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Translational research for bone marrow failure patients.

ABSTRACT: Bone marrow failure syndromes encompass a range of inherited and acquired hematological diseases that result in insufficient blood cell production, which leads to severe complications including anemia, weakening of the immune system, impaired coagulation, and increased risk of cancer. Within inherited bone marrow failure syndromes, a number of genetically distinct diseases have been described including Shwachman-Diamond syndrome and Fanconi anemia. Given the genetic complexity and poor prognosis of these inherited bone marrow failure syndromes, there is increasing interest in both characterizing the genetic landscapes of these diseases and developing novel gene therapies to effectively monitor and cure patients. These topics were the focus of the winter 2021 International Society for Experimental Hematology New Investigator Webinar, which featured presentations by Dr. Akiko Shimamura and Dr. Paula Río. Here, we review the topics covered within this webinar.

SUBMITTER: Malouf C

PROVIDER: S-EPMC9165438 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Translational research for bone marrow failure patients.

Malouf Camille C Loughran Stephen J SJ Wilkinson Adam C AC Shimamura Akiko A Río Paula P

Experimental hematology 20211118

Bone marrow failure syndromes encompass a range of inherited and acquired hematological diseases that result in insufficient blood cell production, which leads to severe complications including anemia, weakening of the immune system, impaired coagulation, and increased risk of cancer. Within inherited bone marrow failure syndromes, a number of genetically distinct diseases have been described including Shwachman-Diamond syndrome and Fanconi anemia. Given the genetic complexity and poor prognosis ...[more]

PMID: 34801643

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Project description:BackgroundPatients with bone marrow failure and undiagnosed underlying Fanconi anemia may experience major toxicity if given standard-dose conditioning regimens for hematopoietic stem cell transplant. Due to clinical variability and/or potential emergence of genetic reversion with hematopoietic somatic mosaicism, a straightforward Fanconi anemia diagnosis can be difficult to make, and diagnostic strategies combining different assays in addition to classical breakage tests in blood may be needed.Design and methodsWe evaluated Fanconi anemia diagnosis on blood lymphocytes and skin fibroblasts from a cohort of 87 bone marrow failure patients (55 children and 32 adults) with no obvious full clinical picture of Fanconi anemia, by performing a combination of chromosomal breakage tests, FANCD2-monoubiquitination assays, a new flow cytometry-based mitomycin C sensitivity test in fibroblasts, and, when Fanconi anemia was diagnosed, complementation group and mutation analyses. The mitomycin C sensitivity test in fibroblasts was validated on control Fanconi anemia and non-Fanconi anemia samples, including other chromosomal instability disorders.ResultsWhen this diagnosis strategy was applied to the cohort of bone marrow failure patients, 7 Fanconi anemia patients were found (3 children and 4 adults). Classical chromosomal breakage tests in blood detected 4, but analyses on fibroblasts were necessary to diagnose 3 more patients with hematopoietic somatic mosaicism. Importantly, Fanconi anemia was excluded in all the other patients who were fully evaluated.ConclusionsIn this large cohort of patients with bone marrow failure our results confirmed that when any clinical/biological suspicion of Fanconi anemia remains after chromosome breakage tests in blood, based on physical examination, history or inconclusive results, then further evaluation including fibroblast analysis should be made. For that purpose, the flow-based mitomycin C sensitivity test here described proved to be a reliable alternative method to evaluate Fanconi anemia phenotype in fibroblasts. This global strategy allowed early and accurate confirmation or rejection of Fanconi anemia diagnosis with immediate clinical impact for those who underwent hematopoietic stem cell transplant.

Project description:UnlabelledCell therapy is an evolving option for patients with end-stage heart failure and ongoing symptoms despite optimal medical therapy. Our goal was to evaluate retrograde bone marrow cell delivery in patients with either ischemic heart failure (IHF) or nonischemic heart failure (NIHF). This was a prospective randomized, multicenter, open-label study of the safety and feasibility of bone marrow aspirate concentrate (BMAC) infused retrograde into the coronary sinus. Sixty patients were stratified by IHF and NIHF and randomized to receive either BMAC infusion or control (standard heart failure care) in a 4:1 ratio. Accordingly, 24 subjects were randomized to the ischemic BMAC group and 6 to the ischemic control group. Similarly, 24 subjects were randomized to the nonischemic BMAC group and 6 to the nonischemic control group. All 60 patients were successfully enrolled in the study. The treatment groups received BMAC infusion without complications. The left ventricular ejection fraction in the patients receiving BMAC demonstrated significant improvement compared with baseline, from 25.1% at screening to 31.1% at 12 months (p=.007) in the NIHF group and from 26.3% to 31.1% in the IHF group (p=.035). The end-systolic diameter decreased significantly in the nonischemic BMAC group from 55.6 to 50.9 mm (p=.020). Retrograde BMAC delivery is safe. All patients receiving BMAC experienced improvements in left ventricular ejection fraction, but only those with NIHF showed improvements in left ventricular end-systolic diameter and B-type natriuretic peptide. These results provide the basis for a larger clinical trial in HF patients.SignificanceThis work is the first prospective randomized clinical trial using high-dose cell therapy delivered via a retrograde coronary sinus infusion in patients with heart failure. This was a multinational, multicenter study, and it is novel, translatable, and scalable. On the basis of this trial and the safety of retrograde coronary sinus infusion, there are three other trials under way using this route of delivery.

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Translational research for bone marrow failure patients.

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Translational research for bone marrow failure patients.

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