilgili
hastalar
evaluated
Change score
medyan (Range)
p value
Change score
medyan (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, Ve 6 aylar. Change scores are the predicted mean (Ve 95% confidence interval) from a linear spline model with knot at 3 aylar.
Abbreviations: EOWPVT, Expressive One‐Word Picture Vocabulary Test‐4; VABS, Vineland Adaptive Behavior Scales‐II; PDDBI, Pervasive Developmental Disorder Behavior Inventory.
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 (Masa 2). Change in the EOWPVT raw score was associated with nonverbal IQ (baseline to 6 aylar: 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, yüz, and upper body) and separate GEE models were fit for each target. Each model included 21 participants who were measured at baseline, 6, Ve 12 aylar. 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 (Masa 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).
Masa 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 aylar, Ve 6 ile 12 aylar).
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 (Masa 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 ile 12 aylar, the EOWPVT and CGI‐I remained statistically significant after application of the FDR procedure.
Masa 4. Raw and corrected p values for tests of the null hypothesis of No change over time in behavioral outcomes
Baseline to 6 aylar 6 ile 12 aylar
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
a p values for the PDDBI are for baseline to 3 months and 3 ile 12 aylar.
Abbreviations: CGI‐I/S, Clinical Global Impression—Improvement/Severity; EOWPVT, Expressive One‐Word Picture Vocabulary Test‐4; FDR, False Discovery Rate; PDDBI, Pervasive Developmental Disorder Behavior Inventory; VABS, Vineland Adaptive Behavior Scales‐II.
Discussion
In this phase I open‐label study, we evaluated the safety and feasibility of a single intravenous infusion of autologous umbilical cord blood in young children with ASD. We also described changes in various behavioral and functional outcome measures to determine which would be best suited for use as endpoints in future cell therapy trials. Assessments of AEs over the 12 months post‐infusion indicated that the cord blood infusion was safe and well tolerated. All related events were considered expected and resolved without sequelae. The most common unrelated AEs were agitation, skin changes, and typical childhood infections. Agitation, in particular, 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. In this study, 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, Communication, 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 Ve 12 months post‐infusion. 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. Fakat, 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. Buna göre, 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 ile 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, sırasıyla, over a 6‐month time period in the cord blood‐treated patients in this study. Fakat, potential cultural variations as well as different timing of assessments make it difficult to directly compare these two groups. Additionally, 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. Üstelik, 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. Öyleyse, 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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Çözüm
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. İlk aşamada gözlemlenen davranıştaki önemli gelişmeleri tanımlıyoruz. 6 infüzyondan aylar sonra ve sürekli olarak 12 aylar. Daha yüksek temel sözel olmayan IQ, daha yüksek derecede iyileşme ile ilişkilendirildi. Uygulanabilir sonuç ölçütlerini belirledik, değişime duyarlı, ve gelişimsel olarak uygun, ve bu nedenle otizmli küçük çocukların tedavisinde kordon kanı tedavisinin etkinliğini test etmek amacıyla gelecekteki klinik çalışmalarda kullanılmaya uygundur..
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