Implications of hematopoietic stem cells heterogeneity for gene therapies

Epah, Jeremy; Schäfer, Richard

doi:10.1038/s41434-021-00229-x

Cited by 16 publications

(12 citation statements)

References 135 publications

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“…Hematopoietic stem and progenitor cells heterogeneity before collection, during enrichment, and through manufacturing can affect product quality. Mutations can cause functional effects, variations in transcriptional activity [ 267 ], and possibly in the efficiency of differentiation to functional NK cells. Additionally, variable transduction rates of different HSC subsets [ 267 ] can affect genetically engineered products.…”

Section: Field Challengesmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.

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Section: Field Challengesmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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“…Ex vivo gene therapy using hematopoietic stem and progenitor cell (HSPC) has been on the rise for treating inherited, immunological, metabolic, and neurodegenerative disorders ( Massaro et al, 2021 ; DiGiusto et al, 2013 ; Drakopoulou et al, 2013 ; Eichler et al, 2017a ; Porter et al, 2011 ; Zhang et al, 2013 ; Tucci et al, 2021 ). Ex vivo HSPC gene therapy has potential key advantages: 1) it avoids immune reaction during an autologous transplantation procedure ( Drysdale et al, 2020 ), 2) it may treat all the complications by a single infusion of hematopoietic stem cells ( Epah and Schäfer, 2021 ); 3) ex vivo gene modification of the patients’ cells will occur in a controlled environment allowing cell characterization prior to transplantation ( Soni and Kohn, 2019 ); 4) it potentially provides once-in-a-lifetime intervention as engrafted, gene modified HSPCs will constitute a long-term reservoir of repopulating healthy cells in the bone marrow; stable transgene expression of over 15 years is reported for severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID) ( Cicalese et al, 2016 ); 5) HSPC-derived monocyte/macrophages can cross the BBB and engraft long-term in the CNS as microglia-like cells in the context of neurodegenerative disorders and after myeloablative conditioning ( Capotondo et al, 2012 ; Peterson et al, 2019 ). and, 6) HSPC-derived macrophages and microglia can deliver lacking protein/enzyme to the disease cells in the injured tissues ( Tan et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich’s Ataxia

Sivakumar

Cherqui

2022

Front. Genome Ed.

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Friedreich’s ataxia (FRDA) is an inherited, multisystemic disorder predominantly caused by GAA hyper expansion in intron 1 of frataxin (FXN) gene. This expansion mutation transcriptionally represses FXN, a mitochondrial protein that is required for iron metabolism and mitochondrial homeostasis, leading to neurodegerative and cardiac dysfunction. Current therapeutic options for FRDA are focused on improving mitochondrial function and increasing frataxin expression through pharmacological interventions but are not effective in delaying or preventing the neurodegeneration in clinical trials. Recent research on in vivo and ex vivo gene therapy methods in FRDA animal and cell models showcase its promise as a one-time therapy for FRDA. In this review, we provide an overview on the current and emerging prospects of gene therapy for FRDA, with specific focus on advantages of CRISPR/Cas9-mediated gene editing of FXN as a viable option to restore endogenous frataxin expression. We also assess the potential of ex vivo gene editing in hematopoietic stem and progenitor cells as a potential autologous transplantation therapeutic option and discuss its advantages in tackling FRDA-specific safety aspects for clinical translation.

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“…This lack of knowledge is mostly due to three factors: the difficulty to perform in vivo studies; the fact that key events occur at minuscule time scales; and the observation that isolated HSCs in vitro do not behave identically to in vivo cells, and seem to require their surrounding environmental cues to guide their developmental path. This is prominently exemplified by the failures of cell engraftment studies in the context of immunodeficiencies ( Epah and Schäfer 2021 ).…”

Section: Introductionmentioning

confidence: 99%

How cell migration helps immune sentinels

Delgado

Lennon-Duménil

2022

Front. Cell Dev. Biol.

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The immune system relies on the migratory capacity of its cellular components, which must be mobile in order to defend the host from invading micro-organisms or malignant cells. This applies in particular to immune sentinels from the myeloid lineage, i.e. macrophages and dendritic cells. Cell migration is already at work during mammalian early development, when myeloid cell precursors migrate from the yolk sac, an extra embryonic structure, to colonize tissues and form the pool of tissue-resident macrophages. Later, this is accompanied by a migration wave of precursors and monocytes from the bone marrow to secondary lymphoid organs and the peripheral tissues. They differentiate into DCs and monocyte-derived macrophages. During adult life, cell migration endows immune cells with the ability to patrol their environment as well as to circulate between peripheral tissues and lymphoid organs. Hence migration of immune cells is key to building an efficient defense system for an organism. In this review, we will describe how cell migratory capacity regulates the various stages in the life of myeloid cells from development to tissue patrolling, and migration to lymph nodes. We will focus on the role of the actin cytoskeletal machinery and its regulators, and how it contributes to the establishment and function of the immune system.

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Implications of hematopoietic stem cells heterogeneity for gene therapies

Cited by 16 publications

References 135 publications

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich’s Ataxia

How cell migration helps immune sentinels

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