Browsing by Subject "Fetal Blood"

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Open Access
A cord blood monocyte-derived cell therapy product accelerates brain remyelination.
(JCI insight, 2016-08-18) Saha, Arjun; Buntz, Susan; Scotland, Paula; Xu, Li; Noeldner, Pamela; Patel, Sachit; Wollish, Amy; Gunaratne, Aruni; Gentry, Tracy; Troy, Jesse; Matsushima, Glenn K; Kurtzberg, Joanne; Balber, Andrew E
Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14⁺ monocytes. We compared the ability of freshly isolated CB CD14⁺ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγ^null mice following cuprizone feeding-mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14⁺ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14⁺ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions.
Open Access
A History of Cord Blood Banking and Transplantation.
(Stem cells translational medicine, 2017-05) Kurtzberg, Joanne
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, 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.
Open Access
A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.
(Stem cells translational medicine, 2024-02) Laskowitz, Daniel T; Troy, Jesse; Poehlein, Emily; Bennett, Ellen R; Shpall, Elizabeth J; Wingard, John R; Freed, Brian; Belagaje, Samir R; Khanna, Anna; Jones, William; Volpi, John J; Marrotte, Eric; Kurtzberg, Joanne
Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.
Open Access
Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis.
(The Lancet. Haematology, 2017-07) Eapen, Mary; Wang, Tao; Veys, Paul A; Boelens, Jaap J; St Martin, Andrew; Spellman, Stephen; Bonfim, Carmem Sales; Brady, Colleen; Cant, Andrew J; Dalle, Jean-Hugues; Davies, Stella M; Freeman, John; Hsu, Katherine C; Fleischhauer, Katharina; Kenzey, Chantal; Kurtzberg, Joanne; Michel, Gerard; Orchard, Paul J; Paviglianiti, Annalisa; Rocha, Vanderson; Veneris, Michael R; Volt, Fernanda; Wynn, Robert; Lee, Stephanie J; Horowitz, Mary M; Gluckman, Eliane; Ruggeri, Annalisa
Background
The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation.
Methods
We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model.
Findings
Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21 × 10⁷ cells per kg compared with 21 × 10⁷ cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 1·31-2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality.
Interpretation
These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.
Funding
National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy.
Open Access
Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase I Safety Study.
(Stem cells translational medicine, 2018-07) Laskowitz, Daniel T; Bennett, Ellen R; Durham, Rebecca J; Volpi, John J; Wiese, Jonathan R; Frankel, Michael; Shpall, Elizabeth; Wilson, Jeffry M; Troy, Jesse; Kurtzberg, Joanne
Stroke is a major cause of death and long-term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase I open-label trial to assess the safety and feasibility of a single IV infusion of non-human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3-9 days post-stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well-tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post-treatment, all participants had improved by at least one grade in mRS (mean 2.8 ± 0.9) and by at least 4 points in NIHSS (mean 5.9 ± 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non-HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo-controlled phase 2 study. Stem Cells Translational Medicine 2018;7:521-529.
Open Access
Announcing a New Journal Section: Cord Blood.
(Stem cells translational medicine, 2017-05) Kurtzberg, Joanne; Atala, Anthony
Open Access
Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight.
(Cancer causes & control : CCC, 2012-04) Hoyo, Cathrine; Fortner, Kimberly; Murtha, Amy P; Schildkraut, Joellen M; Soubry, Adelheid; Demark-Wahnefried, Wendy; Jirtle, Randy L; Kurtzberg, Joanne; Forman, Michele R; Overcash, Francine; Huang, Zhiqing; Murphy, Susan K
Purpose
Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns.
Methods
Questionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels.
Results
Lower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (β = -9.87, p < 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI > 30 kg/m(2), β = -20.21, p < 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p < 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.
Conclusion
Our data suggest that variation in IGF2 DMR methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity.
Unknown
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.
Open Access
Banking or Bankrupting: Strategies for Sustaining the Economic Future of Public Cord Blood Banks.
(PloS one, 2015-01) Magalon, Jeremy; Maiers, Martin; Kurtzberg, Joanne; Navarrete, Cristina; Rubinstein, Pablo; Brown, Colin; Schramm, Catherine; Larghero, Jérome; Katsahian, Sandrine; Chabannon, Christian; Picard, Christophe; Platz, Alexander; Schmidt, Alexander; Katz, Gregory
Background
Cord blood is an important source of stem cells. However, nearly 90% of public cord blood banks have declared that they are struggling to maintain their financial sustainability and avoid bankruptcy. The objective of this study is to evaluate how characteristics of cord blood units influence their utilization, then use this information to model the economic viability and therapeutic value of different banking strategies.
Methods
Retrospective analysis of cord blood data registered between January 1st, 2009 and December 31st, 2011 in Bone Marrow Donor Worldwide. Data were collected from four public banks in France, Germany and the USA. Samples were eligible for inclusion in the analysis if data on cord blood and maternal HLA typing and biological characteristics after processing were available (total nucleated and CD34+ cell counts). 9,396 banked cord blood units were analyzed, of which 5,815 were Caucasian in origin. A multivariate logistic regression model assessed the influence of three parameters on the CBU utilization rate: ethnic background, total nucleated and CD34+ cell counts. From this model, we elaborated a Utilization Score reflecting the probability of transplantation for each cord blood unit. We stratified three Utilization Score thresholds representing four different banking strategies, from the least selective (scenario A) to the most selective (scenario D). We measured the cost-effectiveness ratio for each strategy by comparing performance in terms of number of transplanted cord blood units and level of financial deficit.
Results
When comparing inputs and outputs over three years, Scenario A represented the most extreme case as it delivered the highest therapeutic value for patients (284 CBUs transplanted) along with the highest financial deficit (USD 5.89 million). We found that scenario C resulted in 219 CBUs transplanted with a limited deficit (USD 0.98 million) that charities and public health could realistically finance over the long term. We also found that using a pre-freezing level of 18 x 10(8) TNC would be the most cost-effective strategy for a public bank.
Conclusion
Our study shows that a swift transition from strategy A to C can play a vital role in preventing public cord blood banks worldwide from collapsing.
Open Access
CD34⁺ cell content of 126 341 cord blood units in the US inventory: implications for transplantation and banking.
(Blood advances, 2019-04) Barker, Juliet N; Kempenich, Jane; Kurtzberg, Joanne; Brunstein, Claudio G; Delaney, Colleen; Milano, Filippo; Politikos, Ioannis; Shpall, Elizabeth J; Scaradavou, Andromachi; Dehn, Jason
CD34⁺ cell dose is critical for cord blood (CB) engraftment. However, the CD34⁺ content of the CB inventory in the United States is unknown. We examined the CD34⁺ cell content of 126 341 red blood cell-depleted US units banked from January 2007 to September 2017 with a total nucleated cell (TNC) count of ≥90 × 10⁷ and a cryovolume of 24-55 mL. Median pre-cryopreservation TNC content was 127 × 10⁷ (interquartile range [IQR], 108-156 × 10⁷); CD34⁺ cell content was 44 × 10⁵ (IQR, 29 to 67 × 10⁵). The median CD34⁺:TNC ratio was 0.34%. TNC and CD34⁺ cell content correlation was weak (r = 0.24). Of 7125 units with TNCs of ≥210 × 10⁷, only 47% had CD34⁺ content of ≥100 × 10⁵ However, some units had high CD34⁺ content for a given TNC count. Only 4% of CB units were acceptable as single-unit grafts (TNCs, ≥2.5 × 10⁷/kg; CD34⁺ cells, ≥1.5 × 10⁵/kg) for 70-kg patients; 22% of units were adequate for 70-kg patients using lower dose criteria (TNCs, ≥1.5 × 10⁷/kg; CD34⁺ cells, ≥1.0 × 10⁵/kg) suitable for a double-unit graft. These findings highlight that units with the highest TNC dose may not have the highest CD34⁺ dose, units with unexpectedly high CD34⁺ content (a ratio of >1.0%) should be verified, and the US CB inventory of adequately sized single units for larger patients is small. They also support the ongoing use of double-unit grafts, a focus on banking high-dose units, and development of expansion technologies.
Open Access
Chagas Disease Screening in Maternal Donors of Publicly Banked Umbilical Cord Blood, United States.
(Emerging infectious diseases, 2016-08) Edwards, James M; Gilner, Jennifer B; Hernandez, Jose; Kurtzberg, Joanne; Heine, R Phillips
To assess patterns of Chagas disease, we reviewed results of screening umbilical cord blood from a US public cord blood bank during 2007-2014. Nineteen maternal donors tested positive for Trypanosoma cruzi parasites (0.04%). Because perinatal transmission of Chagas disease is associated with substantial illness, targeted prenatal programs should screen for this disease.
Open 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.
Open Access
Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions.
(Cytotherapy, 2015-06) Aldenhoven, Mieke; Kurtzberg, Joanne
Initially used as an alternative hematopoietic stem cell source for patients without a human leukocyte antigen-matched bone marrow or peripheral blood stem cell donor, unrelated cord blood (UCB) is now the preferred donor source when hematopoietic stem cell transplantation (HSCT) is used to treat patients with lysosomal storage disorders (LSD). Without transplantation, these patients have serious progressive multi-system deterioration and premature death. UCB transplantation favorably alters the natural history of these diseases and prolongs survival. It primarily works through cellular enzyme replacement by healthy engrafted donor cells providing a continuous endogenous supply of enzyme throughout the body and, thorough engraftment of donor-derived microgial cells, in the central nervous system. HSCT in LSD, the majority performed in patients with mucopolysaccharidoses and leukodystrophies, is associated with remarkably high rates of engraftment and survival. Importantly, recipients of UCB, as compared with other donor sources, more often achieve full-donor chimerism and normalization of enzyme levels, which has been associated with superior long-term clinical prognosis. Additionally, UCB units are readily available, reducing time to transplantation and thereby providing access to transplant at young ages, another highly important predictor for long-term neuro-developmental function. For these reasons, UCB grafts are nowadays considered to be the optimal graft source for HSCT in patients with LSD.
Open Access
Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience.
(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017-10) Patel, Sachit A; Allewelt, Heather A; Troy, Jesse D; Martin, Paul L; Driscoll, Timothy A; Prasad, Vinod K; Kurtzberg, Joanne; Page, Kristin M; Parikh, Suhag H
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 10⁷/kg (range, 4.6 to 27.9) and CD34⁺ dose of 3.1 × 10⁵/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.
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, 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.
Open Access
Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy.
(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2012-12) Rocha, Vanderson; Spellman, Stephen; Zhang, Mei-Jie; Ruggeri, Annalisa; Purtill, Duncan; Brady, Colleen; Baxter-Lowe, Lee Ann; Baudoux, Etienne; Bergamaschi, Paola; Chow, Robert; Freed, Brian; Koegler, Gesine; Kurtzberg, Joanne; Larghero, Jerome; Lecchi, Lucilla; Nagler, Arnon; Navarrette, Cristina; Prasad, Vinod; Pouthier, Fabienne; Price, Thomas; Ratanatharathorn, Voravit; van Rood, Jon J; Horowitz, Mary M; Gluckman, Eliane; Eapen, Mary; Eurocord-European Blood and Marrow Transplant Group and the Center for International Blood and Marrow Transplant Research
Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT.
Open Access
Eighth Annual International Umbilical Cord Blood Transplantation Symposium, San Francisco, California, June 3-5, 2010.
(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2011-02) Laughlin, Mary; Kurtzberg, Joanne; McMannis, John; Petz, Lawrence
Open Access
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.
Open Access
Ex vivo expansion of murine and human hematopoietic stem cells.
(Methods Mol Biol, 2014) Doan, Phuong L; Chute, John P
Hematopoietic stem cells have the capacity to self-renew and give rise to the entirety of the mature blood and immune system throughout the lifespan of an organism. Here, we describe methods to isolate and culture murine bone marrow (BM) CD34(-)ckit(+)Sca1(+)Lineage(-) (CD34(-)KSL) hematopoietic stem cells (HSCs). We also describe a method to measure functional HSC content via the competitive repopulation assay. Furthermore, we summarize methods to isolate and culture human CD34(+)CD38(-)Lineage(-) cells which are enriched for human hematopoietic stem and progenitor cells.

Browsing by Subject "Fetal Blood"

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