Publications by authors named "Joanne Kurtzberg"

228 Publications

Guidelines for Pediatric Unrelated Cord Blood Transplantation-Unique Considerations.

Transplant Cell Ther 2021 Sep 24. Epub 2021 Sep 24.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Canter Center, Houston, Texas.

Cord blood (CB) is the stem cell source of choice for approximately 30% of pediatric patients undergoing hematopoietic cell transplantation. Cord blood is readily available and is a particularly appealing stem cell source for patients who lack appropriate HLA-matched related or unrelated donors. Pediatric cord blood transplant (CBT) recipients have low rates of disease relapse in the malignant setting and very low rates of chronic graft-versus-host disease (GVHD). In addition, CB has unique properties that make it the stem cell source of choice for some nonmalignant conditions such as metabolic disorders. This review provides evidence-based and experience-based pediatric-specific guidelines for CBT including considerations for infectious disease management, CB unit selection and infusion, conditioning regimen selection, and GVHD management. In addition, it covers unique bedside considerations for pediatric patients and CB banking. In concert with the other topic specific CB guidelines previously published in this series, it provides a comprehensive overview of the clinical management of pediatric CBT.
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http://dx.doi.org/10.1016/j.jtct.2021.09.013DOI Listing
September 2021

Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.

Transplant Cell Ther 2021 08;27(8):642-649

West Virginia University, Morgantown, West Virginia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.
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http://dx.doi.org/10.1016/j.jtct.2021.04.007DOI Listing
August 2021

Congenital human cytomegalovirus infection is associated with decreased transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia.

Clin Infect Dis 2021 Jul 14. Epub 2021 Jul 14.

Duke Human Vaccine Institute, Duke University, Durham, NC, USA.

Background: Placentally-transferred maternal IgG protects against pathogens in early life, yet vertically-transmitted infections can interfere with transplacental IgG transfer. Although human cytomegalovirus (HCMV) is the most common placentally-transmitted viral infection worldwide, the impact of congenital HCMV (cCMV) infection on transplacental IgG transfer has been underexplored.

Methods: We evaluated total and antigen-specific maternal and cord blood IgG levels and transplacental IgG transfer efficiency in a U.S-based cohort of 93 mother-infant pairs including 27 cCMV-infected and 66 cCMV-uninfected pairs, of which 29 infants were born to HCMV-seropositive non-transmitting mothers and 37 to HCMV-seronegative mothers. Controls were matched on sex, race/ethnicity, maternal age, and delivery year.

Results: Transplacental IgG transfer efficiency was decreased by 23% (95% CI 10-36%, p=0.0079) in cCMV-infected pairs and 75% of this effect (95% CI 28-174%, p=0.0085) was mediated by elevated maternal IgG levels (i.e., hypergammaglobulinemia) in HCMV-transmitting women. Despite reduced transfer efficiency, IgG levels were similar in cord blood from infants with and without cCMV infection.

Conclusions: Our results indicate that cCMV infection moderately reduces transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia; however, infants with and without cCMV infection had similar antigen-specific IgG levels, suggesting comparable protection from maternal IgG acquired via transplacental transfer.
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http://dx.doi.org/10.1093/cid/ciab627DOI Listing
July 2021

Sibling umbilical cord blood infusion is safe in young children with cerebral palsy.

Stem Cells Transl Med 2021 Sep 4;10(9):1258-1265. Epub 2021 Jun 4.

Marcus Center for Cellular Cures, Duke University Medical Center, Durham, North Carolina, USA.

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 × 10 cells/kg based on the pre-cryopreservation count (median infused cell dose, 3.3 × 10 ; range, 1.8-5.2 × 10 ). 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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http://dx.doi.org/10.1002/sctm.20-0470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380440PMC
September 2021

Exploring new therapies for children with autism: "Do no harm" does not mean do not try.

Stem Cells Transl Med 2021 Jun;10(6):823-825

Marcus Center for Cellular Cures at Duke, Duke University School of Medicine, Durham, North Carolina, USA.

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http://dx.doi.org/10.1002/sctm.20-0548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133345PMC
June 2021

Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease.

Mol Genet Metab 2021 Apr 3. Epub 2021 Apr 3.

Marcus Center for Cellular Cures, Duke University School of Medicine, 2400 Pratt Street, Room 9026, Durham, NC 27705, USA.

Objective: To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD).

Methods: KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD.

Results: Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%.

Conclusion: The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.
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http://dx.doi.org/10.1016/j.ymgme.2021.03.016DOI Listing
April 2021

Standardization, workforce development and advocacy in cell and gene therapies: a summary of the 2020 Regenerative Medicine InterCHANGE.

Cytotherapy 2021 Oct 26;23(10):886-893. Epub 2021 Mar 26.

Foundation for the Accreditation of Cellular Therapy at the University of Nebraska Medical Center, Omaha, Nebraska, USA; Departments of Pathology/Microbiology and Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA; Board of Directors, Foundation for the Accreditation of Cellular Therapy at the University of Nebraska Medical Center, Omaha, Nebraska, USA; Regenerative Medicine Task Force, Foundation for the Accreditation of Cellular Therapy at the University of Nebraska Medical Center, Omaha, Nebraska, USA.

Cell and gene therapy is a promising and disruptive new field of medicine for diseases lacking effective treatments. Collaboration among stakeholders has become critically important as investigators, health care providers, manufacturers, couriers, data registries, regulators and payers all become more invested in the success of this field. Many organizations have collaborated with each other to increase clarity, advocate for improvements and share lessons learned. These efforts appear to be making an impact, although the potential for duplicative efforts could slow progress. The second Regenerative Medicine InterCHANGE, hosted by the Foundation for the Accreditation of Cellular Therapy, took place at the Phacilitate Leaders World/World Stem Cell Summit conference in Miami, Florida, on January 24, 2020. Participants from several organizations outlined needs to advance cell and gene therapies. Efforts to address these include standardization, workforce development and advocacy. This article summarizes the major challenges and opportunities discussed during the InterCHANGE.
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http://dx.doi.org/10.1016/j.jcyt.2021.02.004DOI Listing
October 2021

Allogeneic stem cell transplantation with omidubicel in sickle cell disease.

Blood Adv 2021 02;5(3):843-852

Pediatric Blood and Marrow Transplant Program, Duke University School of Medicine, Durham, NC.

Many patients with sickle cell disease (SCD) do not have HLA-matched related donors for hematopoietic stem cell transplantation (HSCT). Unrelated cord blood (UCB) is an alternative graft option but is historically associated with high graft failure rates, with inadequate cell dose a major limitation. Omidubicel is a nicotinamide-based, ex vivo-expanded UCB product associated with rapid engraftment in adults with hematologic malignancies. We hypothesized that increasing the UCB cell dose with this strategy would lead to improved engraftment in pediatric patients undergoing myeloablative HSCT for SCD. We report the outcomes of a phase 1/2 study in 13 patients with severe SCD who received omidubicel in combination with an unmanipulated UCB graft and 3 who received a single omidubicel graft. Grafts were minimally matched with patients at 4 of 6 HLA alleles. Median age at transplant was 13 years. A median CD34+ expansion of ∼80-fold was observed in omidubicel and led to rapid neutrophil engraftment (median, 7 days). Long-term engraftment was derived from the unmanipulated graft in most of the double cord blood recipients. Two of the 3 single omidubicel recipients also had sustained engraftment. Incidence of acute graft-versus-host disease (GVHD) was high, but resolved in all surviving patients. Event-free survival in the double cord group was 85% (median follow-up 4 years). All 3 patients in the single cord group were alive at 1 year after transplantation. Ex vivo expansion of UCB with omidubicel supports engraftment in patients with SCD. This approach to decreasing the incidence of GVHD should be optimized for general use in patients with SCD. This study was registered at www.clinicaltrials.gov as #NCT01590628.
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http://dx.doi.org/10.1182/bloodadvances.2020003248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876871PMC
February 2021

Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.

Bone Marrow Transplant 2021 06 13;56(6):1238-1247. Epub 2021 Jan 13.

Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.
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http://dx.doi.org/10.1038/s41409-020-01179-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189901PMC
June 2021

T cell-depleted cultured pediatric thymus tissue as a model for some aspects of human age-related thymus involution.

Geroscience 2021 06 9;43(3):1369-1382. Epub 2021 Jan 9.

Department of Pathology, Duke University School of Medicine, Durham, NC, USA.

Human age-related thymus involution is characterized by loss of developing thymocytes and the thymic epithelial network that supports them, with replacement by adipose tissue. The mechanisms that drive these changes are difficult to study in vivo due to constant trafficking to and from the thymus. We hypothesized that the loss of thymocytes that occurs during human thymic organ cultures could model some aspects of thymus involution and begin to identify mechanisms that drive age-related changes in the thymic microenvironment. Potential mechanistically important candidate molecules were initially identified by screening conditioned media from human thymus organ cultures using antibody microarrays. These candidates were further validated using cultured tissue extracts and conditioned media. Results were compared with gene expression studies from a panel of well-characterized (non-cultured) human thymus tissues from human donors aged 5 days to 78 years. L-selectin released into conditioned media was identified as a biomarker for the content of viable thymocytes within the cultured thymus. Levels of the chemokines CCL21 and CXCL12, likely produced by surviving thymic epithelial cells, increased markedly in conditioned media as thymocytes were lost during culture. Native non-cultured thymus from adults older than 18 years also showed a strong trend toward increased CCL21 expression, in conjunction with significant decreases in thymocyte-related mRNAs compared with thymus from subjects younger than 18 years. Together, these findings demonstrate that use of postnatal human thymus organ cultures can model some aspects of human age-related thymic involution.
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http://dx.doi.org/10.1007/s11357-020-00301-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190428PMC
June 2021

Stem cell therapies in cerebral palsy and autism spectrum disorder.

Dev Med Child Neurol 2021 05 4;63(5):503-510. Epub 2021 Jan 4.

The Marcus Center for Cellular Cures, Duke University, Durham, NC, USA.

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.
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http://dx.doi.org/10.1111/dmcn.14789DOI Listing
May 2021

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

J Inherit Metab Dis 2021 05 9;44(3):728-739. Epub 2021 Jan 9.

Division of Neurogenetics and The Moser Center for Leukodystrophies, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA.

Background: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.

Methods: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.

Results: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI.

Conclusion: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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http://dx.doi.org/10.1002/jimd.12356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113077PMC
May 2021

Reply.

J Pediatr 2021 03 1;230:272. Epub 2020 Dec 1.

Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, North Carolina.

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http://dx.doi.org/10.1016/j.jpeds.2020.11.064DOI Listing
March 2021

Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies.

Stem Cells 2021 01 9;39(1):115-128. Epub 2020 Nov 9.

Marcus Center for Cellular Cures, Duke University, Durham, North Carolina, USA.

Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over 25 years, most likely due to an incomplete understanding of their mechanism. After MSCs are injected, they traffic to the lungs and other tissues where they are rapidly cleared. Despite being cleared, MSCs suppress the inflammatory response in the long term. Using human cord tissue-derived MSCs (hCT-MSCs), we demonstrated that hCT-MSCs directly interact and reprogram monocytes and macrophages. After engaging hCT-MSCs, monocytes and macrophages engulfed cytoplasmic components of live hCT-MSCs, then downregulated gene programs for antigen presentation and costimulation, and functionally suppressed the activation of helper T cells. We determined that low-density lipoprotein receptor-related proteins on monocytes and macrophages mediated the engulfment of hCT-MSCs. Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p-bodies), we generated p-body deficient hCT-MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo. hCT-MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p-body deficient hCT-MSCs were engulfed by infiltrating lung monocytes and macrophages, p-body deficient hCT-MSCs failed to suppress inflammation and downregulate MHC-II. Overall, we identified a novel mechanism by which hCT-MSCs indirectly suppressed a T-cell response by directly interacting and reprogramming monocytes and macrophages via p-bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long-term effects to suppress inflammation.
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http://dx.doi.org/10.1002/stem.3292DOI Listing
January 2021

Anti-fibrotic effects of different sources of MSC in bleomycin-induced lung fibrosis in C57BL6 male mice.

Respirology 2021 02 26;26(2):161-170. Epub 2020 Aug 26.

Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

Background And Objective: IPF is a fatal and debilitating lung disorder increasing in incidence worldwide. To date, two approved treatments only slow disease progression, have multiple side effects and do not provide a cure. MSC have promising therapeutic potential as a cell-based therapy for many lung disorders based on the anti-fibrotic properties of the MSC.

Methods: Critical questions remain surrounding the optimal source, timing and efficacy of cell-based therapies. The present study examines the most effective sources of MSC. Human MSC were derived from adipose, WJ, chorionic membrane (CSC) and chorionic villi (CVC). MSC were injected into the ageing mouse model of BLM-induced lung fibrosis.

Results: All sources decreased Aschroft and hydroxyproline levels when injected into BLM-treated mice at day 10 with the exception of CSC cells that did not change hydroxyproline levels. There were also decreases in mRNA expression of α -integrin and TNFα in all sources except CSC. Only ASC- and WJ-derived cells reduced AKT and MMP-2 activation, while Cav-1 was increased by ASC treatment as previously reported. BLM-induced miR dysregulation of miR-29 and miR-199 was restored only by ASC treatment.

Conclusion: Our data suggest that sources of MSC may differ in the pathway(s) involved in repair.
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http://dx.doi.org/10.1111/resp.13928DOI Listing
February 2021

The view for cord blood is "cup half full" not "cup half empty".

Authors:
Joanne Kurtzberg

Stem Cells Transl Med 2020 10 3;9(10):1118-1120. Epub 2020 Jul 3.

Marcus Center for Cellular Cures at Duke, Duke University School of Medicine, Durham, North Carolina, USA.

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http://dx.doi.org/10.1002/sctm.20-0260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519759PMC
October 2020

Measuring robustness of brain networks in autism spectrum disorder with Ricci curvature.

Sci Rep 2020 07 2;10(1):10819. Epub 2020 Jul 2.

Department of Psychiatry and Behavioral Sciences, Duke Center for Autism and Brain Development, Duke University School of Medicine, Durham, USA.

Ollivier-Ricci curvature is a method for measuring the robustness of connections in a network. In this work, we use curvature to measure changes in robustness of brain networks in children with autism spectrum disorder (ASD). In an open label clinical trials, participants with ASD were administered a single infusion of autologous umbilical cord blood and, as part of their clinical outcome measures, were imaged with diffusion MRI before and after the infusion. By using Ricci curvature to measure changes in robustness, we quantified both local and global changes in the brain networks and their potential relationship with the infusion. Our results find changes in the curvature of the connections between regions associated with ASD that were not detected via traditional brain network analysis.
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http://dx.doi.org/10.1038/s41598-020-67474-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331646PMC
July 2020

Guidelines for Cord Blood Unit Thaw and Infusion.

Biol Blood Marrow Transplant 2020 10 27;26(10):1780-1783. Epub 2020 Jun 27.

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.bbmt.2020.06.018DOI Listing
October 2020

Infusion of human umbilical cord tissue mesenchymal stromal cells in children with autism spectrum disorder.

Stem Cells Transl Med 2020 10 12;9(10):1137-1146. Epub 2020 Jun 12.

The Marcus Center for Cellular Cures, Duke University, Durham, North Carolina, USA.

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 × 10 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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http://dx.doi.org/10.1002/sctm.19-0434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519773PMC
October 2020

Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome.

Stem Cells Transl Med 2020 09 29;9(9):1007-1022. Epub 2020 May 29.

Department of Pathology and Laboratory Medicine, Department of Health Policy and Management, Rollins School of Public Health, Emory University, The Marcus Foundation, Atlanta, Georgia, USA.

Severe cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO /FiO ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.
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http://dx.doi.org/10.1002/sctm.20-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300743PMC
September 2020

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.

J Pediatr 2020 07 19;222:164-173.e5. Epub 2020 May 19.

Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, NC.

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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http://dx.doi.org/10.1016/j.jpeds.2020.03.011DOI Listing
July 2020

Intrastromal Gene Therapy Prevents and Reverses Advanced Corneal Clouding in a Canine Model of Mucopolysaccharidosis I.

Mol Ther 2020 06 11;28(6):1455-1463. Epub 2020 Apr 11.

Gene Therapy Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA; Department of Ophthalmology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disease characterized by severe phenotypes, including corneal clouding. MPS I is caused by mutations in alpha-l-iduronidase (IDUA), a ubiquitous enzyme that catalyzes the hydrolysis of glycosaminoglycans. Currently, no treatment exists to address MPS I corneal clouding other than corneal transplantation, which is complicated by a high risk for rejection. Investigation of an adeno-associated virus (AAV) IDUA gene addition strategy targeting the corneal stroma addresses this deficiency. In MPS I canines with early or advanced corneal disease, a single intrastromal AAV8G9-IDUA injection was well tolerated at all administered doses. The eyes with advanced disease demonstrated resolution of corneal clouding as early as 1 week post-injection, followed by sustained corneal transparency until the experimental endpoint of 25 weeks. AAV8G9-IDUA injection in the MPS I canine eye with early corneal disease prevented the development of advanced corneal changes while restoring clarity. Biodistribution studies demonstrated vector genomes in ocular compartments other than the cornea and in some systemic organs; however, a capsid antibody response was detected in only the highest dosed subject. Collectively, the results suggest that intrastromal AAV8G9-IDUA therapy prevents and reverses visual impairment associated with MPS I corneal clouding.
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http://dx.doi.org/10.1016/j.ymthe.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264440PMC
June 2020

Histopathologic assessment of cultured human thymus.

PLoS One 2020 24;15(3):e0230668. Epub 2020 Mar 24.

Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, NC, United States of America.

The maintenance and propagation of complex mixtures of cells in vitro in the form of native organs or engineered organoids has contributed to understanding mechanisms of cell and organ development and function which can be translated into therapeutic benefits. For example, allogeneic cultured postnatal human thymus tissue has been shown to support production of naïve recipient T cells when transplanted into patients with complete DiGeorge anomaly and other genetic defects that result in congenital lack of a thymus. Patients receiving such transplants typically exhibit reversal of their immunodeficiency and normalization of their peripheral blood T cell receptor V-beta repertoire, with long-term survival. This study was designed to assess the histopathologic changes that occur in postnatal human thymus slices when cultured according to protocols used for transplanted tissues. Results showed that as thymic organ cultures progressed from days 0 through 21, slices developed increasing amounts of necrosis, increasing condensation of thymic epithelium, and decreasing numbers of residual T cells. The architecture of the thymic epithelial network remained generally well-preserved throughout the 21 days of culture, with focal expression of cytokeratin 14, a putative biomarker of thymic epithelial cells with long-term organ-repopulating potential. All organ slices derived from the same donor thymus closely resembled one another, with minor differences in size, shape, and relative content of cortex versus medulla. Similarly, slices derived from different donors showed similar histopathologic characteristics when examined at the same culture time point. Taken together, these results demonstrate that diagnostic criteria based on structural features of the tissue identifiable via hematoxylin and eosin staining and cytokeratin immunohistochemistry can be used to evaluate the quality of slices transplanted into patients with congenital athymia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093005PMC
June 2020

The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease.

Genet Med 2020 06 24;22(6):1108-1118. Epub 2020 Feb 24.

Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Purpose: Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations.

Methods: PSY was extracted from dried blood spots or erythrocytes with methanol containing d-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry.

Results: Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT).

Conclusion: This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.
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http://dx.doi.org/10.1038/s41436-020-0764-yDOI Listing
June 2020

Noninvasive white blood cell quantification in umbilical cord blood collection bags with quantitative oblique back-illumination microscopy.

Transfusion 2020 03 14;60(3):588-597. Epub 2020 Feb 14.

School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, Georgia.

Background: Umbilical cord blood has become an important source of hematopoietic stem and progenitor cells for therapeutic applications. However, cord blood banking (CBB) grapples with issues related to economic viability, partially due to high discard rates of cord blood units (CBUs) that lack sufficient total nucleated cells for storage or therapeutic use. Currently, there are no methods available to assess the likelihood of CBUs meeting storage criteria noninvasively at the collection site, which would improve CBB efficiency and economic viability.

Materials And Methods: To overcome this limitation, we apply a novel label-free optical imaging method, called quantitative oblique back-illumination microscopy (qOBM), which yields tomographic phase and absorption contrast to image blood inside collection bags. An automated segmentation algorithm was developed to count white blood cells and red blood cells (RBCs) and assess hematocrit. Fifteen CBUs were measured.

Results: qOBM clearly differentiates between RBCs and nucleated cells. The cell-counting analysis shows an average error of 13% compared to hematology analysis, with a near-perfect, one-to-one relationship (slope = 0.94) and strong correlation coefficient (r = 0.86). Preliminary results to assess hematocrit also show excellent agreement with expected values. Acquisition times to image a statistically significant number of cells per CBU were approximately 1 minute.

Conclusion: qOBM exhibits robust performance for quantifying blood inside collection bags. Because the approach is automated and fast, it can potentially quantify CBUs within minutes of collection, without breaching the CBUs' sterile environment. qOBM can reduce costs in CBB by avoiding processing expenses of CBUs that ultimately do not meet storage criteria.
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http://dx.doi.org/10.1111/trf.15704DOI Listing
March 2020

Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-versus-Host Disease in Children.

Biol Blood Marrow Transplant 2020 05 7;26(5):855-864. Epub 2020 Feb 7.

Mesoblast Inc, New York, New York.

Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 10 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292970PMC
May 2020

A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 05 1;26(5):845-854. Epub 2020 Feb 1.

Mesoblast, Inc., New York, NY.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 10 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322819PMC
May 2020

Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry.

Anal Chem 2020 05 16;92(9):6341-6348. Epub 2020 Apr 16.

Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were developed to measure arylsulfatase A (ARSA) activity in leukocytes and dried blood spots (DBS) using deuterated natural sulfatide substrate. These new assays were highly specific and sensitive. Patients with metachromatic leukodystrophy (MLD) and multiple sulfatase deficiency (MSD) displayed a clear deficit in the enzymatic activity and could be completely distinguished from normal controls. The leukocyte assay reported here will be important for diagnosing MLD and MSD patients and for monitoring the efficacy of therapeutic treatments. ARSA activity was measured in DBS for the first time without an antibody. This new ARSA DBS assay can serve as a second-tier test following the sulfatide measurement in DBS for newborn screening of MLD. This leads to an elimination of most of the false positives identified by the sulfatide assay.
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http://dx.doi.org/10.1021/acs.analchem.9b05274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203001PMC
May 2020

Unlicensed Umbilical Cord Blood Units Provide a Safe and Effective Graft Source for a Diverse Population: A Study of 2456 Umbilical Cord Blood Recipients.

Biol Blood Marrow Transplant 2020 04 19;26(4):745-757. Epub 2019 Nov 19.

National Marrow Donor Program/Be The Match, Minneapolis, Minnesota.

Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count ≥500/mm) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n = 48) or unlicensed UCB (n = 382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198366PMC
April 2020
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