Gene therapy using haematopoietic stem and progenitor cells

Ferrari, Giuliana; Thrasher, Adrian J.; Aiuti, Alessandro

doi:10.1038/s41576-020-00298-5

Cited by 162 publications

(148 citation statements)

References 179 publications

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“…SCID usually present in the first year of life with severe opportunistic infections, failure to thrive and chronic diarrhea [78]. In the absence of therapy (specifically, hematopoietic stem cell transplantation (HSCT) [81], gene therapy (GT) [82] or enzyme replacement therapy [83]), patients with SCID usually die within the first years of life. The pre-symptomatic identification of infants with SCID through newborn screening has significantly improved the clinical management of these conditions [84].…”

Section: Immunodeficiencies Affecting Cellular and Humoral Immunitymentioning

confidence: 99%

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

Castagnoli

Pala

Bosticardo

et al. 2021

IJMS

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Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host’s innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.

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Section: Immunodeficiencies Affecting Cellular and Humoral Immunitymentioning

confidence: 99%

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

Castagnoli

Pala

Bosticardo

et al. 2021

IJMS

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“…Gene therapy (GT), the therapeutic delivery of a healthy copy of the mutated gene through viral vectors, has provided a successful cure for many hematopoietic diseases in the past decades ( Ferrari et al, 2021). Preclinical models of GT for TCIRG1 -dependent osteopetrosis have been developed during these years, demonstrating the efficacy and safety of this therapeutic approach as a valid alternative for patients lacking a compatible donor.…”

Section: Innovative Therapies For Aromentioning

confidence: 99%

Autosomal recessive osteopetrosis: mechanisms and treatments

Penna

Villa

Capo

2021

Disease Models &Amp; Mechanisms

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Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Clinical manifestations include dense and brittle bones, anemia and progressive nerve compression, which hamper the quality of patients' lives and cause death in the first 10 years of age. This Review describes the pathogenesis of ARO and highlights the strengths and weaknesses of the current standard of care, namely hematopoietic stem cell transplantation (HSCT). Despite an improvement in the overall survival and outcomes of HSCT, transplant-related morbidity and the pre-existence of neurological symptoms significantly limit the success of HSCT, while the availability of human leukocyte antigen (HLA)-matched donors still remains an open issue. Novel therapeutic approaches are needed for ARO patients, especially for those that cannot benefit from HSCT. Here, we review preclinical and proof-of-concept studies, such as gene therapy, systematic administration of deficient protein, in utero HSCT and gene editing.

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“…For other leukodystrophies, cell-based gene therapies may be extended to direct injection of genetically modified stem or progenitor cells in the future ( Osorio and Goldman, 2016 ). The potential of genome editing using Zinc – finger nucleases, transcription activator like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats (CRISPR) – Cas9 systems offers immense opportunity for targeted correction of disease-causing mutations ( Ferrari et al, 2020 ). Although pre-clinically gene-editing was successfully employed in HSC-GT, further safety and efficacy studies will be conducted ( Schiroli et al, 2017 ; Pavel-Dinu et al, 2019 ).…”

Section: Ex Vivo Gene Therapymentioning

confidence: 99%

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

Jonquières

Rae

Housley

2021

Front. Cell. Neurosci.

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Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type – specific expression pattern of the disease – causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.

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Gene therapy using haematopoietic stem and progenitor cells

Cited by 162 publications

References 179 publications

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

Gut Microbiota–Host Interactions in Inborn Errors of Immunity

Autosomal recessive osteopetrosis: mechanisms and treatments

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

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