Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency

Calcedo, Roberto; Somanathan, Suryanarayan; Qin, Qiuyue; Betts, Michael R.; Rech, Andrew J.; Vonderheide, Robert H.; Mueller, Christian; Flotte, Terence R.; Wilson, James M.

doi:10.1073/pnas.1617726114

Cited by 51 publications

(47 citation statements)

References 27 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this trial, AAVmediated transfer of a mini-dystrophin transgene resulted in poor expression and was associated with the development of T cell responses directed against transgene epitopes or, possibly, in the recall of pre-existing anti-dystrophin T cells response. Similarly, decreased transgene expression and transgene-specific cytotoxic T cells were reported after intramuscular delivery of alpha-1 antitrypsin with rAAV vector in one subject (86), although most of the clinical trial participants achieved longterm expression of the transgene (87). In other clinical trials, the impact of immune response on the treatment outcomes was less clear.…”

Section: Immune Responses Against the Transgene Productmentioning

confidence: 84%

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

2020

View full text Add to dashboard Cite

Recombinant adeno-associated virus (rAAV) vectors are one of the most promising in vivo gene delivery tools. Several features make rAAV vectors an ideal platform for gene transfer. However, the high homology with the parental wild-type virus, which often infects humans, poses limitations in terms of immune responses associated with this vector platform. Both humoral and cell-mediated immunity to wild-type AAV have been documented in healthy donors, and, at least in the case of anti-AAV antibodies, have been shown to have a potentially high impact on the outcome of gene transfer. While several factors can contribute to the overall immunogenicity of rAAV vectors, vector design and the total vector dose appear to be responsible of immune-mediated toxicities. While preclinical models have been less than ideal in predicting the outcome of gene transfer in humans, the current preclinical body of evidence clearly demonstrates that rAAV vectors can trigger both innate and adaptive immune responses. Data gathered from clinical trials offers key learnings on the immunogenicity of AAV vectors, highlighting challenges as well as the potential strategies that could help unlock the full therapeutic potential of in vivo gene transfer.

show abstract

Section: Immune Responses Against the Transgene Productmentioning

confidence: 84%

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

2020

View full text Add to dashboard Cite

show abstract

“…As there is evidence showing that aggregated polymers are degraded by autophagy, interventions to enhance autophagic degradation of aggregation prone proteins are under investigation [17,23]. Gene therapy is a promising strategy to treat AATD [20,24], although approved approaches are currently unavailable [25,26].…”

Section: Discussionmentioning

confidence: 99%

A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Zhang

Pham

et al. 2019

Cells

View full text Add to dashboard Cite

Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4′,′5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis.

show abstract

“…88 Although only a few studies have monitored TCR repertoires in patients or mice treated with rAAV vectors, the robust T-cell response against an AAV transgene in one trial was shown to be associated with a biased TCRBV repertoire. 89 Therefore it was important to assess the repertoire diversity in our gene-corrected mice.…”

Section: Intrathymic Aav8-zap-70 Transduction Promotes Long-term Mainmentioning

confidence: 99%

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Pouzolles

Machado

Guilbaud

et al. 2020

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Background: Patients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes. Objective: We sought to determine the efficacy of intrathymic adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T-cell immunodeficiency in a zetaassociated protein of 70 kDa (ZAP-70)-deficient murine model. Methods: AAV serotypes were injected intrathymically into wild-type mice, and gene transfer efficiency was monitored. ZAP-70 2/2 mice were intrathymically injected with an AAV8 vector harboring the ZAP70 gene. Thymus structure, immunophenotyping, T-cell receptor clonotypes, T-cell function, immune responses to transgenes and autoantibodies, vector copy number, and integration were evaluated. Results: AAV8, AAV9, and AAV10 serotypes all transduced thymocyte subsets after in situ gene transfer, with transduction of up to 5% of cells. Intrathymic injection of an AAV8-ZAP-70 vector into ZAP-70 2/2 mice resulted in a rapid thymocyte differentiation associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T-cell subsets with diverse T-cell receptor clonotypes in the periphery. Although thymocyte reconstitution was transient, gene-corrected peripheral T cells harboring approximately 1 AAV genome per cell persisted for more than 40 weeks, and AAV vector integration was detected. Conclusions: Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function.

show abstract

Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency

Cited by 51 publications

References 27 publications

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Contact Info

Product

Resources

About