scholarly journals Immunomodulation in Administration of rAAV: Preclinical and Clinical Adjuvant Pharmacotherapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Wing Sum Chu ◽  
Joanne Ng
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Neutralizing Antibodies ◽  
Normal Population ◽  
Clinical Stage ◽  
Adaptive Immune Response ◽  
The United States ◽  
Cross Reactivity ◽  
Target Cells ◽  
Enveloped Virus

Recombinant adeno-associated virus (rAAV) has attracted a significant research focus for delivering genetic therapies to target cells. This non-enveloped virus has been trialed in many clinical-stage therapeutic strategies but important obstacle in clinical translation is the activation of both innate and adaptive immune response to the protein capsid, vector genome and transgene product. In addition, the normal population has pre-existing neutralizing antibodies against wild-type AAV, and cross-reactivity is observed between different rAAV serotypes. While extent of response can be influenced by dosing, administration route and target organ(s), these pose concerns over reduction or complete loss of efficacy, options for re-administration, and other unwanted immunological sequalae such as local tissue damage. To reduce said immunological risks, patients are excluded if they harbor anti-AAV antibodies or have received gene therapy previously. Studies have incorporated immunomodulating or suppressive regimens to block cellular and humoral immune responses such as systemic corticosteroids pre- and post-administration of Luxturna® and Zolgensma®, the two rAAV products with licensed regulatory approval in Europe and the United States. In this review, we will introduce the current pharmacological strategies to immunosuppress or immunomodulate the host immune response to rAAV gene therapy.

scholarly journals Mapping an Adeno-associated Virus 9-Specific Neutralizing Epitope To Develop Next-Generation Gene Delivery Vectors

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
April R. Giles ◽  
Lakshmanan Govindasamy ◽  
Suryanarayan Somanathan ◽  
James M. Wilson
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Neutralizing Antibodies ◽  
Viral Vector ◽  
The United States ◽  
Single Amino Acid ◽  
Fold Axis ◽  
Next Generation ◽  
Adeno Associated Virus ◽  
Neutralizing Epitopes

ABSTRACTRecent clinical trials have demonstrated the potential of adeno-associated virus (AAV)-based vectors for treating rare diseases. However, significant barriers remain for the translation of these vectors into widely available therapies. In particular, exposure to the AAV capsid can generate an immune response of neutralizing antibodies. One approach to overcome this response is to map the AAV-specific neutralizing epitopes and rationally design an AAV capsid able to evade neutralization. To accomplish this, we isolated a monoclonal antibody against AAV9 following immunization of BALB/c mice and hybridoma screening. This antibody, PAV9.1, is specific for intact AAV9 capsids and has a high neutralizing titer of >1:160,000. We used cryo-electron microscopy to reconstruct PAV9.1 in complex with AAV9. We then mapped its epitope to the 3-fold axis of symmetry on the capsid, specifically to residues 496-NNN-498 and 588-QAQAQT-592. Capsid mutagenesis demonstrated that even a single amino acid substitution within this epitope markedly reduced binding and neutralization by PAV9.1. In addition,in vivostudies showed that mutations in the PAV9.1 epitope conferred a “liver-detargeting” phenotype to the mutant vectors, unlike AAV9, indicating that the residues involved in PAV9.1 interactions are also responsible for AAV9 tropism. However, we observed minimal changes in binding and neutralizing titer when we tested these mutant vectors for evasion of polyclonal sera from mice, macaques, or humans previously exposed to AAV. Taken together, these studies demonstrate the complexity of incorporating mapped neutralizing epitopes and previously identified functional motifs into the design of novel capsids able to evade immune response.IMPORTANCEGene therapy utilizing viral vectors has experienced recent success, culminating in U.S. Food and Drug Administration approval of the first adeno-associated virus vector gene therapy product in the United States: Luxturna for inherited retinal dystrophy. However, application of this approach to other tissues faces significant barriers. One challenge is the immune response to viral infection or vector administration, precluding patients from receiving an initial or readministered dose of vector, respectively. Here, we mapped the epitope of a novel neutralizing antibody generated in response to this viral vector to design a next-generation capsid to evade immune responses. Epitope-based mutations in the capsid interfered with the binding and neutralizing ability of the antibody but not when tested against polyclonal samples from various sources. Our results suggest that targeted mutation of a greater breadth of neutralizing epitopes will be required to evade the repertoire of neutralizing antibodies responsible for blocking viral vector transduction.

Adaptive Immune Response to Mycobacterium abscessus Complex and Cross-Reactivity of BCG Vaccination

2021 ◽  
Author(s):  
Renan Marrichi Mauch ◽  
Peter Østrup Jensen ◽  
Tavs Qvist ◽  
Mette Kolpen ◽  
Claus Moser ◽  
...  
Keyword(s):  
Immune Response ◽  
Adaptive Immune Response ◽  
Cross Reactivity ◽  
Mycobacterium Abscessus ◽  
Bcg Vaccination ◽  
Adaptive Immune

Potential strategies for cancer gene therapy

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Clinical Stage ◽  
Genetic Material ◽  
Direct Methods ◽  
Cancer Gene Therapy ◽  
Target Cells ◽  
Target Tissue ◽  
Cancer Gene ◽  
P Gene

Gene therapy involves transferring genetic material (DNA or RNA) to repair, regulate or replace genes to cure a disease. One of the most crucial barriers is successful delivery of the targeted gene into the target tissue. Various vector-based approaches have been developed to deliver the transgene to the target cells. In different cancers, numerous of these vectors are being developed for purposes such as immunotherapy, suicide gene therapy, microRNA (miRNA) focused treatment, oncogene silencing, and gene editing using CRISPR/Cas9. This article reviews several alternatives to cancer gene therapy, as well as their preclinical and clinical outcomes, possible limitations, and overall therapy effects. Ways of delivering cancer gene therapy include direct methods for introducing genetic material. Nonviral vectors are easy to manufacture and may be chemically modified to increase their usefulness. Cationic polymers such as Poly-L-Lysine (PLL) and Polyethylenimine (PEI-SS) are the most extensively used polycationic polymers for gene transfer, particularly in vitro. Many RNAi-based therapeutic approaches are approaching the clinical stage, and nanocarriers are likely to play a crucial role in treating specific cancers. In the previous decade, non-viral approaches were used in more than 17 percent of all gene therapy trials. The message is that this is a safe and effective technique for transferring genes to cancer patients who need it to be a safe, successful therapy. Exosomes were developed to carry oncogene-specific short interfering RNA. Sushrut and colleagues revealed that exosomes provide superior carriers of short RNA and prevent tumor growth than liposomes. Inhalation-based gene therapy (aerosol-mediated gene delivery) has gained pace as a feasible treatment approach, especially for lung cancer. Because the intended transgene is steered to specific cells/tissues, this should further increase therapeutic efficiency.

scholarly journals SARS-CoV-2 Serology Status Detected by Commercialized Platforms Distinguishes Previous Infection and Vaccination Adaptive Immune Responses

2021 ◽  
Author(s):  
Raymond T. Suhandynata ◽  
Nicholas J. Bevins ◽  
Jenny T. Tran ◽  
Deli Huang ◽  
Melissa A. Hoffman ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Adaptive Immune Response ◽  
Antibody Assay ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Previous Infection ◽  
A Cell

AbstractBackgroundThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 110 million individuals and led to 2.5 million deaths worldwide. As more individuals are vaccinated, the clinical performance and utility of SARS-CoV-2 serology platforms needs to be evaluated.MethodsThe ability of four commercial SARS-CoV-2 serology platforms to detect previous infection or vaccination were evaluated using a cohort of 53 SARS-CoV-2 PCR-positive patients, 89 SARS-CoV-2-vaccinated healthcare workers (Pfizer or Moderna), and 127 SARS-CoV-2 negative patients. Serology results were compared to a cell based SARS-CoV-2 pseudovirus (PSV) neutralizing antibodies assay.ResultsThe Roche S-(spike) antibody and Diazyme neutralizing antibodies (NAbs) assays detected adaptive immune response in 100.0% and 90.1% of vaccinated individuals who received two-doses of vaccine (initial and booster), respectively. The Roche N-(nucleocapsid) antibody assay and Diazyme IgG assay did not detect adaptive immune response in vaccinated individuals. The Diazyme Nabs assay correlated with the PSV SARS-CoV-2 ID50 neutralization titers (R2= 0.70), while correlation of the Roche S-antibody assay was weaker (R2= 0.39). Median PSV SARS-CoV-2 ID50 titers more than doubled in vaccinated individuals who received two-doses of the Moderna vaccine (ID50: 597) compared to individuals that received a single dose (ID50: 284).ConclusionsThe Roche S-antibody and Diazyme NAbs assays robustly detected adaptive immune responses in SARS-CoV-2 vaccinated individuals and SARS-CoV-2 infected individuals. The Diazyme NAbs assay strongly correlates with the PSV SARS-CoV-2 NAbs in vaccinated individuals. Understanding the reactivity of commercially available serology platforms is important when distinguishing vaccination response versus natural infection.SummaryThe Roche S (spike protein)-antibody and Diazyme neutralizing-antibodies (NAbs) assays were evaluated for their clinical utility in the detection of SARS-CoV-2 related adaptive immune responses by testing SARS-CoV-2 PCR-confirmed patients, SARS-CoV-2-vaccinated individuals, and SARS-CoV-2-negative individuals. Commercial serology results were compared to results generated using a cell-based SARS-CoV-2 pseudovirus (PSV) NAbs assay and previously validated SARS-CoV-2 commercial serology assays (Roche N (nucleocapsid protein) antibody and Diazyme IgG). We demonstrate that the Roche S-antibody and Diazyme NAbs assays detected adaptive immune response in SARS-CoV-2 vaccinated individuals and the presence of SARS-CoV-2 PSV NAbs. The Roche S-antibody assay had an observed positive percent agreement (PPA) of 100% for individuals who received two doses of the Pfizer or Moderna vaccine. By contrast, the Roche N assay and Diazyme IgG assay did not detect vaccine adaptive immune responses. Our findings also indicate that the Diazyme NAbs assay correlates strongly with the levels of SARS-CoV-2 ID50 neutralization titers using the PSV Nab assay in vaccinated individuals.

scholarly journals Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host

2017 ◽  
Vol 413 ◽  
pp. 34-49 ◽  
Author(s):  
Ada W.C. Yan ◽  
Pengxing Cao ◽  
Jane M. Heffernan ◽  
Jodie McVernon ◽  
Kylie M. Quinn ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Infection ◽  
Adaptive Immune Response ◽  
Cross Reactivity ◽  
Adaptive Immune

scholarly journals MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (16) ◽  
pp. 7098-7108 ◽  
Author(s):  
Jincun Zhao ◽  
Rahul Vijay ◽  
Jingxian Zhao ◽  
Michael Gale ◽  
Michael S. Diamond ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
West Nile Virus ◽  
Hematopoietic Cells ◽  
The United States ◽  
Innate Immune ◽  
Target Cells ◽  
West Nile ◽  
Adaptor Molecule ◽  
The Brain

ABSTRACTWest Nile virus (WNV) is the most important cause of epidemic encephalitis in North America. Innate immune responses, which are critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors, RIG-I and MDA5, and their downstream adaptor molecule, MAVS. Here, we show that a deficiency of MAVS in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. InMavs−/−mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus-specific T cells into the infected brain. These T cells were polyfunctional and lysed peptide-pulsed target cellsin vitro. However, virus-specific T cells in the brains of infectedMavs−/−mice exhibited lower functional avidity than those in wild-type animals, and even virus-specific memory T cells generated by prior immunization could not protectMavs−/−mice from WNV-induced lethal disease. Concomitant with ineffective virus clearance, macrophage numbers were increased in theMavs−/−brain, and both macrophages and microglia exhibited an activated phenotype. Microarray analyses of leukocytes in the infectedMavs−/−brain showed a preferential expression of genes associated with activation and inflammation. Together, these results demonstrate a critical role for MAVS in hematopoietic cells in augmenting the kinetics of WNV clearance and thereby preventing a dysregulated and pathogenic immune response.IMPORTANCEWest Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA-sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and overexuberant production of proinflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain.

scholarly journals Postnatal gene therapy for neuromuscular diseases – opportunities and limitations

2021 ◽  
Vol 49 (8) ◽  
pp. 1011-1015
Author(s):  
Janbernd Kirschner
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Neuromuscular Diseases ◽  
Target Cells ◽  
Current Development ◽  
Development Status ◽  
Inherited Diseases ◽  
Gene Therapies ◽  
Future Developments ◽  
Disease Specific

Abstract During the last decade a number of innovative treatments including gene therapies have been approved for the treatment of monogenic inherited diseases. For some neuromuscular diseases these approaches have dramatically changed the course of the disease. For others relevant challenges still remain and require disease specific approaches to overcome difficulties related to the immune response and the efficient transduction of target cells. This review provides an overview of the current development status of mutation specific treatments for neuromuscular diseases and concludes with on outlook on future developments and perspectives.

scholarly journals IMMUNOLOGICAL REACTIONS OF THE COXSACKIE VIRUSES

1950 ◽  
Vol 92 (5) ◽  
pp. 463-482 ◽  
Author(s):  
Joseph L. Melnick ◽  
Nada Ledinko
Keyword(s):  
North Carolina ◽  
Neutralizing Antibodies ◽  
Neutralization Test ◽  
Normal Population ◽  
Standard Procedure ◽  
Neutralizing Antibody ◽  
The United States ◽  
Immune Serum ◽  
Newborn Mice ◽  
Immunological Reactions

The neutralization test is a reliable and useful procedure for following immunological reactions of the Coxsackie viruses (C virus). The standard procedure has been an incubation period of 1 hour at room temperature followed by subcutaneous inoculation into newborn mice. However, this time and temperature are not critical, for the virus in neutralized within 10 minutes of mixing with immune serum and remains neutralized for long periods. During the variable incubation periods used, the control virus remained active, even in dilute suspensions. The neutralization test is not affected by the presence or absence of complement. Neutralizing antibody is stable at 65°C. for 30 minutes, and immune serum has to be heated to 80°C. for 30 minutes before the antibody is no longer detectable. As the quantity of virus is increased, the quantity of serum required for neutralization likewise increases, but not in a regular or predictable fashion. Neutralized mixtures of the virus can be made infective again by simple dilution before inoculation. The neutralization test is a satisfactory means for typing Coxsackie viruses. At least seven antigenic types have been identified. Similar antigenic types have been found to be scattered over wide areas. Thus the Conn.-5 type was present in 1948 in Massachusetts, Connecticut, New York, and North Carolina. The Texas-1 type was present in 1943 in Connecticut and in 1948 in North Carolina and Texas. Further information on the specificity of the neutralizing antibody response has been obtained from a study of the occurrence and development of antibodies in 6 patients who contracted infections with one or another of the C viruses while working with them in the laboratory. From each patient a virus was isolated during the illness. No patient had detectable antibodies to his strain before his illness, but each soon thereafter developed antibodies to his own strain and to the prototype strain to which it was related. By means of the neutralization test, it has been shown that a family epidemic may include two different immunological types of virus. Neutralizing antibodies appear at the time of or soon after onset of illness, increase rapidly to titers of about 1:1000 which are maintained during the period of 1 to 3 months following infection, and are still present 2 years later, although at lower levels. Neutralizing antibodies are present in the normal population. In North Carolina, over 80 per cent of the children have antibodies at birth. The level falls rapidly to a minimum of 14 per cent at the age of 1, and then it quickly rises to reach the adult level at the age of 7. Gamma globulin collected in various parts of the United States between 1944 and 1949 and in Denmark in 1949 neutralizes at least four antigenically different Coxsackie viruses.

scholarly journals SARS-CoV-2 and interferon blockade

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Betty Diamond ◽  
Bruce T. Volpe ◽  
Sonya VanPatten ◽  
Yousef Al Abed
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune System ◽  
Neutralizing Antibodies ◽  
Cytotoxic T Cells ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Interferon Production ◽  
Therapeutic Implications ◽  
Adaptive Immune

Abstract The response to viral infection generally includes an activation of the adaptive immune response to produce cytotoxic T cells and neutralizing antibodies. We propose that SARS-CoV-2 activates the innate immune system through the renin-angiotensin and kallikrein-bradykinin pathways, blocks interferon production and reduces an effective adaptive immune response. This model has therapeutic implications.

Sign in / Sign up

Export Citation Format

Share Document