Mitigating Serious Adverse Events in Gene Therapy with AAV Vectors: Vector Dose and Immunosuppression

One of the well-known X-linked genetic disorders is hemophilia, which could be hemophilia A as a result of a mutation in the F8 (factor VIII) gene or hemophilia B as a result of a mutation in the F9 (factor IX) gene, leading to insufficient levels of the proteins essential for blood coagulation cascade. In patients with severe hemophilia, factor VIII or factor IX activities in the blood plasma are considerably low, estimated to be less than 1%. This is responsible for spontaneous or post-traumatic bleeding episodes, or both, leading to disease complications and death. Current treatment of hemophilia relies on the prevention of bleeding, which consists of expensive lifelong replacement infusion therapy of blood plasma clotting factors, their recombinant versions, or therapy with recombinant monoclonal antibodies. Recently emerged gene therapy approaches may be a potential game changer that could reshape the therapeutic outcomes of hemophilia A or B using a one-off vector in vivo delivery and aim to achieve long-term endogenous expression of factor VIII or IX. This review examines both traditional approaches to the treatment of hemophilia and modern methods, primarily focusing on gene therapy, to update knowledge in this area. Recent technological advances and gene therapeutics in the pipeline are critically reviewed and summarized. We consider gene therapy to be the most promising method as it may overcome the problems associated with more traditional treatments, such as the need for constant and expensive infusions and the presence of an immune response to the antibody drugs used to treat hemophilia. 

Recent Advances in Gene Therapy for Hemophilia: Projecting the Perspectives

Peripheral artery disease (PAD) is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of PAD is increasing globally with >200 million people affected. PAD remains a growing global health problem as the population continues to age and diabetes incidence grows. Many patients with PAD, most notably those with critical limb ischemia, fail attempts at surgical and percutaneous intervention to improve blood flow and are at risk of amputation. Gene therapy provides an opportunity to change the clinical course of PAD in these patients via strategies that increase vascular supply through angiogenesis and arteriogenesis improving muscle perfusion and function in ischemic legs. This article discusses gene therapy approaches in the context of PAD, both intermittent claudication and critical limb ischemia, and the promise of adeno-associated virus-based strategies delivering not just VEGFs (vascular endothelial growth factors) but a range of other mediators as potential new therapeutics. We also highlight challenges and failures in the clinical translation of gene therapy for PAD and how at least some of these obstacles may be overcome using adeno-associated virus.

https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.122.318902

Gene Therapeutic Strategies for Peripheral Artery Disease and New Opportunities Provided by Adeno-Associated Virus Vectors.

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies. Graphical Abstract 

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Gene therapy is a technique to correct genetic abnormalities, through introduction of a functional gene or through direct genome editing. Adeno-associated virus (AAV)-mediated gene replacement shows promise for targeted therapies in treatment of inherited cardiomyopathies and is the most used approach in clinical trials. However, immune responses from the host to the virus and gene product pose delivery and safety challenges. This review explores the immunological reactions to AAV-based gene therapy, their potential toxic effects, with a focus on myocarditis, and future directions for gene therapy. 

Gene therapy vector-related myocarditis.

Evading and overcoming AAV neutralization in gene therapy.

Epitope Mapping by Molecular Imprinting of Adeno-Associated Virus Serotype 8(AAV8)-Antibody Complexes and Use of Fab Peptides as a Novel Strategy of Evadingneutralisation to Improve the Efficiency of AAV8-Mediated Gene Therapy


 In rod-pumped systems, the locations to install rod guides along the rod are determined through the analysis of calculated side forces exerted on/by the rod string. The side forces are computed from axial forces in combination with information about the trajectory of the rod string in the well. Traditionally, the trajectory of the rod string is estimated from directional survey data, obtained by magnetic or gyroscopic surveys at typically 100ft reporting intervals. However, because the surveys are run in open hole, in casing, or in tubing, it is the trajectory of these structures that are described by the directional data. None of them are accurate representations of the actual trajectory of the rod string, implying that the resulting side forces may suffer from reduced accuracy, and therefore are not optimal for decisions on rod guide placement. Additionally, due to the low resolution survey data, local variations in the wellbore trajectory within the survey intervals, which may affect the forces on the rods, may be undetected.
 In a previous paper we developed a method for analyzing the small-scale tortuosity of a wellbore from high-resolution (1ft) survey data. One important outcome of this analysis is the finding that high small-scale tortuosity substantially narrows the free passage through a wellbore or tubing. The narrowing is quantified in terms of the reduction in the effective diameter of a device that can be placed in the wellbore. In this paper, the technique has been extended for the calculation of points along the wellbore where the rod string is expected to make contact with the tubing. This is an important result by itself, indicating where rod guides may be needed along the rod string. With these points of contact, the trajectory, or shape of the rod within the production tubing is estimated. The use of this estimate instead of the traditional directional survey data in the calculations of side forces is expected to improve the accuracy of the results.
 The technique has been applied to a number of field cases, and two are presented in this paper. The results show that the forces on the rod calculated from the proposed technique are similar to, and exhibit the same general trend as the forces calculated with conventional methods. However, there are some differences, due primarily to the use of the estimated shape of the rod string in the proposed method. The forces on the rod at the estimated points of contact of the rod and the tubing can be extracted and used for rod guide placement decisions.
 By providing improved estimates of contact point locations and the forces acting between the rod and the tubing, the method may help to optimize the rod pumping system for producing wells. It may help to explain occurrences of pump failures, erosion of the production tubing by the rods, and other issues that are not fully understood. This may result in reduced failure rates, energy savings, and cost savings resulting from reduced workovers and production losses.

Rod-Guide Placement Based on High-Resolution Tortuosity Analysis of Production Tubing

Analysis of Adeno-Associated Virus Serotype 8 (AAV8)-antibody complexes using epitope mapping by molecular imprinting leads to the identification of Fab peptides that potentially evade AAV8 neutralisation.

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Evading and overcoming AAV neutralization in gene therapy.

Epitope Mapping by Molecular Imprinting of Adeno-Associated Virus Serotype 8(AAV8)-Antibody Complexes and Use of Fab Peptides as a Novel Strategy of Evadingneutralisation to Improve the Efficiency of AAV8-Mediated Gene Therapy

Rod-Guide Placement Based on High-Resolution Tortuosity Analysis of Production Tubing

Analysis of Adeno-Associated Virus Serotype 8 (AAV8)-antibody complexes using epitope mapping by molecular imprinting leads to the identification of Fab peptides that potentially evade AAV8 neutralisation.