Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management

Vissers, Lotte T. W.; van der Burg, Mirjam; Lankester, Arjan C.; Smiers, Frans J. W.; Bartels, Marije; Mohseny, Alexander B.

doi:10.3390/jcm12227185

Cited by 4 publications

(1 citation statement)

References 213 publications

(294 reference statements)

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“…Patients with inherited bone marrow failure syndromes may be potentially cured by an allogeneic hematopoietic stem cell transplant, with improved results following lower toxicity protocols in Fanconi anemia (reviewed in [141]). However, an allogeneic transplant is not always offered due to its potential complications, as reviewed in November 2023 [142]. In 2019, lentiviralmediated autologous gene therapy showed promising results, including stopping the progression of bone marrow failure in patients with Fanconi anemia harboring FANCA germline mutations [143].…”

Section: Gene Therapy Applications In Inherited Bone Marrow Syndromesmentioning

confidence: 99%

CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies

Kansal

2024

Preprint

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Clustered regularly interspaced short palindromic repeats (CRISPR) based gene-editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single guide RNA (sgRNA)-based gene-editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, instructive, and inspiring for future advances. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent beta thalassemia has renewed hope for treating other hematologic diseases, including patients with germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-based gene therapies. The purpose of this manuscript is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy; and third, the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with germline predisposition to hematologic malignancies.

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Section: Gene Therapy Applications In Inherited Bone Marrow Syndromesmentioning

confidence: 99%

CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies

Kansal

2024

Preprint

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Immunodeficiency: Quantitative and qualitative phagocytic cell defects

Mickey,

Camacho,

Khan

et al. 2024

allergy asthma proc

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The immune system is divided into two major branches: innate and adaptive. The innate immune system is the body's first line of defense and rapidly responds in a nonspecific manner to various microorganisms, foreign materials, or injuries. Phagocytes, which include macrophages, monocytes, and neutrophils, are innate immune cells that can surround and kill microorganisms, ingest foreign material, and remove dead cells. They also indirectly boost both innate and adaptive immune responses through various activation signals. Phagocytic defects characteristically lead to fungal and bacterial infections of the respiratory tract, lymph nodes, skin, and other organ systems, and they are commonly associated with inflammatory bowel disease. This primer will review high-yield innate defects of phagocytic cells, including defects of respiratory (oxidative) burst, defects of neutrophil migration, cyclic and severe congenital neutropenias and associated disorders, and other phagocyte defect disorders.

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Potential role of B- and NK-cells in the pathogenesis of pediatric aplastic anemia through deep phenotyping

Vissers,

van Ostaijen-ten Dam,

Melsen

et al. 2024

Front. Immunol.

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IntroductionPediatric patients with unexplained bone marrow failure (BMF) are often categorized as aplastic anemia (AA). Based on the accepted hypothesis of an auto-immune mechanism underlying AA, immune suppressive therapy (IST) might be effective. However, due to the lack of diagnostic tools to identify immune AA and prognostic markers to predict IST response together with the unequaled curative potential of hematopoietic stem cell transplantation (HSCT), most pediatric severe AA patients are momentarily treated by HSCT if available. Although several studies indicate oligoclonal T-cells with cytotoxic activities towards the hematopoietic stem cells, increasing evidence points towards defective inhibitory mechanisms failing to inhibit auto-reactive T-cells.MethodsWe aimed to investigate the role of NK- and B-cells in seven pediatric AA patients through a comprehensive analysis of paired bone marrow and peripheral blood samples with spectral flow cytometry in comparison to healthy age-matched bone marrow donors. ResultsWe observed a reduced absolute number of NK-cells in peripheral blood of AA patients with a skewed distribution towards CD56bright NK-cells in a subgroup of patients. The enriched CD56bright NK-cells had a lower expression of CD45RA and TIGIT and a higher expression of CD16, compared to healthy donors. Functional analysis revealed no differences in degranulation. However, IFN-γ production and perforin expression of NK-cells were reduced in the CD56bright-enriched patient group. The diminished NK-cell function in this subgroup might underly the auto-immunity. Importantly, NK-function of AA patients with reduced CD56bright NK-cells was comparable to healthy donors. Also, B-cell counts were lower in AA patients. Subset analysis revealed a trend towards reduction of transitional B-cells in both absolute and relative numbers compared to healthy controls. As these cells were previously hypothesized as regulatory cells in AA, decreased numbers might be involved in defective inhibition of auto-reactive T-cells. Interestingly, even in patients with normal distribution of precursor B-cells, the transitional compartment was reduced, indicating partial differentiation failure from immature to transitional B-cells or a selective loss. DiscussionOur findings provide a base for future studies to unravel the role of transitional B-cells and CD56bright NK-cells in larger cohorts of pediatric AA patients as diagnostic markers for immune AA and targets for therapeutic interventions.

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Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management

Cited by 4 publications

References 213 publications

CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies

CRISPR RNA-Guided Gene Editing and its Clinical Research Applications in Hematology with Focus on Inherited Germline Predisposition to Hematologic Malignancies

Immunodeficiency: Quantitative and qualitative phagocytic cell defects

Potential role of B- and NK-cells in the pathogenesis of pediatric aplastic anemia through deep phenotyping

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