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Adeno-Associated Virus-Based Delivery Systems
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
The adeno-associated virus (AAV) has been the subject of intense study recently by investigators working with viral-based gene delivery systems. AAV is a member of the Dependovirus genus in the Parvoviridae family. Parvoviruses are small, single-stranded DNA viruses with a host range in both the vertebrates and invertebrates (1). AAV is often called a defective or dependent virus because it requires a helper virus to generate a productive infection. From 49% to 80% of human adults are seropositive for AAV type 2 (2-5). It has been speculated that AAV evolved from cellular “junk” DNA into a protective interfering transposon under evolutionary pressures which favored its transposonlike qualities (6). Transposons would interfere with invading pathogenic viruses (such as the parvovirus B19) by competing with the pathogen DNA for replicative enzymes. Thus the common ancestry for autonomous and defective parvoviruses may have been in cellular DNA which then developed under different evolutionary pressures to establish two genera. The features that make AAV an attractive potential gene therapy vector include nonpathogenicity, site-specific integration in the absence of a helper virus infection, and the ability to remove all of the viral genes without loss of infectivity.
Gene therapy in uveitis
Published in A Peyman MD Gholam, A Meffert MD Stephen, D Conway MD FACS Mandi, Chiasson Trisha, Vitreoretinal Surgical Techniques, 2019
Lim Wee-Kiak, Nussenblatt Robert B
Adeno-associated virus (AAV) was originally identified as a contaminant in adenovirus preparations. AAV is a parvo-virus, a single-stranded DNA virus, which has so far showed no pathologic signs upon infection in humans for any of the six serotypes, each with a different cell specificity. AAV is a small virus with only two viral genes, rep and cap , which encode for replication and encapsulation. Deletion of these two genes allows therapeutic genes to be inserted.19–;21 For
Lung cancer inhalation therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Adverse effects due to inhaled nonchemotherapeutic agents include reduction in forced vital capacity, bilateral infiltrates, pleural effusion, and bronchospasm with inhaled GM-CSF in patients with metastatic disease (113,114). In contrast, other investigators have reported only minor toxicity in patients who received inhaled GM-CSF. Inhalation of IL-2 is limited by the development of pulmonary vascular leakage, which is dose-, route-, and formulation-dependent (182). Adenoviral vectors tend to create neutralizing antibodies and can be associated with significant local and systemic inflammation involving neutralizing antibodies and cytotoxic lymphocytes. In contrast, adeno-associated virus has not been associated with any significant toxicity. Nonviral vectors and polymers exhibit cytotoxicity that is mainly due to their strong electrostatic charge. The molecular weight of the polymers plays an important role, with higher molecular weight polymers producing higher incidence of adverse respiratory effects (165,166). Systemic absorption of inhaled NPs and their distribution to various body organs raises concerns about toxicity. Cytotoxicity, allergic, and inflammatory reactions are more likely with particles smaller than 100 nm in size compared to larger particles with similar composition. NPs composed of endogenous chemicals, such as dipalmitoylphosphatidylcholine, have less potential for toxicity.
Genetic modification and preconditioning strategies to enhance functionality of mesenchymal stromal cells: a clinical perspective
Published in Expert Opinion on Biological Therapy, 2023
Kasra Moeinabadi-Bidgoli, Radman Mazloomnejad, Alireza Beheshti Maal, Hamid Asadzadeh Aghdaei, Mandana Kazem Arki, Nikoo Hossein-Khannazer, Massoud Vosough
Even though integrated vectors are very efficient in genetic modification, the immunogenicity of viral vectors is a limiting factor. Specific components of viral vectors such as capsids or nucleic acids at the first encounter with the virus, or the virus’ genome integration to the hosts and the possibility of expression of viral antigens in the infected cells will lead to the production of pro-inflammatory cytokines and the eventual attenuation of gene modification [165,168]. In this regard, non-integrated viral vectors are another category of viruses used for infecting cells without integrating their genes with the host genome. Adeno-associated viral vectors are among the most common non-integrated viruses. They have become a viable option due to their efficient gene transfer, stable target gene expression, and low immunogenicity [169,170].
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Delivery vehicles for gene therapy fall broadly into two categories: viral and non-viral vectors (Figure 2). Viral vectors are usually more effective. Adenoviruses or adeno-associated viruses have a natural tropism for airway cells and can cross the mucus barrier. Several clinical trials in CF using these viral vectors failed to show a sufficient level of CFTR transgene expression. Preexisting and induced immune responses to the viral vector limited transduction efficacy. New modified viral vectors are being studied [34]. Current strategies include the use of a simian-based lentiviral vector, pseudotyped with Sendai virus fusion glycoprotein which exhibit an effective transduction of human airway cells in vitro and in vivo in murine lung epithelium with a 2 year-long expression [35]. The use of adeno-associated virus is also studied [36].
Blockade of the Notch1/Jagged1 pathway in Kupffer cells aggravates ischemia-reperfusion injury of orthotopic liver transplantation in mice
Published in Autoimmunity, 2019
He Bai, Jian Wen, Jian-Ping Gong, Hao Wu, Fang-Chao Yuan, Ding Cao, Ya-Kun Wu, Xing Lai, Meng-Hao Wang
We used an established mouse model of ex vivo hepatic cold storage and OLT [15]. To mimic the “marginal” human OLT setting, donor livers were stored in University of Wisconsin solution at 4 °C for 18 h prior to transplantation into syngeneic mice. The Adeno-associated virus (AAV)-Jagged1 treatments in each group were administered intravenously for 2 weeks before surgery. Following pretreatment, mice were randomly divided into six groups:Sham group (n = 15): did not receive a transplant but still underwent abdominal cutting and vascular exposures around the liver.NS group (n = 15): treated with NS via caudal vein injection.Adeno-associated virus–green fluorescent protein (AAV-GFP) group (n = 15): received 0.35 mg/mouse of AAV-GFP via caudal vein injection.AAV-Jagged1 group (n = 15): received 0.35 mg/mouse of AAV-Jagged1 via caudal vein injection.Clodronate liposome (CL) group (n = 15): received 200 uL of CL (5 mg/mL) via caudal vein injection.CL+AAV-Jagged1 group (n = 15): received 200 uL of CL (5 mg/mL) and 0.35 mg/mouse of AAV-Jagged1 via caudal vein injection.