Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

Humbert, Olivier; Chan, Frieda; Rajawat, Yogendra Singh; Torgerson, Troy R.; Burtner, Christopher R.; Hubbard, Nicholas; Humphrys, Daniel; Norgaard, Zachary K.; O’Donnell, Patricia; Adair, Jennifer E.; Trobridge, Grant D.; Scharenberg, Andrew M.; Felsburg, Peter J.; Rawlings, David J.; Kiem, Hans–Peter

doi:10.1182/bloodadvances.2018016451

Cited by 27 publications

(41 citation statements)

References 58 publications

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“…18 Preclinical studies have highlighted that reconstitution of functional B cells can be achieved if a preconditioning regimen is combined with gene therapy. 28,29 Our results show that busulfan facilitates durable engraftment of gene-corrected hematopoietic stem cells, allowing for long-term replenishment of all affected lymphocyte lineages in infants with newly diagnosed SCID-X1. 18,30 The use of pharmacokinetic-guided administration of busulfan ensured consistent drug exposure, which is especially critical in infants and young children -a patient population in which metabolism and clearance of busulfan vary considerably.…”

Section: Discussionmentioning

confidence: 72%

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

et al. 2019

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BACKGROUND Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS We performed a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four in-fants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, .)

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Section: Discussionmentioning

confidence: 72%

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

et al. 2019

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“…In regard to off target viral integrations, two such sites were recorded: one in the gut, another (potential) at the virus infusion site and none in the germ cells. An improved protocol was later implemented from the same group that included stem cell mobilization with G-CSF/AMD3100 prior to FV vector delivery and the substitution of the EF1a promoter with that of the pgk gene in the FV vector [59]. The data argue for the faster recovery of T cell numbers and a broad TcR repertoire, and are clinically relevant when considering the overall survival that climbed to 2.5 years as compared to 330 days in the previous study.…”

Section: Large Animal Preclinical Modelsmentioning

confidence: 98%

“…FV vectors have also been used for the genetic correction of the Wiskott-Aldrich syndrome (WAS) mouse model [58]. WAS is an X-linked disorder characterized by eczema, immunodeficiency, and micro-thrombocytopenia resulting in bleeding tendency [59]. Uchiyama et al, used a WAS cDNA under the control of two different promoters (an endogenous and an A2UOCE-derived 631 bp fragment) and demonstrated the correction of the WAS phenotypic disorders.…”

Section: Therapeutic Gene Transfer In Murine Preclinical Modelsmentioning

confidence: 99%

FV Vectors as Alternative Gene Vehicles for Gene Transfer in HSCs

Simantirakis

Tsironis

Vassilopoulos

2020

Viruses

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Hematopoietic Stem Cells (HSCs) are a unique population of cells, capable of reconstituting the blood system of an organism through orchestrated self-renewal and differentiation. They play a pivotal role in stem cell therapies, both autologous and allogeneic. In the field of gene and cell therapy, HSCs, genetically modified or otherwise, are used to alleviate or correct a genetic defect. In this concise review, we discuss the use of SFVpsc_huHSRV.13, formerly known as Prototype Foamy Viral (PFV or FV) vectors, as vehicles for gene delivery in HSCs. We present the properties of the FV vectors that make them ideal for HSC delivery vehicles, we review their record in HSC gene marking studies and their potential as therapeutic vectors for monogenic disorders in preclinical animal models. FVs are a safe and efficient tool for delivering genes in HSCs compared to other retroviral gene delivery systems. Novel technological advancements in their production and purification in closed systems, have allowed their production under cGMP compliant conditions. It may only be a matter of time before they find their way into the clinic.

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“…Transfer of therapeutic genes into long-term repopulating HSPCs can potentially cure blood disorders such as hemoglobinopathies and primary immunodeficiencies. Specifically, with regards to X-linked severe combined immunodeficiency (SCID-X1), recent data showed that this approach could be curative in animal models [7,8] together with very promising clinical results using gene therapy in SCID-X1 patients [1,9]. Despite these advances, gene therapy continues to face a number of challenges which, if not resolved, could be detrimental to the clinical translation of these approaches [4].…”

Section: Introductionmentioning

confidence: 99%

“…Since then, our laboratory has optimized parameters for efficient transduction of human and canine CD34+ HSPCs by FVVs [31][32][33]. In the last decade, our group has demonstrated efficacy of FVV in correction of monogenetic diseases of hematopoietic origin in large animal models (non-human primates and canine) and has established the safety of FVV in-vivo [7,8,34,35]. In these pre-clinical studies, FVV-mediated transgene delivery maintained high and persistent levels of marker-gene expression possibly due to improved transduction of quiescent cells and to the novel envelope/receptor system used for stem cell entry [7,8].…”

Section: Introductionmentioning

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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Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

Abstract: Key Points• IV delivery of FV vector using the phosphoglycerate kinase promoter outperforms EF1a-containing vector in the canine SCID-X1 model.• G-CSF/AMD3100 mobilization before in vivo FV vector delivery improves kinetics and clonal diversity of lymphocyte reconstitution.

Cited by 27 publications

References 58 publications

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

FV Vectors as Alternative Gene Vehicles for Gene Transfer in HSCs

In-Vivo Gene Therapy with Foamy Virus Vectors

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