Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Rintz, Estera; Higuchi, Takashi; Kobayashi, Hiroshi; Galileo, Deni S.; Węgrzyn, Grzegorz; Tomatsu, Shunji

doi:10.1016/j.omtm.2021.11.007

Cited by 9 publications

(3 citation statements)

References 127 publications

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“…TCRγ5 chain with or without EH mutation and TCRδ1 chain were separated by a P2A ribosome-skipping site (ATNFSLLKQAGDVEENPGP) and cloned into the lentiCRISPR v2 vector 72 with a spleen focus-forming virus (SFFV) promoter 73 and a mGreenLantern 74 at the C terminus. TCRγ9 chain and TCRδ2 chain were cloned using the same strategy.…”

Section: Methodsmentioning

confidence: 99%

Structures of human γδ T cell receptor–CD3 complex

Xin,

Huang,

Chi

et al. 2024

Nature

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Gamma delta (γδ) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology1–3. The γδ T cell receptor (TCR), which is generated by γδ T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex2. The γδ TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy4. Here we report the structures of two prototypical human Vγ9Vδ2 and Vγ5Vδ1 TCR–CD3 complexes5,6, revealing two distinct assembly mechanisms that depend on Vγ usage. The Vγ9Vδ2 TCR–CD3 complex is monomeric, with considerable conformational flexibility in the TCRγ–TCRδ extracellular domain and connecting peptides. The length of the connecting peptides regulates the ligand association and T cell activation. A cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signalling. The Vγ5Vδ1 TCR–CD3 complex displays a dimeric architecture, whereby two protomers nestle back to back through the Vγ5 domains of the TCR extracellular domains. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the Vγ5Vδ1 TCR is essential for T cell activation. These findings reveal organizing principles of the γδ TCR–CD3 complex, providing insights into the unique properties of γδ TCR and facilitating immunotherapeutic interventions.

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Section: Methodsmentioning

confidence: 99%

Structures of human γδ T cell receptor–CD3 complex

Xin,

Huang,

Chi

et al. 2024

Nature

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“…In the field of MPS research, the first report using retroviral vectors was published in 1992, in which full-length human α-L-iduronidase (IDUA) cDNA was successfully administered to MPS I skin fibroblasts in vitro, ameliorating the intracellular accumulation of glycosaminoglycans observed by scintillation counting [310]. The expression level of IDUA differed among three promoters [310], suggesting the importance of the promoter, which is also of current interest in gene therapy [311]. Following in vivo animal experiments, in 2018, the first clinical trial of ex vivo LV gene therapy for MPS patients began, targeting hematopoietic stem cells from eight MPS I patients who could not find suitable donors for allogeneic HSCT (ClinicalTrials.gov identifier: NCT03488394, phase 1/2) [312], followed by the second one for MPS IIIA patients (ClinicalTrials.gov identifier: NCT04201405, phase 1/2).…”

Section: Retroviral Vectors Including Lentiviral Vectormentioning

confidence: 99%

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Ago,

Rintz,

Musini

et al. 2024

IJMS

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Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood–brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.

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“…Third-generation vectors lack accessory genes and part of the native U3 promoter. Apart from these advances, gene therapy researchers investigate more adequate promoters, modifiers, and the 3′-UTR region that may enhance the stability of the transcript [ 29 ]. Despite the possibility of multiple applications, LV-mediated gene therapy is mostly used for autologous transplantation.…”

Section: Treatment Strategiesmentioning

confidence: 99%

Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

Mashima

Nakanishi²

2022

IJMS

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Sulfatases are enzymes that catalyze the removal of sulfate from biological substances, an essential process for the homeostasis of the body. They are commonly activated by the unusual amino acid formylglycine, which is formed from cysteine at the catalytic center, mediated by a formylglycine-generating enzyme as a post-translational modification. Sulfatases are expressed in various cellular compartments such as the lysosome, the endoplasmic reticulum, and the Golgi apparatus. The substrates of mammalian sulfatases are sulfolipids, glycosaminoglycans, and steroid hormones. These enzymes maintain neuronal function in both the central and the peripheral nervous system, chondrogenesis and cartilage in the connective tissue, detoxification from xenobiotics and pharmacological compounds in the liver, steroid hormone inactivation in the placenta, and the proper regulation of skin humidification. Human sulfatases comprise 17 genes, 10 of which are involved in congenital disorders, including lysosomal storage disorders, while the function of the remaining seven is still unclear. As for the genes responsible for pathogenesis, therapeutic strategies have been developed. Enzyme replacement therapy with recombinant enzyme agents and gene therapy with therapeutic transgenes delivered by viral vectors are administered to patients. In this review, the biochemical substrates, disease manifestation, and therapy for sulfatases are summarized.

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Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Cited by 9 publications

References 127 publications

Structures of human γδ T cell receptor–CD3 complex

Structures of human γδ T cell receptor–CD3 complex

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

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