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Joshua Lederberg (1925–2008)
Published in Krishna Dronamraju, A Century of Geneticists, 2018
Josh was sympathetic to the application of Norton Zinder for graduate study in genetics, both because Zinder had unsuccessfully aspired to enter medical school and because he had been recommended by Francis Ryan. Zinder joined the laboratory in the fall of 1948 and was immediately steered to a project on Salmonella typhimurium, with the expectation that bacterial conjugation in E. coli could be extended to include this closely related pathogen. Zinder, in a relatively short period, was able to isolate single mutants and complete the standard conjugation experiment. The promising results led to the demand for double nutritional mutants, with somewhat confusing results. There were many twists and turns as Zinder and Josh ruled out back mutation, complementary cross-feeding of nutrients, and even the need for actual cell contact. Ultimately, the critical bacteriophage vector was discovered, and the mechanism of generalized genetic transduction, that is, the unilateral transfer of a limited number of genes by a viral vector, began to unfold (Zinder and Lederberg 1952).
Adenoviral Vectors for Gene Therapy of Inherited and Acquired Disorders of the Lung
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
David T. Curiel, Robert I. Garver
Because of their relevance to the pathogenesis of CF, attempts have also been made to achieve transduction of bronchial submucosal gland cells. In this regard, initial attempts to achieve genetic transduction of this cell subset via luminal delivery did not show the high levels of transduction (26). Studies have shown that this may largely reflect issues related to mechanical access to these cells via the luminal route (27,28). Based on this, attempts have been made to achieve transduction of this cellular target viral alternate means. These strategies have included mechanical abrasion to enhance vector access to target cells. In addition, it has been recognized that non-luminal routes may offer attractive alternatives for accessing these cells. In this regard, the desire to transduce the bronchial submucosa gland cells for CF gene therapy thus led to the exploration of other routing of adenoviral vector delivery to the lung. To this end, Crystal and colleagues delivered the adenovirus via the pulmonary vascular route. Their study demonstrated that vascular administration of the vector could accomplish high levels of transduction of pulmonary vascular cells (28). In these studies, some level of transduction of bronchial submucosal gland cells was also achieved. The ability to modify pulmonary vascular epithelium has also been noted by Dichek et al. They showed higher transduction levels with local delivery via a cellular-lumen system than with simple vascular delivery (29). Whereas these various studies have not demonstrated an effective means to accomplish adenoviral vector modified submucosal gland gene transfer, they have related the capacity to transduce other pulmonary cellular subsets by nonluminal routing strategies. This recognition, however, may provide the means to develop gene therapy strategies based upon the capacity to transduce these pulmonary cells in vivo.
Tracing the origins of extracellular DNA in bacterial biofilms: story of death and predation to community benefit
Published in Biofouling, 2021
Davide Campoccia, Lucio Montanaro, Carla Renata Arciola
A better understanding of the origin of eDNA and on how controlled bacterial death can represent a real advantage for the bacterial population is of paramount importance. Alternative measures for prevention and treatment of biofilm-based infections that do not strictly target DNA have to be meticulously thought and assessed, carefully considering the risk of causing the release of eDNA and, thus, enhancing biofilm formation. For instance, this is a case of the much-discussed phage therapy. Therapies based on the use of phage viruses certainly represent a promising tool to partly obviate the problem of the current shortage of efficacious antibiotic treatments. However, phages are not only implicated in horizontal gene transfer through genetic transduction, but they can also establish symbiotic relationships that induce and strengthen biofilms (Pires et al. 2021). Furthermore, prophagic autolysins have themselves emerged among the mechanisms used by bacteria to release eDNA and thrive in hostile environments. Thus, an initial bactericidal effect obtained by experimental phage therapies should not be confused with a successful cure, and final complete and long-lasting remission of an infection should be proved after a prolonged follow-up, particularly in the presence of prosthetic devices.
Molecular-based and antibody-based targeted pharmacological approaches in childhood acute lymphoblastic leukemia
Published in Expert Opinion on Pharmacotherapy, 2021
Magalie Tardif, Amalia Souza, Maja Krajinovic, Henrique Bittencourt, Thai Hoa Tran
Natural killer (NK) cells are promising avenues in CAR-based immunotherapies. NK cells are potent effector cells that destroy tumor cells through ADCC mechanism and recruit other immune cells by secreting an array of cytokines and chemokines upon a malignant encounter. CAR NK therapies are mostly designed against solid tumors. In a seminal paper, Liu et al. showed that CAR-NK cells are safe and active against CD19-positive cancers in adults, with 7 out of 11 patients achieving CR [154]. Genetic transduction and expansion of NK cells remains the main challenge of CAR NK therapy. Common toxic effects of CAR T cells (discussed below) have not been associated with CAR-NK cells transfer. A hypothetic explanation for the decreased toxicity is the reduced secretion of inflammatory cytokines, including IL-6, by NK cells compared to T-cells.
Challenges and advances in translating gene therapy for hearing disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
Hildegard Büning, Axel Schambach, Michael Morgan, Axel Rossi, Helena Wichova, Hinrich Staecker, Athanasia Warnecke, Thomas Lenarz
In humans, a variety of genetic hearing disorders that can be observed in postnatal mouse models are already manifested in utero, and some cases develop complete degeneration of inner ear architecture by birth. The recessive genes that could be targeted by current gene replacement approaches tend to have congenital presentations, whereas many but not all dominant mutations present with late-onset progressive hearing loss [21]. As shown in several models, effective rescue requires delivery of the vector prior to the degeneration of the inner ear and loss of mature hearing. Gubbels et al. were the first to introduce proof-of-concept for a successful in utero delivery of plasmids [22]. Subsequent studies showed the feasibility that intra-uterine delivery of anti-sense oligonucleotides could correct a form of Usher’s syndrome [23] and that plasmids expressing wild type GJB6 (connexin30; Cx30) could be used to correct hearing loss induced by small hairpin RNA, which mimics the knock-out mouse model [24]. Even in homozygous Cx30 deficient mice, in utero transfection with a plasmid expressing wild type Cx26 into otocysts was demonstrated to restore auditory function [24]. Another study examined different viral vectors for in utero genetic transduction and discovered AAV serotypes 1 and 2 to be superior compared to lentiviral vectors [25]. It is without a doubt that certain forms of hereditary hearing loss will necessitate inner ear gene therapy to be carried out at the embryonic stage. In utero gene therapy is still very preliminary in its development and human translational studies are still distant. However, such a corrective procedure is not inconceivable, since human fetal surgery is already established in clinical practice [26].