About
146
Publications
13,281
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
3,335
Citations
Introduction
Additional affiliations
June 2005 - present
Publications
Publications (146)
The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has revolutionized the gene editing field, making it possible to interrupt, insert or replace a sequence of interest with high precision in the human genome. Its easy design and wide applicability open up a variety of therapeutic alternatives for the treatment of gen...
Fanconi Anemia (FA) is a debilitating genetic disorder with a wide range of severe symptoms including bone marrow failure and predisposition to cancer. CRISPR-Cas genome editing manipulates genotypes by harnessing DNA repair and has been proposed as a potential cure for FA. But FA is caused by deficiencies in DNA repair itself, preventing the use o...
Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point ou...
Leukocyte adhesion deficiency type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene, which encodes for the CD18 subunit of β2 integrins. Deficient expression of β2 integrins results in impaired neutrophil migration in response to bacterial and fungal infections. Using a lentiviral vector that mediates a preferential mye...
Fanconi Anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules...
Fanconi Anemia (FA) is a debilitating genetic disorder with a wide range of severe symptoms including bone marrow failure and predisposition to cancer. CRISPR-Cas genome editing manipulates genotypes by harnessing DNA repair and has been proposed as a potential cure for FA. But FA is caused deficiencies in DNA repair itself, preventing the use of e...
Background: Fanconi anemia (FA) is a disorder of defective deoxyribonucleic acid (DNA) repair, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. Approximately 60 to 70% of all cases result from a mutation in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). 80% of FA patients exp...
Introduciton
Despite impressive preliminary efficacy of CAR-T cells in multiple myeloma (MM), NK cell engineering has emerged as a competitive and safer approach, as they entail an ‘off-the-shelf’ strategy with no graft-versus-host disease. NK-92 is a universal, cheap and fast obtainable cellular therapy previously used in clinical trials. Although...
CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this...
PARAGRAPH
Fanconi anemia (FA) is a monogenic inherited disease associated with mutations in genes that encode for proteins participating in the FA/BRCA DNA repair pathway. Mutations in FA genes result in chromosomal instability and cell death, leading to cancer risks and progressive cell mortality, most notably in hematopoietic stem and progenitor...
Difficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine...
Fanconi anemia (FA) is characterized by chromosome fragility, bone marrow failure (BMF) and predisposition to cancer. As reverse genetic mosaicism has been described as “natural gene therapy” in patients with FA, we sought to evaluate the clinical course of a cohort of FA mosaic patients followed at referral centers in Spain over a 30‐year period....
Fanconi anemia (FA) patients have an exacerbated risk of head and neck squamous cell carcinoma (HNSCC). Treatment is challenging as FA patients display enhanced toxicity to standard treatments, including radio/chemotherapy. Therefore, better therapies as well as new disease models are urgently needed. We have used CRISPR/Cas9 editing tools in order...
Inherited bone marrow failure syndromes (IBMFSs) are a group of congenital rare diseases characterized by bone marrow failure, congenital anomalies, high genetic heterogeneity, and predisposition to cancer. Appropriate treatment and cancer surveillance ideally depend on the identification of the mutated gene. A next-generation sequencing (NGS) pane...
Fanconi anemia (FA) patients have an exacerbated risk of head and neck squamous cell carcinoma (HNSCC). Treatment is challenging as FA patients display enhanced toxicity to standard treatments, including radio/chemotherapy. Therefore better therapies as well as new disease models are urgently needed. We have used CRISPR/Cas9 editing tools in order...
Background: Fanconi anemia (FA) is a rare inherited disorder of defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities and characterized by progressive bone marrow failure (BMF) and a predisposition to hematologic malignancies and solid tumors. Approximately 60-70% of all cases result from mutations in th...
Fanconi anemia (FA) patients have an exacerbated risk of head and neck squamous cell carcinoma (HNSCC). Treatment is challenging as FA patients display enhanced toxicity to standard treatments, including radio/chemotherapy. Therefore better therapies as well as new disease models are urgently needed. We have used CRISPR/Cas9 editing tools in order...
Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be a...
The promising ability to genetically modify hematopoietic stem and progenitor cells by precise gene editing remains challenging due to their sensitivity to in vitro manipulations and poor efficiencies of homologous recombination. This study represents the first evidence of implementing a gene editing strategy in a murine safe harbor locus site that...
Background
Fanconi anemia (FA) is a rare genetic disorder characterized by defective cellular DNA repair, associated developmental abnormalities, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. 80% of FA patients develop BMF due to progressive depletion of their BM stem cells. Although allog...
Background: Fanconi anemia (FA) is a rare genetic disorder characterized by defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. 80% of FA patients develop BMF. Although allogeneic hematopoietic st...
Nine Fanconi anemia patients complementation group A (FA-A), age 2-6 years, have been infused with autologous hematopoietic cells after genetic correction with the therapeutic PGK-FANCA.Wpre* lentiviral vector. In all instances patients underwent CD34+ cell mobilization with G-CSF and plerixafor and were subsequently infused in the absence of any p...
The efficacy of lentiviral gene therapy for the treatment of primary immunodeficiencies (PIDs) has been extensively demonstrated in diseases such as X1-SCID, ADA-SCID, X-CGD and WAS. Leukocyte Adhesion Deficiency type I (LAD-I) has also emerged as a PID that is potentially correctable by gene therapy. To this aim during the recent years we have com...
Background:
Acute myeloid leukemia (AML) is a hematological malignancy with a very low overall survival. Among the new treatment modalities, chimeric antigen receptor (CAR) therapy is showing promising results in other hematological malignancies. Since AML exhibits high heterogeneity and does not have specific differential antigens of the hematopoi...
Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only curative treatment for the bone marrow failure in Fanconi anemia (FA) patients. However, recent advances in lentiviral-mediated gene therapy have shown that corrected FA HSCs develop an in vivo proliferation advantage, facilitating the engraftment of corrected HSCs in no...
Purpose
Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients’ charact...
Non-homologous end-joining (NHEJ) is the preferred mechanism used by hematopoietic stem cells (HSCs) to repair double-stranded DNA breaks and is particularly increased in cells deficient in the Fanconi anemia (FA) pathway. Here, we show feasible correction of compromised functional phenotypes in hematopoietic cells from multiple FA complementation...
Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that...
Hematopoietic gene therapy has markedly progressed during the last 15 years both in terms of safety and efficacy. While a number of serious adverse events (SAE) were initially generated as a consequence of genotoxic insertions of gamma‐retroviral vectors in the cell genome, no SAEs and excellent outcomes have been reported in patients infused with...
Fanconi anemia (FA) is a DNA repair syndrome characterized by bone marrow failure, congenital abnormalities and cancer predisposition. Based on previous experimental results showing the in vivo proliferative advantage of gene corrected FA patients' hematopoietic stem cells (HSCs; Rio, Navarro et al. Blood 2017) a gene therapy trial in non-condition...
Introduction
Immunotherapy represents a new weapon in the fight against multiple myeloma. Current clinical outcomes using CAR-T cell therapy against multiple myeloma show promise in the eradication of the disease. However, these CARs observe relapse as a common phenomenon after treatment due to the reemergence of neoantigens or negative cells. CARs...
Fanconi anemia (FA) is a rare inherited disease associated with bone marrow failure (BMF) and cancer predisposition. Previous clinical trials have shown the difficulties of treating BMF of FA patients by gene therapy. Nevertheless, the discovery of new drugs capable of efficiently mobilizing hematopoietic stem cells (HSC) and the development of opt...
The promising ability to genetically modify hematopoietic stem and progenitor cells (HSPCs) by precise gene editing remains challenging due to their sensitivity and poor permissiveness. This represents the first evidence of implementing a gene editing strategy in a murine safe harbor locus that phenotypically corrects primary cells derived from a m...
Expanded View Figures PDF
Hematopoietic stem cell (HSC)–based gene therapy trials are now moving toward the use of lentiviral vectors (LVs) with success. However, one challenge in the field remains: efficient transduction of HSCs without compromising their stem cell potential. Here we showed that measles virus glycoprotein–displaying LVs (hemagglutinin and fusion protein LV...
Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first exper...
Key Points
First evidence of phenotypic correction in FA hematopoietic repopulating cells by optimized collection and short transduction of CD34+ cells. Optimized ex vivo gene therapy of FA CD34+ cells confers proliferation advantage to phenotypically corrected repopulating cells.
Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive marrow failure. Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential cure since it is a monogenetic disease with mutations in the FANC genes, coding for DNA repair enzymes (See review[1]). However, the collection of hCD34...
Fanconi anemia (FA) is a genetic disease mainly characterized by progressive bone marrow failure (BMF), congenital abnormalities, and increased predisposition to cancer (1,2). Although most patients with FA develop BMF generally during childhood, the molecular mechanism underlying BMF has remained elusive for a long time and is still a matter of de...
Current sources of platelets for transfusion are insufficient and associated with risk of alloimmunization and blood-borne infection. These limitations could be addressed by the generation of autologous megakaryocytes (MKs) derived in vitro from somatic cells with the ability to engraft and differentiate in vivo. Here, we show that overexpression o...
Gene targeting is rapidly progressing thanks to the development of improved nucleases and donor constructs, and represents a new gene therapy-based strategy for the treatment of inherited diseases, such as Fanconi anemia (FA). Because FA can be generated by multiple mutations in up to 19 different genes, we focused our interests in the insertion of...
Introduction: Fanconi anemia (FA) is a rare inherited disease characterized by congenital abnormalities, bone marrow failure (BMF) and cancer predisposition. Although allogeneic hematopoietic stem cell transplantation (HSCT) is the preferential therapy for restoring the bone marrow (BM) function of FA patients, gene therapy represents a new alterna...
BCR-JAK2 is an infrequent gene fusion found in chronic/acute, myeloid/lymphoid Philadelphia chromosome-negative leukemia. In this study, we demonstrate that in vivo expression of BCR-JAK2 in mice induces neoplasia with fatal consequences. Transplantation of BCR-JAK2 bone marrow progenitors promoted splenomegaly with megakaryocyte infiltration and e...
Supplementary Figure S1
Supplementary Figure S5
Supplementary Figure S4
Supplementary Figure S6
Review Process File
Supplementary Figure S2
Supplementary Figure S8
Supplementary Figure S9
Supplementary Table S2
Supplementary Figure S3
Supplementary Figure S7
Supplementary Table S1
Supplementary Materials and Methods
Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective...
Fanconi anemia (FA) is a complex genetic disease associated with a defective DNA repair pathway known as the FA pathway. In contrast to many other FA proteins, BRCA2 participates downstream in this pathway and has a critical role in homology-directed recombination (HDR). In our current studies, we have observed an extremely low reprogramming effici...
Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. H...
Poster presentation
Background: Previous studies have shown that around 10% of solid and
hematological tumors have a disrupted Fanconi anemia (FA) pathway either
because of gene mutations or due to the silencing in any of the 15 FA genes
so far discovered.
Because the FA pathway is involved in the repair of interstrand crosslinks,
in this study we...