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INTRODUCTION: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.
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Transplante de Células-Tronco Mesenquimais , Osteogênese Imperfeita , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Células-Tronco Fetais/transplante , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais , Estudos Multicêntricos como Assunto , Osteogênese Imperfeita/terapia , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the maternal and fetal safety of In utero stem cell transplantation (IUSCT). METHODS: Medline®, Embase and Cochrane library (1967-2023) search for publications reporting IUSCT in humans. Two reviewers independently screened abstracts and full-text papers. RESULTS: Sixty six transplantation procedures in 52 fetuses were performed for haemoglobinopathies (n = 14), red cell/bleeding disorders (n = 4), immunodeficiencies (n = 15), storage disorders (n = 7), osteogenesis imperfecta (n = 2) and healthy fetuses (n = 10). The average gestational age was 18.9 weeks; of procedures reporting the injection route, cells were delivered by intraperitoneal (n = 37), intravenous (n = 19), or intracardiac (n = 4) injection or a combination (n = 3); most fetuses received one injection (n = 41). Haematopoietic (n = 40) or mesenchymal (n = 12) stem cells were delivered. The cell dose was inconsistently reported (range 1.8-3.3 × 109 cells total (n = 27); 2.7-5.0 × 109 /kg estimated fetal weight (n = 17)). The acute fetal procedural complication rate was 4.5% (3/66); the acute fetal mortality rate was 3.0% (2/66). Neonatal survival was 69.2% (36/52). Immediate maternal and pregnancy outcomes were reported in only 30.8% (16/52) and 44.2% (23/52) of cases respectively. Four fetal/pregnancy outcomes would also classify as ≥ Grade 2 maternal adverse events. CONCLUSIONS: Short-, medium-, and long-term maternal and fetal adverse events should be reported in all IUSCT studies.
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Resultado da Gravidez , Cuidado Pré-Natal , Gravidez , Recém-Nascido , Feminino , Humanos , Lactente , Feto , Idade GestacionalRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Expression of OCT4A is one of the hallmarks of pluripotency, defined as a stem cell's ability to differentiate into all the lineages of the three germ layers. Despite being defined as non-tumorigenic cells with high translational potential, human mid-trimester amniotic fluid stem cells (hAFSCs) are often described as sharing features with embryonic stem cells, including the expression of OCT4A, which could hinder their clinical potential. To clarify the OCT4A status of hAFSCs, we first undertook a systematic review of the literature. We then performed extensive gene and protein expression analyses to discover that neither frozen, nor fresh hAFSCs cultivated in multipotent stem cell culture conditions expressed OCT4A, and that the OCT4A positive results from the literature are likely to be attributed to the expression of pseudogenes or other OCT4 variants. To address this issue, we provide a robust protocol for the assessment of OCT4A in other stem cells.
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Líquido Amniótico/citologia , Regulação da Expressão Gênica no Desenvolvimento , Fator 3 de Transcrição de Octâmero/genética , Células-Tronco/citologia , Linhagem da Célula , Éxons , Feminino , Perfilação da Expressão Gênica , Variação Genética , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Microscopia de Fluorescência , Células-Tronco Multipotentes/citologia , Gravidez , Segundo Trimestre da Gravidez , Isoformas de ProteínasRESUMO
The present chapter summarizes our current knowledge on fetal stem cell and gene therapy. It focuses on these therapeutic alternatives in regard to past experiences and ongoing and planned studies in humans. Several methodological challenges are discussed that may have wide implications on how these methods could be introduced in clinical practices. Although still promising, the methods are afflicted with very special requirements not least in regard to safety and ethical questions. Furthermore, careful monitoring and extended follow-up of the child and his/hers mother who receive prenatal stem cell or gene treatments are of outmost importance. Taken these prerequisites into consideration, it is natural that this type of experimental fetal therapies requires collaboration between different disciplinaries and institutions within medicine.
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Doenças Fetais/cirurgia , Terapias Fetais/métodos , Terapia Genética/métodos , Transplante de Células-Tronco/métodos , Feminino , Doenças Fetais/genética , Humanos , GravidezRESUMO
PURPOSE OF REVIEW: The aim of the study is to provide an overview on the possibility of treating congenital disorders prenatally with mesenchymal stromal cells (MSCs). RECENT FINDINGS: MSCs have multilineage potential and a low immunogenic profile and are immunomodulatory and more easy to expand in culture. Their ability to migrate, engraft and differentiate, or act via a paracrine effect on target tissues makes MSCs candidates for clinical therapies. Fetal and extra-fetal MSCs offer higher therapeutic potential compared to MSCs derived from adult sources. SUMMARY: MSCs may be safely transplanted prenatally via ultrasound-guided injection into the umbilical cord. Due to these characteristics, fetal MSCs are of great interest in the field of in utero stem cell transplantation for treatment of congenital disease.
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Adverse events in maternity care are frequently avoidable and litigation costs for maternity care are rising for many health services across the world. Whilst families for whom this injury was preventable suffer from this tragedy, there is an enormous loss of resource to healthcare in general. It is axiomatic that preventing avoidable harm is better for women, their families and society in general, and downstream this improvement should also reduce both litigation and costs. However, there are few initiatives that have reduced adverse clinical events in maternity services and fewer still that have demonstrated decreases in litigation costs. Where these data do exist, the involvement and engagement of insurers seem to have been crucial, but often unrecognized. Insurers could play a much broader role in preventing harm, and this article explores this potential.