Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity

Bartolo, Laurent; Tong, Stéphanie Li Chung; Chappert, Pascal; Urbain, Dominique; Colella, Pasqualina; Richard, Isabelle; Ronzitti, Giuseppe; Demengeot, Jocelyne; Gross, David-Alexandre; Mingozzi, Federico; Davoust, Jean

doi:10.1172/jci.insight.127008

Cited by 19 publications

(18 citation statements)

References 55 publications

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“…Exhaustion is specifically involved in the control of the immune response when the transgene is expressed in both muscle and liver, and blockade of PD-1 and LAG3 is required to break tolerance. These results are consistent with our recent work in which the ovalbumin model antigen was used to study liver-induced muscle tolerance, 46 and provide additional mechanistic insights on the role of effector T cell homing to the liver and subsequent expression of checkpoint markers for the control of transgene immunogenicity.…”

Section: Discussionsupporting

confidence: 91%

Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

Poupiot

Verdera

Hardet

et al. 2019

Molecular Therapy - Methods & Clinical Development

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The pro-tolerogenic environment of the liver makes this tissue an ideal target for gene replacement strategies. In other peripheral tissues such as the skeletal muscle, anti-transgene immune response can result in partial or complete clearance of the transduced fibers. Here, we characterized liver-induced transgene tolerance after simultaneous transduction of liver and muscle. A clinically relevant transgene, α-sarcoglycan, mutated in limb-girdle muscular dystrophy type 2D, was fused with the SIINFEKL epitope (hSGCA-SIIN) and expressed with adeno-associated virus vectors (AAV-hSGCA-SIIN). Intramuscular delivery of AAV-hSGCA-SIIN resulted in a strong inflammatory response, which could be prevented and reversed by concomitant liver expression of the same antigen. Regulatory T cells and upregulation of checkpoint inhibitor receptors were required to establish and maintain liver-mediated peripheral tolerance. This study identifies the fundamental role of the synergy between Tregs and upregulation of checkpoint inhibitor receptors in the liver-mediated control of anti-transgene immunity triggered by muscle-directed gene transfer.

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Section: Discussionsupporting

confidence: 91%

Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

Poupiot

Verdera

Hardet

et al. 2019

Molecular Therapy - Methods & Clinical Development

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“…What may be responsible for the absence of ADAs in 84-05 and the continued high level of production of the transgene product over this prolonged period? Factors that have been shown to influence whether, or not, ADAs are observed following AAV-mediated expression of a transgene product include the following: the particular sequence of the transgene product (69); whether the recipient is already making a similar or identical protein (39); the serotype of AAV used (38); and targeted delivery or targeted expression at particular sites or in particular tissues or cells (54,(70)(71)(72)(73)(74)(75)(76). AAV-delivered 5L7 antibody certainly has the potential to be immunogenic in rhesus monkeys since 50% of monkeys receiving it have had robust ADA responses (1).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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Long-term delivery of anti-HIV monoclonal antibodies using adeno-associated virus (AAV) holds promise for the prevention and treatment of HIV infection. We previously reported that after receiving a single administration of AAV vector coding for anti-SIV antibody 5L7, monkey 84-05 achieved high levels of AAV-delivered 5L7 IgG1 in vivo which conferred sterile protection against six successive, escalating dose, intravenous challenges with highly infectious, highly pathogenic SIVmac239, including a final challenge with 10 animal infectious doses (1). Here we report that monkey 84-05 has successfully maintained 240-350 µg/ml of anti-SIV antibody 5L7 for over 6 years. Approximately 2% of the circulating IgG in this monkey is this one monoclonal antibody. This monkey generated little or no anti-drug antibodies (ADA) to the AAV-delivered antibody for the duration of the study. Due to the nature of the high-dose challenge used and in order to rule out a potential low-level infection not detected by regular viral loads, we have used ultrasensitive techniques to detect cell-associated viral DNA and RNA in PBMCs from this animal. In addition, we have tested serum from 84-05 by ELISA against overlapping peptides spanning the whole envelope sequence for SIVmac239 (PepScan) and against recombinant p27 and gp41 proteins. No reactivity has been detected in the ELISAs indicating the absence of naturally arising anti-SIV antibodies; moreover, the ultrasensitive cell-associated viral tests yielded no positive reaction. We conclude that macaque 84-05 was effectively protected and remained uninfected. Our data show that durable, continuous antibody expression can be achieved after one single administration of AAV and support the potential for lifelong protection against HIV from a single vector administration.

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“…Several studies of gene transfer with rAAV in both small and large animals indicated that hepatocyterestricted transgene expression induced a robust, antigenspecific peripheral tolerance (60,92,93). In animal models, liver-induced immunological tolerance has been exploited to counteract deleterious immune responses induced by gene transfer targeting more immunogenic tissues, such as the muscle (89,94). The different antigen presenting cells (APCs) resident in the liver are involved in the tolerogenic effect after liver gene transfer.…”

Section: Immune Responses Against the Transgene Productmentioning

confidence: 99%

“…This, together with the secretion of the anti-inflammatory cytokine IL-10 (97-99) by Kupffer cells leads to poor T cell-activation. Antigen presentation through MHC class I expressed onto hepatocytes has been associated with incomplete CD8 + T cell activation and increased exhaustion and apoptosis (89,93,94,(100)(101)(102)(103). Liver sinusoidal endothelial cells (LSECs) can also act as professional APCs and promote tolerance through the induction of T regulatory cells (Tregs) (104,105).…”

Section: Immune Responses Against the Transgene Productmentioning

confidence: 99%

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

2020

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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.

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Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity

Cited by 19 publications

References 55 publications

Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

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

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