Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia

Rı́o, Paula; Navarro, Susana; Wang, Wei; Sanchez-Dominguez, Rebeca; Pujol, Roser; Segovia, José C.; Bogliolo, Massimo; Merino, Eva; Wu, Ning; Salgado, Rocío; Lamana, María L.; Yáñez, Rosa María Pérez; Casado, José Antonio; Giménez, Yari; Roman-Rodriguez, Francisco J; Álvarez, Lara; Alberquilla, Omaira; Raimbault, Anna; Güenechea, Guillermo; Lozano, M. Luz; Cerrato, Laura; Hernando, Miriam; Gálvez, Eva; Hladun, Raquel; Giralt, Irina; Barquinero, Jordi; Galy, Anne; Andoin, Nagore García de; López, R. de la Prieta; Catalá, Albert; Schwartz, Jonathan D.; Surrallés, Jordi; Soulier, Jean; Schmidt, Manfred; Heredia, Cristina Díaz de; Sevilla, Julián; Bueren, Juan A.

doi:10.1038/s41591-019-0550-z

Cited by 127 publications

(88 citation statements)

References 40 publications

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“…This was the case for different gene therapy clinical trials using gamma retroviral vectors such as X-linked severe combined immunodeficiency (SCID-X1) [13,14], CGD [15] and Wiskott-Aldrich syndrome (WAS) [16]. In more recent clinical trials that used LVs, a more polyclonal pattern of corrected hematopoietic cells has been observed [17][18][19][20].…”

Section: Lentiviral Vectorsmentioning

confidence: 98%

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

Gutiérrez‐Guerrero

Cosset

Verhoeyen

2020

Viruses

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Viruses have been repurposed into tools for gene delivery by transforming them into viral vectors. The most frequently used vectors are lentiviral vectors (LVs), derived from the human immune deficiency virus allowing efficient gene transfer in mammalian cells. They represent one of the safest and most efficient treatments for monogenic diseases affecting the hematopoietic system. LVs are modified with different viral envelopes (pseudotyping) to alter and improve their tropism for different primary cell types. The vesicular stomatitis virus glycoprotein (VSV-G) is commonly used for pseudotyping as it enhances gene transfer into multiple hematopoietic cell types. However, VSV-G pseudotyped LVs are not able to confer efficient transduction in quiescent blood cells, such as hematopoietic stem cells (HSC), B and T cells. To solve this problem, VSV-G can be exchanged for other heterologous viral envelopes glycoproteins, such as those from the Measles virus, Baboon endogenous retrovirus, Cocal virus, Nipah virus or Sendai virus. Here, we provide an overview of how these LV pseudotypes improved transduction efficiency of HSC, B, T and natural killer (NK) cells, underlined by multiple in vitro and in vivo studies demonstrating how pseudotyped LVs deliver therapeutic genes or gene editing tools to treat different genetic diseases and efficiently generate CAR T cells for cancer treatment.

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Section: Lentiviral Vectorsmentioning

confidence: 98%

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

Gutiérrez‐Guerrero

Cosset

Verhoeyen

2020

Viruses

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“…These early setbacks paved the path for the design of novel and safe viral vectors. In the past two decades, not only have there been inventions of a variety of safer viral vector such as "gutless adenoviral vectors" [54][55][56] and self-inactivating (SIN) γ-RVVs [9,57] and LVVs [12,58], but these vectors have also become the backbone of ex-vivo gene therapy clinical trials [24,[59][60][61].…”

Section: Viral and Non-viral Vectors Platforms For In-vivo Gene Therapymentioning

confidence: 99%

In-Vivo Gene Therapy with Foamy Virus Vectors

Rajawat

Humbert

Kiem

2019

Viruses

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Foamy viruses (FVs) are nonpathogenic retroviruses that infect various animals including bovines, felines, nonhuman primates (NHPs), and can be transmitted to humans through zoonotic infection. Due to their non-pathogenic nature, broad tissue tropism and relatively safe integration profile, FVs have been engineered as novel vectors (foamy virus vector, FVV) for stable gene transfer into different cells and tissues. FVVs have emerged as an alternative platform to contemporary viral vectors (e.g., adeno associated and lentiviral vectors) for experimental and therapeutic gene therapy of a variety of monogenetic diseases. Some of the important features of FVVs include the ability to efficiently transduce hematopoietic stem and progenitor cells (HSPCs) from humans, NHPs, canines and rodents. We have successfully used FVV for proof of concept studies to demonstrate safety and efficacy following in-vivo delivery in large animal models. In this review, we will comprehensively discuss FVV based in-vivo gene therapy approaches established in the X-linked severe combined immunodeficiency (SCID-X1) canine model.

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“…Fanconi anemia (FA) is a genetic disorder that has intrigued scientists and illuminated medical discoveries for at least half a century. The first patient to ever receive a curative bone marrow transplant from umbilical-cord blood had FA [ 1 ], the first documented case of pre-implantation embryo selection to create a matched donor was in FA [ 2 ], and the first successful trials of gene therapy for a bone marrow failure syndrome were recently successfully completed in patients with FA [ 3 ]. The first discovered breast cancer predisposition genes, BRCA1 and BRCA2 also turned out to be FANC genes, named FANCS and FANCD1 [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Structural insight into FANCI–FANCD2 monoubiquitination

Tan

Deans

2020

Essays in Biochemistry

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The Fanconi anemia (FA) pathway coordinates a faithful repair mechanism for DNA damage that blocks DNA replication, such as interstrand cross-links. A key step in the FA pathway is the conjugation of ubiquitin on to FANCD2 and FANCI, which is facilitated by a large E3 ubiquitin ligase complex called the FA core complex. Mutations in FANCD2, FANCI or FA core complex components cause the FA bone marrow failure syndrome. Despite the importance of these proteins to DNA repair and human disease, our molecular understanding of the FA pathway has been limited due to a deficit in structural studies. With the recent development in cryo-electron microscopy (EM), significant advances have been made in structural characterization of these proteins in the last 6 months. These structures, combined with new biochemical studies, now provide a more detailed understanding of how FANCD2 and FANCI are monoubiquitinated and how DNA repair may occur. In this review, we summarize these recent advances in the structural and molecular understanding of these key components in the FA pathway, compare the activation steps of FANCD2 and FANCI monoubiquitination and suggest molecular steps that are likely to be involved in regulating its activity.

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Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia

Cited by 127 publications

References 40 publications

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

In-Vivo Gene Therapy with Foamy Virus Vectors

Structural insight into FANCI–FANCD2 monoubiquitination

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