Autologous Stem-Cell-Based Gene Therapy for Inherited Disorders: State of the Art and Perspectives

Staal, Frank J. T.; Aiuti, Alessandro; Cavazzana, Marina

doi:10.3389/fped.2019.00443

Cited by 64 publications

(57 citation statements)

References 71 publications

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“…We generated a self-inactivating LV with a pCCL backbone, which has been widely used in gene therapy clinical trials, 25 , 26 as a therapeutic vehicle for the expression of a native form of hGAA in HSPCs and compared the GAA expression under the control of the EFS-1α promoter in the presence or absence of the human β-globin LCR enhancer, as previously described 43 ( Figure 1 A; LV.LCR-EFS.GAA and LV.EFS.GAA, respectively). The presence of the LCR enhancer led to a 3-fold increase of GAA expression, measured by intracellular enzymatic activity, in K562 cells and a 6-fold increase in MEL cells, when differentiated into more mature erythroid cells in the presence of DMSO ( Figures 1 B and 1C, respectively).…”

Section: Resultsmentioning

confidence: 99%

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Piras

Montiel-Equihua

Chan

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease.

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Section: Resultsmentioning

confidence: 99%

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Piras

Montiel-Equihua

Chan

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Although HSCs can be used for the treatment of hematological disorders [66,67], the bone marrow biopsy is an invasive procedure with chronic graftversus-host diseases (GVHD), morbidity, and mortality in patients who received allogeneic HSC therapy [68,69]. Autologous HSCs are an alternative option with a lower mortality rate, though in some cases, genetic correction is necessary before autologous HSCs transplantation [70][71][72]. However, in vitro expansion of HSCs is one of the main hurdles of autologous HSCs [73,74].…”

Section: In Vitro Culture Of Human Ipsc-derived Rbcsmentioning

confidence: 99%

Differentiation of human induced pluripotent stem cells into erythroid cells

et al. 2020

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During the last years, several strategies have been made to obtain mature erythrocytes or red blood cells (RBC) from the bone marrow or umbilical cord blood (UCB). However, UCB-derived hematopoietic stem cells (HSC) are a limited source and in vitro large-scale expansion of RBC from HSC remains problematic. One promising alternative can be human pluripotent stem cells (PSCs) that provide an unlimited source of cells. Human PSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are self-renewing progenitors that can be differentiated to lineages of ectoderm, mesoderm, and endoderm. Several previous studies have revealed that human ESCs can differentiate into functional oxygen-carrying erythrocytes; however, the ex vivo expansion of human ESC-derived RBC is subjected to ethical concerns. Human iPSCs can be a suitable therapeutic choice for the in vitro/ex vivo manufacture of RBCs. Reprogramming of human somatic cells through the ectopic expression of the transcription factors (OCT4, SOX2, KLF4, c-MYC, LIN28, and NANOG) has provided a new avenue for disease modeling and regenerative medicine. Various techniques have been developed to generate enucleated RBCs from human iPSCs. The in vitro production of human iPSC-derived RBCs can be an alternative treatment option for patients with blood disorders. In this review, we focused on the generation of human iPSC-derived erythrocytes to present an overview of the current status and applications of this field.

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“…Communication between researchers, industrial representatives, and regulators is key to learn and grow together in this new field, adapting as the therapy evolves to design solid guidelines for the standard implementation of gene therapy as a medicinal treatment. Although the focus of this review has been on autologous HSC-based gene therapy for immune deficiencies, similar approaches are being used successfully for red blood cell disorders (such as thalassemia) and a wide range of metabolic disorders affecting brain, liver, and muscle (reviewed by Staal, Aiuti and Cavazzana [ 186 ]). In all these diseases, a long path of development ( Figure 2 ), starting with suitable vectors and disease-specific mouse models, was required to reach clinical implementation.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

et al. 2020

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Recent clinical trials using patient’s own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott–Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles).

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Autologous Stem-Cell-Based Gene Therapy for Inherited Disorders: State of the Art and Perspectives

Cited by 64 publications

References 71 publications

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease

Differentiation of human induced pluripotent stem cells into erythroid cells

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

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