Browsing by Author "Sun, Jessica M"

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    ItemOpen Access
    A Phase II Randomized Clinical Trial of the Safety and Efficacy of Intravenous Umbilical Cord Blood Infusion for Treatment of Children with Autism Spectrum Disorder.
    (The Journal of pediatrics, 2020-07) Dawson, Geraldine; Sun, Jessica M; Baker, Jennifer; Carpenter, Kimberly; Compton, Scott; Deaver, Megan; Franz, Lauren; Heilbron, Nicole; Herold, Brianna; Horrigan, Joseph; Howard, Jill; Kosinski, Andrzej; Major, Samantha; Murias, Michael; Page, Kristin; Prasad, Vinod K; Sabatos-DeVito, Maura; Sanfilippo, Fred; Sikich, Linmarie; Simmons, Ryan; Song, Allen; Vermeer, Saritha; Waters-Pick, Barbara; Troy, Jesse; Kurtzberg, Joanne

    Objective

    To evaluate whether umbilical cord blood (CB) infusion is safe and associated with improved social and communication abilities in children with autism spectrum disorder (ASD).

    Study design

    This prospective, randomized, placebo-controlled, double-blind study included 180 children with ASD, aged 2-7 years, who received a single intravenous autologous (n = 56) or allogeneic (n = 63) CB infusion vs placebo (n = 61) and were evaluated at 6 months postinfusion.

    Results

    CB infusion was safe and well tolerated. Analysis of the entire sample showed no evidence that CB was associated with improvements in the primary outcome, social communication (Vineland Adaptive Behavior Scales-3 [VABS-3] Socialization Domain), or the secondary outcomes, autism symptoms (Pervasive Developmental Disorder Behavior Inventory) and vocabulary (Expressive One-Word Picture Vocabulary Test). There was also no overall evidence of differential effects by type of CB infused. In a subanalysis of children without intellectual disability (ID), allogeneic, but not autologous, CB was associated with improvement in a larger percentage of children on the clinician-rated Clinical Global Impression-Improvement scale, but the OR for improvement was not significant. Children without ID treated with CB showed significant improvements in communication skills (VABS-3 Communication Domain), and exploratory measures including attention to toys and sustained attention (eye-tracking) and increased alpha and beta electroencephalographic power.

    Conclusions

    Overall, a single infusion of CB was not associated with improved socialization skills or reduced autism symptoms. More research is warranted to determine whether CB infusion is an effective treatment for some children with ASD.
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    ItemOpen Access
    Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial.
    (Stem cells translational medicine, 2017-05) Dawson, Geraldine; Sun, Jessica M; Davlantis, Katherine S; Murias, Michael; Franz, Lauren; Troy, Jesse; Simmons, Ryan; Sabatos-DeVito, Maura; Durham, Rebecca; Kurtzberg, Joanne
    Despite advances in early diagnosis and behavioral therapies, more effective treatments for children with autism spectrum disorder (ASD) are needed. We hypothesized that umbilical cord blood-derived cell therapies may have potential in alleviating ASD symptoms by modulating inflammatory processes in the brain. Accordingly, 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 years (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) and 6 and 12 months later. 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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    ItemOpen Access
    Cell therapy for diverse central nervous system disorders: inherited metabolic diseases and autism.
    (Pediatric research, 2018-01) Sun, Jessica M; Kurtzberg, Joanne
    The concept of utilizing human cells for the treatment of medical conditions is not new. In its simplest form, blood product transfusion as treatment of severe hemorrhage has been practiced since the 1800s. The advent of hematopoietic stem cell transplantation (HSCT) began with the development of bone marrow transplantation for hematological malignancies in the mid-1900s and is now the standard of care for many hematological disorders. In the past few decades, HSCT has expanded to additional sources of donor cells, a wider range of indications, and the development of novel cell products. This trajectory has sparked a rapidly growing interest in the pursuit of innovative cell therapies to treat presently incurable diseases, including neurological conditions. HSCT is currently an established therapy for certain neurologically devastating inherited metabolic diseases, in which engrafting donor cells provide lifelong enzyme replacement that prevents neurological deterioration and significantly extends the lives of affected children. Knowledge gained from the treatment of these rare conditions has led to refinement of the indications and timing of HSCT, the study of additional cellular products and techniques to address its limitations, and the investigation of cellular therapies without transplantation to treat more common neurological conditions, such as autism spectrum disorder.
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    ItemOpen Access
    Cord blood for brain injury.
    (Cytotherapy, 2015-06) Sun, Jessica M; Kurtzberg, Joanne
    Recovery from neurological injuries is typically incomplete and often results in significant and permanent disabilities. Currently, most available therapies are limited to supportive or palliative measures, aimed at managing the symptoms of the condition. Because restorative therapies targeting the underlying cause of most neurological diseases do not exist, cell therapies targeting anti-inflammatory, neuroprotective and regenerative potential hold great promise. Cord blood (CB) cells can induce repair through mechanisms that involve trophic or cell-based paracrine effects or cellular integration and differentiation. Both may be operative in emerging CB therapies for neurologic conditions, and there are numerous potential applications of CB-based regenerative therapies in neurological diseases, including genetic diseases of childhood, ischemic events such as stroke and neurodegenerative diseases of adulthood. CB appears to hold promise as an effective therapy for patients with brain injuries. In this Review, we describe the state of science and clinical applications of CB therapy for brain injury.
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    Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial.
    (Stem cells translational medicine, 2017-12) Sun, Jessica M; Song, Allen W; Case, Laura E; Mikati, Mohamad A; Gustafson, Kathryn E; Simmons, Ryan; Goldstein, Ricki; Petry, Jodi; McLaughlin, Colleen; Waters-Pick, Barbara; Chen, Lyon W; Wease, Stephen; Blackwell, Beth; Worley, Gordon; Troy, Jesse; Kurtzberg, Joanne
    Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 107 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 107 /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071-2078.
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    Electrophysiological Biomarkers Predict Clinical Improvement in an Open-Label Trial Assessing Efficacy of Autologous Umbilical Cord Blood for Treatment of Autism.
    (Stem cells translational medicine, 2018-11) Murias, Michael; Major, Samantha; Compton, Scott; Buttinger, Jessica; Sun, Jessica M; Kurtzberg, Joanne; Dawson, Geraldine
    This study was a phase I, single-center, and open-label trial of a single intravenous infusion of autologous umbilical cord blood in young children with autism spectrum disorder (ASD). Twenty-five children between the ages of 2 and 6 with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit were enrolled. Safety results and clinical outcomes measured at 6 and 12 months post-infusion have been previously published. The purpose of the present analysis was to explore whether measures of electroencephalography (EEG) theta, alpha, and beta power showed evidence of change after treatment and whether baseline EEG characteristics were predictive of clinical improvement. The primary endpoint was the parent-reported Vineland adaptive behavior scales-II socialization subscale score, collected at baseline, 6- and 12-month visits. In addition, the expressive one word picture vocabulary test 4 and the clinical global impression-improvement scale were administered. Electrophysiological recordings were taken during viewing of dynamic social and nonsocial stimuli at 6 and 12 months post-treatment. Significant changes in EEG spectral characteristics were found by 12 months post-infusion, which were characterized by increased alpha and beta power and decreased EEG theta power. Furthermore, higher baseline posterior EEG beta power was associated with a greater degree of improvement in social communication symptoms, highlighting the potential for an EEG biomarker to predict variation in outcome. Taken together, the results suggest that EEG measures may be useful endpoints for future ASD clinical trials. Stem Cells Translational Medicine 2018;7:783-791.
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    Infusion of human umbilical cord tissue mesenchymal stromal cells in children with autism spectrum disorder.
    (Stem cells translational medicine, 2020-10) Sun, Jessica M; Dawson, Geraldine; Franz, Lauren; Howard, Jill; McLaughlin, Colleen; Kistler, Bethany; Waters-Pick, Barbara; Meadows, Norin; Troy, Jesse; Kurtzberg, Joanne
    Ongoing neuroinflammation may contribute to symptoms of autism spectrum disorder (ASD) in at least a portion of affected individuals. Mesenchymal stromal cells (MSCs) have demonstrated the capacity to modulate neuroinflammation, but safety and feasibility of MSC administration in children with ASD have not been well established. In this open-label, phase I study, 12 children with ASD between 4 and 9 years of age were treated with intravenous (IV) infusions of human cord tissue mesenchymal stromal cells (hCT-MSCs), a third-party MSC product manufactured from unrelated donor umbilical cord tissue. Children received one, two, or three doses of 2 × 106 cells per kilogram at 2-month intervals. Clinical and laboratory evaluations were performed in person at baseline and 6 months and remotely at 12 months after the final infusion. Aside from agitation during the IV placement and infusion in some participants, hCT-MSCs were well tolerated. Five participants developed new class I anti-human leukocyte antigen (HLA) antibodies, associated with a specific lot of hCT-MSCs or with a partial HLA match between donor and recipient. These antibodies were clinically silent and not associated with any clinical manifestations to date. Six of 12 participants demonstrated improvement in at least two ASD-specific measures. Manufacturing and administration of hCT-MSCs appear to be safe and feasible in young children with ASD. Efficacy will be evaluated in a subsequent phase II randomized, placebo-controlled clinical trial.
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    Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: An open-label, randomized trial.
    (Developmental medicine and child neurology, 2022-07-10) Sun, Jessica M; Case, Laura E; McLaughlin, Colleen; Burgess, Alicia; Skergan, Natalie; Crane, Sydney; Jasien, Joan M; Mikati, Mohamad A; Troy, Jesse; Kurtzberg, Joanne

    Aim

    To evaluate safety and motor function after treatment with allogeneic umbilical cord blood (AlloCB) or umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in children with cerebral palsy (CP).

    Method

    Ninety-one children (52 males, 39 females; median age 3 years 7 months [range 2-5 years]) with CP due to hypoxic-ischemic encephalopathy, stroke, or periventricular leukomalacia were randomized to three arms: (1) the AlloCB group received 10 × 107 AlloCB total nucleated cells (TNC) per kilogram at baseline (n = 31); (2) the hCT-MSC group received 2 × 106 hCT-MSC at baseline, 3 months, and 6 months (n = 28); (3) the natural history control group received 10 × 107 AlloCB TNC per kilogram at 12 months (n = 31). Motor function was assessed with the Gross Motor Function Measure-66 (GMFM-66) and Peabody Developmental Motor Scale, Second Edition.

    Results

    Infusions (n = 143) were well tolerated, with eight infusion reactions (three in the AlloCB group, five in hCT-MSC) and no other safety concerns. At 12 months, the mean differences (95% confidence intervals [CI]) between actual and expected changes in GMFM-66 score were AlloCB 5.8 points (3.4-8.2), hCT-MSC 4.3 (2.2-6.4), and natural history 3.1 (1.4-5.0). In exploratory, post hoc analysis, the mean GMFM-66 score (95% CI) of the hCT-MSC group was 1.4 points higher than natural history (-1.1 to 4.0; p = 0.27), and the AlloCB group was 3.3 points higher than natural history (0.59-5.93; p = 0.02) after adjustment for baseline Gross Motor Function Classification System level, GMFM-66 score, and etiology.

    Interpretation

    High-dose AlloCB is a potential cell therapy for CP and should be further tested in a randomized, blinded, placebo-controlled trial.
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    ItemOpen Access
    Repeated autologous umbilical cord blood infusions are feasible and had no acute safety issues in young babies with congenital hydrocephalus.
    (Pediatric research, 2015-12) Sun, Jessica M; Grant, Gerald A; McLaughlin, Colleen; Allison, June; Fitzgerald, Anne; Waters-Pick, Barbara; Kurtzberg, Joanne

    Background

    Babies with congenital hydrocephalus often experience developmental disabilities due to brain injury associated with prolonged increased pressure on the developing brain parenchyma. Umbilical cord blood (CB) infusion has favorable effects in animal models of brain hypoxia and stroke and is being investigated in clinical trials of brain injury in both children and adults. We sought to establish the safety and feasibility of repeated intravenous infusions of autologous CB in young babies with congenital hydrocephalus.

    Methods

    Infants with severe congenital hydrocephalus and an available qualified autologous CB unit traveled to Duke for evaluation and CB infusion. When possible, the CB unit was utilized for multiple infusions. Patient and CB data were obtained at the time of infusion and analyzed retrospectively.

    Results

    From October 2006 to August 2014, 76 patients with congenital hydrocephalus received 143 autologous CB infusions. Most babies received repeated doses, for a total of two (n = 45), three (n = 18), or four (n = 4) infusions. There were no infusion-related adverse events. As expected, all babies experienced developmental delays.

    Conclusion

    Cryopreserved CB products may be effectively manipulated to provide multiple CB doses. Repeated intravenous infusion of autologous CB is safe and feasible in young babies with congenital hydrocephalus.
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    Sibling umbilical cord blood infusion is safe in young children with cerebral palsy.
    (Stem cells translational medicine, 2021-09) Sun, Jessica M; Case, Laura E; Mikati, Mohamad A; M Jasien, Joan; McLaughlin, Colleen; Waters-Pick, Barbara; Worley, Gordon; Troy, Jesse; Kurtzberg, Joanne
    Preclinical and early phase clinical studies suggest that an appropriately dosed umbilical cord blood (CB) infusion has the potential to help improve motor function in young children with cerebral palsy (CP). As many children with CP do not have their own CB available, use of allogeneic cells would extend access to this potentially beneficial therapy to more children. In this phase I, open-label study, 15 children, aged 1 to 6 years, with moderate to severe spastic CP were treated with a single intravenous infusion of allogeneic human leukocyte antigen (HLA) matched or partially matched sibling CB with a cell dose of ≥2.5 × 107 cells/kg based on the pre-cryopreservation count (median infused cell dose, 3.3 × 107 ; range, 1.8-5.2 × 107 ). There were a total of 49 adverse events (AEs) over a 2-year time period, but there were no AEs related to the CB infusions. Specifically, there were no acute infusion reactions and no antibody formation against platelets, red blood cells, or donor-specific HLA antigens. Donor cells were not detected in peripheral blood 6 months later. Six months after infusion, participants were assessed for response and experienced a mean ± SD increase of 4.7 ± 2.5 points on the Gross Motor Function Measure-66 and 1 ± 2.9 points on the Peabody Gross Motor Quotient. Appropriately dosed, allogeneic partially or fully HLA-matched sibling CB infusion is well tolerated and potentially beneficial in young children with CP.
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    Stem cell therapies in cerebral palsy and autism spectrum disorder.
    (Developmental medicine and child neurology, 2021-05) Sun, Jessica M; Kurtzberg, Joanne
    Across disciplines, there is great anticipation that evolving cell therapies may finally provide a therapeutic option for conditions in dire need. These conditions are typically complex and their pathophysiology incompletely understood, hindering the development of robust preclinical models and the precise assessment of therapeutic effects in human studies. This article provides an overview of the status of cell therapy investigations in two common neurodevelopmental disorders, cerebral palsy and autism spectrum disorder. Challenges facing this line of study, including inherent heterogeneity, knowledge gaps, and unrealistic expectations, are discussed. Much progress has been made in the past decade, but to definitively determine if cell therapies have a role in the treatment of neurodevelopmental disorders, both fields will need to evolve together. WHAT THIS PAPER ADDS: The safety profile of reported cell therapies in children with neurodevelopmental disorders is encouraging. Efficacy trials in cerebral palsy and autism spectrum disorder are ongoing in the United States and Asia. Unresolved issues pertain to the properties of the cells being studied and the characteristics of the neurodevelopmental conditions themselves.