Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation

Capo, Valentina; Castiello, Maria Carmina; Fontana, Elena; Penna, Sara; Bosticardo, Marita; Drăghici, Elena; Poliani, Luigi P.; Sergi, Lucia Sergi; Rigoni, Rosita; Cassani, Barbara; Zanussi, Monica; Carrera, Paola; Uva, Paolo; Dobbs, Kerry; Sacchetti, Nicolò; Notarangelo, Luigi D.; Til, Niek P. van; Wagemaker, Gerard; Villa, Anna

doi:10.1016/j.jaci.2017.11.015

Cited by 29 publications

(29 citation statements)

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“…Finally, gene therapy‐treated mice produced specific antibodies to T‐dependent and T‐independent antigens. This improvement of immune function was accompanied by normalization of autoantibody production and mitigation of immune infiltrates in the skin . Overall, these data suggest that gene therapy for RAG2 deficiency may be feasible also for patients carrying hypomorphic RAG2 mutations associated with autoimmune and inflammatory manifestations.…”

Section: Treatment Of Rag Deficiency: From Hematopoietic Cell Transplmentioning

confidence: 66%

“…Cellular infiltrates are often seen also in other organs of these mutant mice, including the gut, liver, and lung . Despite the severe B‐cell lymphopenia, high‐affinity antibodies directed against self‐antigens are present in the serum of Rag2 R229Q/R229Q mutant mice, reflecting important immune dysregulation and contributing to tissue organ damage …”

Section: Mouse Models Of Null and Hypomorphic Rag Mutationsmentioning

confidence: 99%

“…In the periphery, polyclonality of the T‐cell repertoire, normalization of T‐cell subsets and of immunoglobulin levels, and production of antibodies to T‐dependent and T‐independent antigens were detected. Based on these results, we have recently tested the UCOE‐RAG2co lentiviral vector in the Rag2 R229Q mouse model of OS, where selective advantage for gene‐transduced cells is expected to be less prominent because of the presence of residual presence of endogenous T and B cells . As compared to Rag2 R229Q mice who had received Rag2 R229Q bone marrow cells, gene therapy‐treated mice showed a significant improvement of T‐ and B‐cell counts, although these remained lower than what observed in Rag2 R229Q mice transplanted with wildtype bone marrow cells.…”

Section: Treatment Of Rag Deficiency: From Hematopoietic Cell Transplmentioning

confidence: 99%

“…45 ing to tissue organ damage. 88,98 At the same time when we described Rag2 R229Q/R229Q mice, the Marrack laboratory reported a spontaneous mouse mutant (named mutant mouse, MM), carrying a homozygous point mutation (R972Q) in the Rag1 gene. 99 Compound heterozygosity for the equivalent mutation (R975Q) in human RAG1, in association with the R396L mutation, had been previously reported by our group in another patient with OS.…”

Section: Mous E Model S Of N Ull and Hyp Omorphic R Ag M Utati O N Smentioning

confidence: 99%

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RAG gene defects at the verge of immunodeficiency and immune dysregulation

Villa

Notarangelo

2018

Immunological Reviews

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Summary Mutations of the Recombinase Activating Genes (RAG) in humans underlie a broad spectrum of clinical and immunological phenotypes that reflect different degrees of impairment of T and B cell development and alterations of mechanisms of central and peripheral tolerance. Recent studies have shown that this phenotypic heterogeneity correlates, albeit imperfectly, with different levels of recombination activity of the mutant RAG proteins. Furthermore, studies in patients and in newly developed animal models carrying hypomorphic RAG mutations have disclosed various mechanisms underlying immune dysregulation in this condition. Careful annotation of clinical outcome and immune reconstitution in RAG-deficient patients who have received hematopoietic stem cell transplantation has shown that progress has been made in the treatment of this disease, but new approaches remain to be tested to improve stem cell engraftment and durable immune reconstitution. Finally, initial attempts have been made to treat RAG deficiency with gene therapy.

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Section: Treatment Of Rag Deficiency: From Hematopoietic Cell Transplmentioning

confidence: 66%

Section: Mouse Models Of Null and Hypomorphic Rag Mutationsmentioning

confidence: 99%

Section: Treatment Of Rag Deficiency: From Hematopoietic Cell Transplmentioning

confidence: 99%

Section: Mous E Model S Of N Ull and Hyp Omorphic R Ag M Utati O N Smentioning

confidence: 99%

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RAG gene defects at the verge of immunodeficiency and immune dysregulation

Villa

Notarangelo

2018

Immunological Reviews

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“…The efficient gene therapy depends on the ability to efficiently deliver the appropriate therapeutic materials into the target tissues or cells . Currently, viral vectors including retroviruses, adenoviruses and lentiviruses as delivery system have been widely used in gene therapy . However, viral vectors have limited their clinical applications for safety concern such as oncogenic potentials, immuno‐recognition of the viral capsid proteins and generation of various immune responses in vivo .…”

Section: Introductionmentioning

confidence: 99%

H1/pAIM2 nanoparticles exert anti‐tumour effects that is associated with the inflammasome activation in renal carcinoma

Chai

Liu

et al. 2018

J Cellular Molecular Medi

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Renal cell carcinoma (RCC) is a high metastasis tumour with less effective treatment available currently. Absent in melanoma 2 (AIM2) as a tumour suppressor might be used as a potential therapeutic target for RCC treatment. Here, we found that AIM2 expression was significantly decreased in RCC patient specimens and renal carcinoma cell lines (786‐O and OSRC‐2). To establish a safe and effective AIM2 gene delivery system, we formed the nanoparticles consisting of a folate grafted PEI600‐CyD (H1) nanoparticle‐mediated AIM2 gene (H1/pAIM2) as an effective delivery agent. Delivery of H1/pAIM2 in renal carcinoma cells could remarkably increase the expression of AIM2, and subsequently decrease cell proliferation, migration, and invasion as well as enhance cell apoptosis. In order to evaluate the therapeutic efficacy of AIM2 in vivo, H1/pAIM2 nanoparticles were injected intratumorally into 786‐O‐xenograft mice. Administration of H1/pAIM2 nanoparticles could inhibit the tumour growth as evidenced by reduced tumour volume and weight. Furthermore, Blockade of inflammasome activation triggered by H1/pAIM2 nanoparticles using inflammasome inhibitor YVAD‐CMK abrogated the anti‐tumoral activities of H1/AIM2. These results indicated the therapeutic effect of H1/pAIM2 nanoparticles was mainly attributable to its capability to enhance the inflammasome activation. H1/AIM2 nanoparticles might act as an efficient therapeutic approach for RCC treatment.

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RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

2021

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The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T − B − SCID) and susceptibility to life-threatening, early-onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.

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Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation

Abstract: Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment.

Cited by 29 publications

References 58 publications

RAG gene defects at the verge of immunodeficiency and immune dysregulation

RAG gene defects at the verge of immunodeficiency and immune dysregulation

H1/pAIM2 nanoparticles exert anti‐tumour effects that is associated with the inflammasome activation in renal carcinoma

RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

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