The prognosis for Matthew's condition was stark: most children with Fanconi anemia died of bone marrow failure or leukemia in the first decade of life, unless treated with a bone marrow transplant ...from a human leukocyte antigen (HLA)-matched donor. ...Dr. Boyse had performed preliminary testing of the concept in mice, although biological differences limited the usefulness of animal-model testing, Dr. Auerbach, who had been working with Broxmeyer on some of the biological aspects of patients with Fanconi anemia who converted from one disease phenotype to another, was aware of a mutual interest. HLA typing was confirmed at Duke, and the cord blood was taken to Hal Broxmeyer's laboratory at MSKCC and cryopreserved, after addition of dimethyl sulfoxide but without other processing, in his research liquid nitrogen freezer. From 2005–2012, I was a co-principal investigator with Dr. John Wagner on a multicenter, randomized trial to test whether two cords would be superior to one cord blood graft in children with hematologic malignancies , but surprisingly, in children who could receive an adequate cell dose from a single cord blood unit, one cord was sufficient.
...the size of the baby was determined to predict the size of a CB unit and since babies can only be so big, increasing the volume of collected CB was not going to solve this problem. 9 In 2005, ...Juliet Barker and John Wagner showed that the dose of cells could be increased by utilizing 2 CB units for a single patient's transplant. 10 Interestingly, only one CB donor would ultimately engraft, but the other unit appeared to serve a helper function that improved outcomes; yet, a landmark pediatric study conducted by the BMT‐CTN failed to demonstrate an advantage of double cord blood transplantation over single cord blood transplantation in pediatric patients with leukemia. 11 Alternative approaches to expand CB cells prior to transplantation have been under investigation for more than a decade, and in the past few months, Nicord (Omidubicel), expansion of CD133 cells in nicotinamide, manufactured by Gamida Cell Ltd in Jerusalem, achieved the primary endpoint of accelerating neutrophil engraftment in a phase III registration trial and is under consideration for licensure from the US FDA. ...CB banks have developed unique expertise in GMP manufacturing of cellular products. Highly effective immunotherapies including allogeneic CAR‐NK and cytotoxic T‐cells (CTLs) have been manufactured from cord blood and are in development for commercialization. 13,14 Derivatives of cord blood CD14 monocytes are in clinical trials for treatment of hypoxic and demyelinating diseases 15‐18 and cord blood is being investigated as a therapy for children with autism spectrum disorder, a severely disabling disease with increasing prevalence in our society. 19,20 Finally cord and placental tissues are robust sources of mesenchymal stromal cells which are undergoing testing in many diseases as immune modulators and suppressors of pro‐inflammatory states, 21 including as a treatment for complications of COVID‐19.
The use of two units of cord blood to reconstitute hematopoiesis in transplantation for relapsed hematologic cancers in patients 1 to 21 years of age proved to be no better and was in some ways worse ...than the standard one-unit transplant.
Since 1993, unrelated-donor umbilical-cord blood has been used as the source of hematopoietic stem cells for transplantation in an estimated 30,000 patients with malignant and nonmalignant diseases.
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As compared with stem-cell grafts from adult donors, cord blood has the advantages of more rapid availability, relative absence of donor attrition, and, after transplantation, a reduced risk of graft-versus-host disease (GVHD) despite donor–recipient HLA disparity.
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In addition, less restriction on HLA matching permits greater use of cord blood for members of racial minorities, who are less likely to have a suitably HLA-matched volunteer adult donor.
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However, the use of cord blood . . .
There are currently no approved therapies that address the core symptoms of autism. ...there is a keen interest in exploring novel therapeutic approaches to the condition. Cellular‐based therapy is ...undergoing testing in clinical trials for many neurological diseases including, but not limited to, cerebral palsy, hypoxic ischemic encephalopathy, severe traumatic brain injury, spinal cord injury, stroke, and ASD. 1‐3 Mesenchymal stromal cells (MSCs) derived from bone marrow or cord or other birthing tissues, cord blood cells, and bone marrow cells are all undergoing testing in early phase clinical trials. Dawson and colleagues conducted a phase I, open‐label study, determining that autologous cord blood infusions were safe and feasible. 4 The authors hypothesized that the treatment reduced symptoms in children with ASD because cord blood cells modulate inflammatory processes in the brain. A subset analysis of children without intellectual disability, the intended study population, showed significant improvements in the VABS Communication Domain, eye‐tracking, EEG, and the Clinical Global Impression‐Improvement scale in children treated with cord blood.
Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being ...explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene.
We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m².
Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome.
While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HSCT is also associated with risks of graft-versus-host disease and treatment-related toxicity.1–4 Additionally, small trials of intrathecal gene therapy in mice or humans did not result in ...improvement in symptoms of clinical disease.5 Thus, new therapeutic approaches are desperately needed. Tetra Images/Getty Images In The Lancet, Francesca Fumagalli and colleagues6 report results of the first haematopoietic stem-cell gene therapy (atidarsagene autotemcel arsa-cel) clinical trial for young paediatric patients with early-onset MLD. The coprimary efficacy endpoints were an improvement of more than 10% with respect to the natural history cohort in the total gross motor function measure (GMFM-88) and change from baseline of total peripheral blood mononuclear cell ARSA activity at 2 years after treatment compared with pre-treatment values.
Objective To determine whether aberrant DNA methylation at differentially methylated regions (DMRs) regulating insulin-like growth factor 2 ( IGF2 ) expression in umbilical cord blood is associated ...with overweight or obesity in a multiethnic cohort. Study design Umbilical cord blood leukocytes of 204 infants born between 2005 and 2009 in Durham, North Carolina, were analyzed for DNA methylation at two IGF2 DMRs by using pyrosequencing. Anthropometric and feeding data were collected at age 1 year. Methylation differences were compared between children >85th percentile of the Centers for Disease Control and Prevention growth charts weight-for-age (WFA) and children ≤85th percentile of WFA at 1 year by using generalized linear models, adjusting for post-natal caloric intake, maternal cigarette smoking, and race/ethnicity. Results The methylation percentages at the H19 imprint center DMR was higher in infants with WFA >85th percentile (62.7%; 95% CI, 59.9%-65.5%) than in infants with WFA ≤85th percentile (59.3%; 95% CI, 58.2%-60.3%; P = .02). At the intragenic IGF2 DMR, methylation levels were comparable between infants with WFA ≤85th percentile and infants with WFA >85th percentile. Conclusions Our findings suggest that IGF2 plasticity may be mechanistically important in early childhood overweight or obese status. If confirmed in larger studies, these findings suggest aberrant DNA methylation at sequences regulating imprinted genes may be useful identifiers of children at risk for the development of early obesity.
Summary
Progressive degeneration of the central nervous system leading to the loss of neuromotor, neurophysiological and cognitive abilities is the fundamental clinical problem in patients with many ...inherited metabolic diseases (IMD). Worldwide experience shows that morbidity, quality of life, and survival in these patients can be improved by allogeneic haematopoietic stem cell transplantation (HSCT), particularly when performed early in the course of the disease. At present, while available for some conditions, exogenous enzyme replacement therapy is unable to correct cognitive and central nervous system disease because of its inability to cross the blood‐brain barrier. In contrast, HSCT allows donor‐derived, enzyme‐producing cells to migrate to the brain and other organs providing a permanent enzyme replacement therapy. HSCT may also mediate non‐hematopoietic cell regeneration or repair. Traditionally, bone marrow has been the graft source for IMD patients. However, in the last 5 years many studies utilizing unrelated donor umbilical cord blood (UCB) as a graft source have demonstrated that UCB provides rapid and increased access to transplantation with favourable outcomes. This review describes preclinical studies and past and present clinical treatment approaches and discusses current controversies and future directions of this promising field.
Objective 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 × 107 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.
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