Challenges Posed by Immune Responses to AAV Vectors: Addressing Root Causes.
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ABSTRACT:
SUBMITTER: Hamilton BA
PROVIDER: S-EPMC8168460 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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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Project description:Alipogene tiparvovec (Glybera(®)) is an adeno-associated virus serotype 1 (AAV1)-based gene therapy that has been developed for the treatment of patients with lipoprotein lipase (LPL) deficiency. Alipogene tiparvovec contains the human LPL naturally occurring gene variant LPL(S447X) in a non-replicating viral vector based on AAV1. Such virus-derived vectors administered to humans elicit immune responses against the viral capsid protein and immune responses, especially cellular, mounted against the protein expressed from the administered gene have been linked to attenuated transgene expression and loss of efficacy. Therefore, a potential concern about the use of AAV-based vectors for gene therapy is that they may induce humoral and cellular immune responses in the recipient that may impact on efficacy and safety. In this paper, we review the current understanding of immune responses against AAV-based vectors and their impact on clinical efficacy and safety. In particular, the immunogenicity findings from the clinical development of alipogene tiparvovec up to licensing in Europe will be discussed demonstrating that systemic and local immune responses induced by intra-muscular injection of alipogene tiparvovec have no deleterious effects on clinical efficacy and safety. These findings show that muscle-directed AAV-based gene therapy remains a promising approach for the treatment of human diseases.
| S-EPMC3939780 | biostudies-literature
Project description:Over the past decade, vectors derived from adeno-associated virus (AAV) have established themselves as a powerful tool for in vivo gene transfer, allowing long-lasting and safe transgene expression in a variety of human tissues. Nevertheless, clinical trials demonstrated how B and T cell immune responses directed against the AAV capsid, likely arising after natural infection with wild-type AAV, might potentially impact gene transfer safety and efficacy in patients. Seroprevalence studies have evidenced that most individuals carry anti-AAV neutralizing antibodies that can inhibit recombinant AAV transduction of target cells following in vivo administration of vector particles. Likewise, liver- and muscle-directed clinical trials have shown that capsid-reactive memory CD8+ T cells could be reactivated and expanded upon presentation of capsid-derived antigens on transduced cells, potentially leading to loss of transgene expression and immune-mediated toxicities. In celebration of the 25th anniversary of the European Society of Gene and Cell Therapy, this review article summarizes progress made during the past decade in understanding and modulating AAV vector immunogenicity. While the knowledge generated has contributed to yield impressive clinical results, several important questions remain unanswered, making the study of immune responses to AAV a priority for the field of in vivo transfer.
| S-EPMC5649404 | biostudies-literature
Project description:In the last two decades, recombinant adeno-associated virus has emerged as the most popular gene therapy vector. Recently AAV gene therapy has been approved by the FDA for the treatment of two rare genetic disorders, namely the early childhood blindness disease Leber congenital amaurosis and spinal muscular atrophy (SMA). As is the case for the treatment of SMA, if the AAV vector must be administered systemically, very high vector doses are often required for therapeutic efficacy. But higher vector doses inevitably increase the risk of adverse events. The tragic death of three children in a clinical trial to treat X-linked myotubular myopathy with an AAV vector has thrown this limitation into sharp relief. Regardless of the precise cause(s) that led to the death of the two children, it is critical that we develop better AAV vectors to achieve therapeutic levels of expression with lower vector doses. To transduce successfully a target cell, AAV has to overcome both systemic as well as cellular roadblocks. In this review, we discuss some of the most prominent cellular roadblocks that AAV must get past to deliver successfully its therapeutic payload. We also highlight recent advancements in our knowledge of AAV biology that can potentially be harnessed to improve AAV vector performance and thereby make AAV gene therapy safer.
| S-EPMC8413391 | biostudies-literature
Project description:The field of gene therapy has made considerable progress over the past several years. Adeno-associated virus (AAV) vectors have emerged as promising and attractive tools for in vivo gene therapy. Despite the recent clinical successes achieved with recombinant AAVs (rAAVs) for therapeutics, host immune responses against the vector and transgene product have been observed in numerous preclinical and clinical studies. These outcomes have hampered the advancement of AAV gene therapies, preventing them from becoming fully viable and safe medicines. The human immune system is multidimensional and complex. Both the innate and adaptive arms of the immune system seem to play a concerted role in the response against rAAVs. While most efforts have been focused on the role of adaptive immunity and developing ways to overcome it, the innate immune system has also been found to have a critical function. Innate immunity not only mediates the initial response to the vector, but also primes the adaptive immune system to launch a more deleterious attack against the foreign vector. This Review highlights what is known about innate immune responses against rAAVs and discusses potential strategies to circumvent these pathways.
| S-EPMC7773343 | biostudies-literature
Project description:Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here we systemically evaluated the biological properties of three types of "empty" AAV particles: syngeneic pseudo-vectors with partial AAV genomes derived from DNA of the corresponding full particles, allogeneic pseudo-vectors with partial genomes different from the corresponding full particles, and null pseudo-vectors with no DNA inside the capsids. The syngeneic particles in excess increased the corresponding full AAV vector transgene expression both in vivo and in vitro. However, such effects were not observed with null or allogeneic particles. The observed differences among these pseudo-AAV particles may be ascribed to the syngeneic pseudo-vector DNA facilitating the complementary DNA synthesis of the corresponding full AAV particles. Our study suggests that the DNA content in the pseudo-vectors plays a key role in dictating their effects on AAV transduction. The effects of residual "empty" particles should be adequately assessed when comparing AAV vector performance. The syngeneic AAV pseudo-vectors may be used to enhance the efficacy of gene therapy.
| S-EPMC5363323 | biostudies-literature
Project description:Under intravenous delivery, recombinant adeno-associated vectors (rAAVs) interact with blood-borne components in ways that can critically alter their therapeutic efficiencies. We have previously shown that interaction with human galectin 3 binding protein dramatically reduces rAAV-6 efficacy, whereas binding of mouse C-reactive protein improves rAAV-1 and rAAV-6 transduction effectiveness. Herein we have assessed, through qualitative and quantitative studies, the proteins from mouse and human sera that bind with rAAV-8 and rAAV-9, two vectors that are being considered for clinical trials for patients with neuromuscular disorders. We show that, in contrast to rAAV-1 and rAAV-6, there was a substantial similarity in protein binding patterns between mouse and human sera for these vector serotypes. To establish an in vivo role for the vector binding of these sera proteins, we chose to study platelet factor 4 (PF4), which interacts with both vectors in both mouse and human sera. Experiments using PF4-knockout mice showed that a complete lack of PF4 did not alter skeletal muscle transduction for these vectors, whereas heart transduction was moderately improved. Our results strongly support our position that the impact of serum proteins on the transduction properties of rAAV-8 and rAAV-9, already observed in mouse models, should be similar in human preclinical trials.
| S-EPMC6111067 | biostudies-literature
Project description:Immune responses directed against viral capsid proteins constitute a main safety concern in the use of adeno-associated virus (AAV) as gene transfer vectors in humans. Pharmacological immunosuppression has been proposed as a solution to the problem; however, the approach suffers from several potential limitations. Using MHC class II epitopes initially identified within human IgG, named Tregitopes, we showed that it is possible to modulate CD8+ T cell responses to several viral antigens in vitro. We showed that incubation of peripheral blood mononuclear cells with these epitopes triggers proliferation of CD4+CD25+FoxP3+ T cells that suppress killing of target cells loaded with MHC class I antigens in an antigen-specific fashion, through a mechanism that seems to require cell-to-cell contact. Expression of a construct encoding for the AAV capsid structural protein fused to Tregitopes resulted in reduction of CD8+ T cell reactivity against the AAV capsid following immunization with an adenoviral vector expressing capsid. This was accompanied by an increase in frequency of CD4+CD25+FoxP3+ T cells in spleens and lower levels of inflammatory infiltrates in injected tissues. This proof-of-concept study demonstrates modulation of CD8+ T cell reactivity to an antigen using regulatory T cell epitopes is possible.
| S-EPMC3776637 | biostudies-other
Project description:BackgroundMajor infectious disease outbreaks are a constant threat to human health. Clinical research responses to outbreaks generate evidence to improve outcomes and outbreak control. Experiences from previous epidemics have identified multiple challenges to undertaking timely clinical research responses. This scoping review is a systematic appraisal of political, economic, administrative, regulatory, logistical, ethical and social (PEARLES) challenges to clinical research responses to emergency epidemics and solutions identified to address these.MethodsA scoping review. We searched six databases (MEDLINE, Embase, Global Health, PsycINFO, Scopus and Epistemonikos) for articles published from 2008 to July 2018. We included publications reporting PEARLES challenges to clinical research responses to emerging epidemics and pandemics and solutions identified to address these. Two reviewers screened articles for inclusion, extracted and analysed the data.ResultsOf 2678 articles screened, 76 were included. Most presented data relating to the 2014-2016 Ebola virus outbreak or the H1N1 outbreak in 2009. The articles related to clinical research responses in Africa (n = 37), Europe (n = 8), North America (n = 5), Latin America and the Caribbean (n = 3) and Asia (n = 1) and/or globally (n = 22). A wide range of solutions to PEARLES challenges was presented, including a need to strengthen global collaborations and coordination at all levels and develop pre-approved protocols and equitable frameworks, protocols and standards for emergencies. Clinical trial networks and expedited funding and approvals were some solutions implemented. National ownership and community engagement from the outset were a key enabler for delivery. Despite the wide range of recommended solutions, none had been formally evaluated.ConclusionsTo strengthen global preparedness and response to the COVID-19 pandemic and future epidemics, identified solutions for rapid clinical research deployment, delivery, and dissemination must be implemented. Improvements are urgently needed to strengthen collaborations, funding mechanisms, global and national research capacity and capability, targeting regions vulnerable to epidemics and pandemics. Solutions need to be flexible to allow timely adaptations to context, and research led by governments of affected regions. Research communities globally need to evaluate their activities and incorporate lessons learnt to refine and rehearse collaborative outbreak response plans in between epidemics.
| S-EPMC7315698 | biostudies-literature
Project description:One of the major goals of in vivo gene transfer is to achieve long-term expression of therapeutic transgenes in terminally differentiated cells. The extensive clinical experience and the recent approval of Luxturna® (Spark Therapeutics, now Roche) and Zolgensma® (AveXis, now Novartis) place vectors derived from adeno-associated viruses (AAV) among the best options for gene transfer in multiple tissues. Despite these successes, limitations remain to the application of this therapeutic modality in a wider population. AAV was originally identified as a promising virus to derive gene therapy vectors because, despite infecting humans, it was not associated with any evident disease. Thee large proportion of AAV infections in the human population is now revealing as a limitation because after exposure to wild-type AAV, anti-AAV antibodies develops and may neutralize the vectors derived from the virus. Injection of AAV in humans is generally well-tolerated although the immune system can activate after the recognition of AAV vectors capsid and genome. The formation of high-titer neutralizing antibodies to AAV after the first injection precludes vector re-administration. Thus, both pre-existing and post-treatment humoral responses to AAV vectors greatly limit a wider application of this gene transfer modality. Different methods were suggested to overcome this limitation. The extensive preclinical data available and the large clinical experience in the control of AAV vectors immunogenicity are key to clinical translation and to demonstrate the safety and efficacy of these methods and ultimately bring a curative treatment to patients.
| S-EPMC9022790 | biostudies-literature