Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of <i>Ex Vivo</i> Gene Therapy: Review of Nonproliferative and Proliferative Changes

Chanut, Franck; Sanvito, Francesca; Ferrari, Giuliana; Visigalli, Ilaria; Carriglio, Nicola; Hernández, Raisa Jofra; Norata, Rossana; Doglioni, Claudio; Naldini, Luigi; Cristofori, Patrizia

doi:10.1089/hum.2020.135

Cited by 11 publications

(9 citation statements)

References 43 publications

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“…These findings were observed only in the groups that underwent busulfan conditioning, that is administered intraperitoneally, followed by transplantation of HSPCs (either transduced or untransduced), and they occurred more frequently in animals that managed to survive longer than 260 days. In line with our observation, the toxicity associated with the route of administration of busulfan that in mice must be intraperitoneal for technical reasons, was reported in the context of other long-term observation preclinical studies 26 .…”

Section: Safety Of Hppt1-lv Hspcs Transplantation In Ppt1 -/Micesupporting

confidence: 89%

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An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Peviani

Das

Patel

et al. 2022

Preprint

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Hematopoietic stem and progenitor cells (HSPCs) can lead to the establishment of a long-lasting microglia-like progeny in the brain of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses, due to deficiency of palmitoyl-protein thioesterase 1 (hPPT1). We here provide first evidence that: i) transplantation of wild type HSPCs exerts a partial but long-lasting mitigation of the symptoms; ii) transplantation of HSPCs over-expressing hPPT1 by lentiviral gene transfer enhances therapeutic benefit as compared to wild type cell transplant, with first demonstration of such a dose-effect benefit for a purely neurodegenerative condition like CLN1 disease; iii) transplantation of hPPT1 over-expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1 disease symptomatology in the absence of hematopoietic tissue engraftment of the transduced cells; and iv) the combinatorial transplantation of transduced HSPCs intravenously and ICV results in the most robust therapeutic benefit among the tested approaches on both pre-symptomatic as well as symptomatic animals. Overall, these findings provide first evidence of the efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application.

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Section: Safety Of Hppt1-lv Hspcs Transplantation In Ppt1 -/Micesupporting

confidence: 89%

“…This was further investigated by necropsy and histopathological assessments and the ICDs were generally not attributed to disease progression (Fig. S4B), but rather to conditioning related effects 26 .…”

Section: S2e)mentioning

confidence: 99%

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Peviani

Das

Patel

et al. 2022

Preprint

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“…However, in spite of low-intensity conditioning regimens which have been developed, there are still negative side effects of busulfan potentially at long term (i.e. organ toxicity, infertility and risk of secondary malignancy), therefore efforts to develop alternative, safer and more specific conditioning regimes have been made ( Chanut et al, 2021 ). The use of specific antibodies against antigens specifically expressed by HSPCs has been the main focus for novel approaches to ablate the resident HSPCs niche.…”

Section: Advances In Hspc Mobilization Culture and Patients Conditioningmentioning

confidence: 99%

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders

et al. 2023

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Lessons learned from decades-long practice in the transplantation of hematopoietic stem and progenitor cells (HSPCs) to treat severe inherited disorders or cancer, have set the stage for the current ex vivo gene therapies using autologous gene-modified hematopoietic stem and progenitor cells that have treated so far, hundreds of patients with monogenic disorders. With increased knowledge of hematopoietic stem and progenitor cell biology, improved modalities for patient conditioning and with the emergence of new gene editing technologies, a new era of hematopoietic stem and progenitor cell-based gene therapies is poised to emerge. Gene editing has the potential to restore physiological expression of a mutated gene, or to insert a functional gene in a precise locus with reduced off-target activity and toxicity. Advances in patient conditioning has reduced treatment toxicities and may improve the engraftment of gene-modified cells and specific progeny. Thanks to these improvements, new potential treatments of various blood- or immune disorders as well as other inherited diseases will continue to emerge. In the present review, the most recent advances in hematopoietic stem and progenitor cell gene editing will be reported, with a focus on how this approach could be a promising solution to treat non-blood-related inherited disorders and the mechanisms behind the therapeutic actions discussed.

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“…Busulfan therefore clears endogenous HSCs from the HSC niche so that space is made available for transplanted genetically modified HSCs to engraft, without any lymphoablation 120 . However, the use of such genotoxic conditioning is also associated with significant toxicities to patients including infertility, organ toxicity and risk of secondary malignancy, thus limiting the application of HSC gene therapy to only the most severe forms of genetic disease 121 . The negative side effects of genotoxic conditioning regimens have spurred significant investigation into alternative methods to facilitate the engraftment of transplanted HSCs into a patient.…”

Section: Immunity To Next-generation Therapiesmentioning

confidence: 99%

Immunological barriers to haematopoietic stem cell gene therapy

et al. 2022

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Cell and gene therapies using haematopoietic stem cells (HSCs) epitomize the transformative potential of regenerative medicine. Recent clinical successes for gene therapies involving autologous HSC transplantation (HSCT) demonstrate the potential of genetic engineering in this stem cell type for curing disease. With recent advances in CRISPR gene-editing technologies, methodologies for the ex vivo expansion of HSCs and non-genotoxic conditioning protocols, the range of clinical indications for HSC-based gene therapies is expected to significantly expand. However, substantial immunological challenges need to be overcome. These include pre-existing immunity to gene-therapy reagents, immune responses to neoantigens introduced into HSCs by genetic engineering, and unique challenges associated with next-generation and off-the-shelf HSC products. By synthesizing these factors in this Review, we hope to encourage more research to address the immunological issues associated with current and next-generation HSC-based gene therapies to help realize the full potential of this field.

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Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes

Cited by 11 publications

References 43 publications

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders

Immunological barriers to haematopoietic stem cell gene therapy

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