Browsing by Author "Waters-Pick, Barbara"
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Item Open 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, JoanneObjective
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.Item Open Access Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders.(Transfusion, 2010-09) Sun, Jessica; Allison, June; McLaughlin, Colleen; Sledge, Linda; Waters-Pick, Barbara; Wease, Stephen; Kurtzberg, JoanneBackground
A pilot study was conducted to determine the safety and feasibility of intravenous administration of autologous umbilical cord blood (CB) in young children with acquired neurologic disorders. Most CB units (CBUs) were electively stored in private CB banks. Unlike public banks, which utilize specific criteria and thresholds for banking, private banks generally store all collected CBUs.Study design and methods
CBUs of eligible patients containing more than 1 × 10⁷ cells/kg were shipped to Duke from the banks of origin after confirming identity by HLA typing. On the day of infusion, CBUs were thawed and washed in dextran-albumin and infused intravenously. Patients were medicated with acetaminophen, diphenhydramine, and methylprednisolone before transfusion. Data regarding patients, infusions, and CBUs were collected retrospectively. Characteristics of CBUs were compared to existing data from CBUs publicly banked at the Carolinas Cord Blood Bank.Results
From March 2004 to December 2009, 184 children received 198 CB infusions. Three patients had infusion reactions, all responsive to medical therapy and stopping the infusion. Median precryopreservation volume (60 mL vs. 89 mL, p < 0.0001), total nucleated cell count (4.7 × 10⁸ vs. 10.8 × 10⁸, p < 0.0001), and CD34 count (1.8 × 10⁶ vs. 3.0 × 10⁶, p < 0.0001) were significantly lower than publicly stored CBUs. Postthaw sterility cultures were positive in 7.6% of infused CBUs.Conclusion
IV infusion of autologous CB is safe and feasible in young children with neurologic injuries. Quality parameters of privately banked CBUs are inferior to those stored in public banks. If efficacy of autologous CB is established clinically, the quality of autologous units should be held to the same standards as those stored in public banks.Item Open Access 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, JoanneCerebral 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.Item Open Access Expanded Access Protocol of Umbilical Cord Blood Infusion for Children with Neurological Conditions: An Update.(Stem cells translational medicine, 2021-09) McLaughlin, Colleen; West, Tara; Hollowell, Rachel; Skergan, Natalie; Giguere, Paige; Vinesett, Richard; Arbuckle, Erin; Cash, Jayne; Hoyle, Kerry; Crane, Sydney; Moore, Lettie; Waters-Pick, Barbara; Hawkins, Tiffany; Prasad, Vinod; Sun, Jessica; Kurtzberg, JoanneItem Open Access Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy.(The Journal of pediatrics, 2014-05) Cotten, C Michael; Murtha, Amy P; Goldberg, Ronald N; Grotegut, Chad A; Smith, P Brian; Goldstein, Ricki F; Fisher, Kimberley A; Gustafson, Kathryn E; Waters-Pick, Barbara; Swamy, Geeta K; Rattray, Benjamin; Tan, Siddhartha; Kurtzberg, JoanneObjective
To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE).Study design
We enrolled infants in the intensive care nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to 4 doses adjusted for volume and red blood cell content, 1-5 × 10(7) cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post-infusion vital signs. As exploratory analyses, we compared cell recipients' hospital outcomes (mortality, oral feeds at discharge) and 1-year survival with Bayley Scales of Infant and Toddler Development, 3rd edition scores ≥85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells.Results
Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 mL. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1-year outcomes survived with scores >85.Conclusions
Collection, preparation, and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed.Item Open Access Hydroxyethyl starch as a substitute for dextran 40 for thawing peripheral blood progenitor cell products.(Cytotherapy, 2015-12) Zhu, Fenlu; Heditke, Sarah; Kurtzberg, Joanne; Waters-Pick, Barbara; Hari, Parameswaran; Margolis, David A; Keever-Taylor, Carolyn ABackground aims
Removing DMSO post-thaw results in: reduced infusion reactions, improved recovery and stability of viable CD34+ cells. Validated methods use 5%-8.3% Dextran 40 with 2.5%-4.2% HSA for this purpose. Recent shortages of clinical grade Dextran require identification of suitable alternatives.Methods
PBPC were used to compare a standard 2X wash medium of 5 parts 10% Dextran 40 in saline (DEX) with 1 part 25% HSA (8.3% DEX/ 4.2% HSA) with Hydroxyethyl Starch (HES)-based solutions. Cells in replicate bags were diluted with an equal volume of wash solution, equilibrated 5 minutes, the bag filled with wash medium, pelleted and the supernatant expressed. Bags were restored to the frozen volume in wash medium and tested by single platform flow cytometry and CFU. Total viability, viable TNC, MNC, and CD34+ cell recovery, and CD34+ cell viability were compared immediately post-thaw and after 90 minutes.Results
5.2% HES/4.2% HSA did not differ from our standard in CD34 recovery or viability. Due to concerns that high concentrations of HES could affect renal function we tested 0.6% HES/2.5% HSA resulting in significantly poorer CD34 recovery and viability. Results improved using 2.4% HES/4.2% HSA and when 0.6% HES/4.2%HSA was used no significant differences were seen. CFU assays confirmed no differences between the standard dextran arm and HES at 2.4% or 0.6% so long as HSA was at 4.2%.Conclusions
We conclude that HES from 0.6% to 5.2% with 4.2% HSA is a suitable substitute for Dextran 40 as a reconstitution/washing medium for PBPC products.Item Open Access 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, JoanneOngoing 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.Item Open 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, JoanneBackground
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.Item Open Access 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, JoannePreclinical 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.Item Open Access Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.(The Journal of clinical investigation, 2014-07) Horwitz, Mitchell E; Chao, Nelson J; Rizzieri, David A; Long, Gwynn D; Sullivan, Keith M; Gasparetto, Cristina; Chute, John P; Morris, Ashley; McDonald, Carolyn; Waters-Pick, Barbara; Stiff, Patrick; Wease, Steven; Peled, Amnon; Snyder, David; Cohen, Einat Galamidi; Shoham, Hadas; Landau, Efrat; Friend, Etty; Peleg, Iddo; Aschengrau, Dorit; Yackoubov, Dima; Kurtzberg, Joanne; Peled, TonyBackground
Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.Methods
In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.Results
No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.Conclusion
UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.Trial registration
Clinicaltrials.gov NCT01221857.Funding
Gamida Cell Ltd.