Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease

Squeri, Giorgia; Passerini, Laura; Ferro, Francesca; Laudisa, Cecilia; Tomasoni, Daniela; Deodato, Federica; Gasperini, Serena; Aiuti, Alessandro; Bernardo, Maria Ester; Gentner, Bernhard; Naldini, Luigi; Annoni, Andrea; Biffi, Alessandra; Gregori, Silvia

doi:10.1016/j.ymthe.2019.04.014

Cited by 18 publications

(16 citation statements)

References 59 publications

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“…A potential concern with the older in life approach is the busulfan conditioning cell ablation regimen used as adults (irradiation was used for the neonate transplants as analogous conditioning). We did not observe any overt side effects with the busulfan conditioning, and as it is being used clinically for other disorders, our data demonstrate strong evidence for the use of this therapy to treat AS ( 52 ).…”

Section: Discussionsupporting

confidence: 59%

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Adhikari

Copping

Beegle

et al. 2021

Human Molecular Genetics

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Angelman Syndrome is a rare neurodevelopmental disorder characterized by impaired communication skills, ataxia, motor and balance deficits, intellectual disabilities, and seizures. The genetic cause of Angelman syndrome is the neuronal loss of UBE3A expression in the brain. A novel approach, described here, is a stem cell gene therapy which uses lentivector transduced hematopoietic stem and progenitor cells to deliver functional UBE3A to affected cells. We have demonstrated both the prevention and reversal of Angelman syndrome phenotypes upon transplantation and engraftment of human CD34+ cells transduced with a Ube3a lentivector in a novel immunodeficient Ube3amat−/pat+ IL2rg−/y mouse model of Angelman syndrome. A significant improvement in motor and cognitive behavioral assays as well as normalized delta power measured by EEG was observed in neonates and adults transplanted with the gene modified cells. Human hematopoietic profiles observed in the lymphoid organs by detection of human immune cells were normal. Expression of UBE3A was detected in the brains of the adult treatment group following immunohistochemical staining illustrating engraftment of the gene modified cells expressing UBE3A in the brain. As demonstrated with our data, this stem cell gene therapy approach offers a promising treatment strategy for Angelman syndrome, not requiring a critical treatment window.

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Section: Discussionsupporting

confidence: 59%

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Adhikari

Copping

Beegle

et al. 2021

Human Molecular Genetics

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“…A more complex immune response to ERT, including both humoral and T cells response, cannot be ruled out, as recently suggested by Squeri et al, who studied MPS I mice and found the activation of an innate response inducing anti-IDUA CD8+ T cells in concomitance with ERT [216].…”

Section: Immunogenicitymentioning

confidence: 90%

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Parini

Deodato

2020

IJMS

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The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

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“… 134 , 135 Moreover, a recent study has shown that enzyme replacement therapy for treatment of lysosomal storage disorders (LSDs) may induce CD8 + T cells that can target LV HSC gene therapy. 136 , 137 Therefore, ex vivo gene therapy for LSDs in patients with prior protein therapy may require adjunct immunotherapy. Others are using ex vivo HSC gene transfer with LV vectors to target transgene expression to megakaryocytes for protein delivery via platelets.…”

Section: Main Textmentioning

confidence: 99%

Immune Responses to Viral Gene Therapy Vectors

et al. 2020

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Several viral vector-based gene therapy drugs have now received marketing approval. A much larger number of additional viral vectors are in various stages of clinical trials for the treatment of genetic and acquired diseases, with many more in pre-clinical testing. Efficiency of gene transfer and ability to provide long-term therapy make these vector systems very attractive. In fact, viral vector gene therapy has been able to treat or even cure diseases for which there had been no or only suboptimal treatments. However, innate and adaptive immune responses to these vectors and their transgene products constitute substantial hurdles to clinical development and wider use in patients. This review provides an overview of the type of immune responses that have been documented in animal models and in humans who received gene transfer with one of three widely tested vector systems, namely adenoviral, lentiviral, or adeno-associated viral vectors. Particular emphasis is given to mechanisms leading to immune responses, efforts to reduce vector immunogenicity, and potential solutions to the problems. At the same time, we point out gaps in our knowledge that should to be filled and problems that need to be addressed going forward.

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Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease

Cited by 18 publications

References 59 publications

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Immune Responses to Viral Gene Therapy Vectors

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