Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions

Shafqat, Shameel; Tariq, Eleze; Parnes, Aric; Dasouki, Majed; Ahmed, Syed Osman; Hashmi, Shahrukh K.

doi:10.1016/j.hemonc.2021.02.001

Cited by 8 publications

(11 citation statements)

References 39 publications

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“…FA has several clinical features, namely aplastic anemia, congenital abnormalities (skin hyperpigmentation such as café au lait spots, short stature, and thumb and radius deformities or abnormalities), and predisposition to epithelial cancers and acute myelogenous leukemia [65][66][67]. Other classic clinical manifestations are major diagnostic keys, such as Fanconi facies, microcephaly (small head size), microphthalmia, developmental delay, structural abnormalities (renal, cardiac, genitourinary, and other malformations), and radial ray defects.…”

Section: Clinical Features Of Famentioning

confidence: 99%

“…Retroviruses have the potential to exchange defective FA genes, such as FANCC, with a normal one. With the current advances, LVs, which are retroviruses, have favorable safety profiles with optimized transcriptional levels for improving hematopoietic progenitors in FA, whereas γ-retroviruses are correlated with genotoxicity [66]. The use of LVs in GT for FA management is supported by the favorable results of clinical trials involving β-thalassemia, adrenoleukodystrophy (ALD), Wiskott-Aldrich syndrome, and metachromatic leukodystrophy [76].…”

Section: Gt Approaches For Famentioning

confidence: 99%

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Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Anurogo

Budi

Ngo

et al. 2021

IJMS

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Hereditary anemia has various manifestations, such as sickle cell disease (SCD), Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency (G6PDD), and thalassemia. The available management strategies for these disorders are still unsatisfactory and do not eliminate the main causes. As genetic aberrations are the main causes of all forms of hereditary anemia, the optimal approach involves repairing the defective gene, possibly through the transplantation of normal hematopoietic stem cells (HSCs) from a normal matching donor or through gene therapy approaches (either in vivo or ex vivo) to correct the patient’s HSCs. To clearly illustrate the importance of cell and gene therapy in hereditary anemia, this paper provides a review of the genetic aberration, epidemiology, clinical features, current management, and cell and gene therapy endeavors related to SCD, thalassemia, Fanconi anemia, and G6PDD. Moreover, we expound the future research direction of HSC derivation from induced pluripotent stem cells (iPSCs), strategies to edit HSCs, gene therapy risk mitigation, and their clinical perspectives. In conclusion, gene-corrected hematopoietic stem cell transplantation has promising outcomes for SCD, Fanconi anemia, and thalassemia, and it may overcome the limitation of the source of allogenic bone marrow transplantation.

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Section: Clinical Features Of Famentioning

confidence: 99%

Section: Gt Approaches For Famentioning

confidence: 99%

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Anurogo

Budi

Ngo

et al. 2021

IJMS

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“…Gene therapy can avoid the main adverse effects of hematopoietic stem cell transplantation, such as endocrine diseases and solid malignancies; this is a promising path [18]. In recent years, the progress of molecular genetic research has contributed to the comprehensive study of FA, and, as the molecular mechanism of FA has become clearer, gene therapy has become possible [19][20][21]. However, owing to the limitations of current disease models, the pathogenesis of FA is still not fully understood [22].…”

Section: Introductionmentioning

confidence: 99%

Identification of Immune Infiltration, Differentially Expressed Genes, and Signaling Pathways in Fanconi Anemia Based on Bioinformatics Analysis

Shen

Shi

Chen

et al. 2022

Preprint

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Background and Objective: Fanconi anemia (FA) patients have a reduced ability to form blood cells, accompanied by multiple congenital malformations, mental retardation, solid tumors, and other symptoms. However, the molecular mechanism that causes FA is unclear, and few studies have addressed the regulatory mechanism of immune infiltration in FA. Here, we aimed to identify differentially expressed genes (DEGs), pathways, and immune infiltration involved in FA using integrated bioinformatics analysis and molecular mechanisms. Methods: The GEO gene chip database was searched for FA low density bone marrow tissue, and the content and proportion of 22 types of immune cells in the FA group and the normal group were analyzed using CIBERSORT. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of FA differentially expressed genes (DEGs) using R language and related package programs was also performed.Results: The expression levels of T cells regulatory (Tregs), M2 macrophages, T cells CD8, dendritic cells resting, and T cells CD4 naïve in FA were higher than in the normal group. Furthermore, the expression levels of naïve B cells, monocytes, and resting mast cells in FA were lower than in the normal group. GO analysis of FA differential genes showed that “neutrophil degranulation,” “neutrophil activation,” and “neutrophil activation involved in immune response,” were most frequently enriched among biological processes, with “specific granule,” “tertiary granule,” “tertiary granule lumen” among cellular components, and “carbohydrate binding” among molecular functions. For the KEGG analysis, “Asthma” was most often enriched.Conclusion: This study obtained useful data related to immune infiltration, DEGs, and gene pathways of FA, and provides new evidence for immunotherapy and clinical assessment of FA patients. These results are potentially a useful reference for subsequent related scientific research.

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“…In the last 20 years there have been four clinical trials of FA gene therapy [ 15 ]. The first three of these studies have included nine total patients that were successfully transplanted, all using lentiviral FANCA complementation constructs in patients with varying FANCA mutations.…”

Section: Introductionmentioning

confidence: 99%

“…The second trial involved two patients infused with HSPCs transduced using a lentiviral vector encoding a FANCA expressing cDNA (MSCV-FANCA) (NCT00272857) [ 18 ]. At six months post-transplant, blood counts had increased moderately with no adverse events in either patient, however longer-term follow-up is necessary to gauge efficacy [ 15 ]. The third trial (NCT01221018) included two patients, both of whom tolerated treatment well with no adverse events reported, but low and declining levels of transduced cells were observed in the peripheral blood [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Correction of Fanconi Anemia Mutations Using Digital Genome Engineering

Sipe

Kluesner

Bingea

et al. 2022

IJMS

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Fanconi anemia (FA) is a rare genetic disease in which genes essential for DNA repair are mutated. Both the interstrand crosslink (ICL) and double-strand break (DSB) repair pathways are disrupted in FA, leading to patient bone marrow failure (BMF) and cancer predisposition. The only curative therapy for the hematological manifestations of FA is an allogeneic hematopoietic cell transplant (HCT); however, many (>70%) patients lack a suitable human leukocyte antigen (HLA)-matched donor, often resulting in increased rates of graft-versus-host disease (GvHD) and, potentially, the exacerbation of cancer risk. Successful engraftment of gene-corrected autologous hematopoietic stem cells (HSC) circumvents the need for an allogeneic HCT and has been achieved in other genetic diseases using targeted nucleases to induce site specific DSBs and the correction of mutated genes through homology-directed repair (HDR). However, this process is extremely inefficient in FA cells, as they are inherently deficient in DNA repair. Here, we demonstrate the correction of FANCA mutations in primary patient cells using ‘digital’ genome editing with the cytosine and adenine base editors (BEs). These Cas9-based tools allow for C:G > T:A or A:T > C:G base transitions without the induction of a toxic DSB or the need for a DNA donor molecule. These genetic corrections or conservative codon substitution strategies lead to phenotypic rescue as illustrated by a resistance to the alkylating crosslinking agent Mitomycin C (MMC). Further, FANCA protein expression was restored, and an intact FA pathway was demonstrated by downstream FANCD2 monoubiquitination induction. This BE digital correction strategy will enable the use of gene-corrected FA patient hematopoietic stem and progenitor cells (HSPCs) for autologous HCT, obviating the risks associated with allogeneic HCT and DSB induction during autologous HSC gene therapy.

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Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions

Cited by 8 publications

References 39 publications

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Identification of Immune Infiltration, Differentially Expressed Genes, and Signaling Pathways in Fanconi Anemia Based on Bioinformatics Analysis

Correction of Fanconi Anemia Mutations Using Digital Genome Engineering

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