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Challenges in Delivering Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
For gene therapy to work, DNA much be delivered to the target tissue and then transported to the nucleus for protein expression. Within this problem there is another underlying problem. The first problem is that a system must be established to deliver DNA to the target tissues and must be preventive to degradation. The second problem stems from the establishment of another system to build a DNA construct, and then allow the target cell to express that protein at efficient therapeutic levels [25, 26]. To establish a system which delivers DNA to the tissues and nucleus, a mechanism to circumvent extra and intracellular barriers must be taken into account. Some of these barriers include stability of the biological environment, cellular uptake, lysosomal escape, cytosolic transport, and gene unpacking [27–31]. These are some of the barriers that must be overcome, and such solutions must be provided with trials and experimentation.
Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
Chimeric antigen T-cells (CarT) are T-cells engineered to express a T-cell receptor with specificity for an antigen of choice expressed on the target cell. In ALL the commonest target has been CD19, though CD22 has also been used and other targets are in development. The T-cells are most commonly autologous though allogeneic CarT have also been developed. The artificial engineered DNA construct is inserted into the T-cells by viral transfection.
Gene Therapy for Acute Diseases of the Lungs
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
To use gene therapy to treat acute lung disease, acquired rather than inherited, the rationale is more complex, and the strategies, in some cases, are more convoluted. First the pathogenesis of the disease must be understood in sufficient detail to identify a protein that, if increased (or decreased) at an appropriate site, will alter the course of the disease in favor of the host. Having done that, a DNA construct and a delivery system must be designed that delivers the therapeutic gene to the right site and assures that it functions for a limited period of time to an appropriate degree (3). The therapeutic gene need not qualitatively alter the host response but, like more conventional drugs, simply tilt the host-toxin interaction in the host’s favor.
Vaccine for a neglected tropical disease Taenia solium cysticercosis: fight for eradication against all odds
Published in Expert Review of Vaccines, 2021
Rimanpreet Kaur, Naina Arora, Suraj S Rawat, Anand Kumar Keshri, Shubha Rani Sharma, Amit Mishra, Gagandeep Singh, Amit Prasad
Vaccination with encoded DNA is a unique mode to immunize the host against infections, as it involves less cost, time, and effort than conventional protein/peptide-based vaccine production. In a DNA vaccine, the encoded antigen in a suitable expression vector is directly injected under the skin, muscles or other suitable tissue of the host. Earlier DNA vaccine has been used against unicellular organisms or bacterial infections only; later on, it was used for multi-cellular pathogens such as helminths or against other multicellular parasitic infections too [59]. The DNA vaccines have their advantages such as we can easily modify the DNA construct to enhance the immunogenicity of the vaccine and as compare to protein vaccines. The downstream purification processes involved with proteins are mostly cumbersome and tedious and need a constant cold chain to keep the efficacy intact, while there is no such necessity for DNA vaccine.
A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control
Published in OncoImmunology, 2019
Elena Tondini, Tsolere Arakelian, Koen Oosterhuis, Marcel Camps, Suzanne van Duikeren, Wanda Han, Ramon Arens, Gerben Zondag, Jeroen van Bergen, Ferry Ossendorp
We first analyzed whether these five artificially connected sequences lead to the generation of the expected peptide epitopes and their presentation on MHC molecules. Upon transfection of the designed DNA construct, the translated protein product needs to be processed in such a way that the T cell epitopes are generated and presented by MHC molecules. MC38 cells, which do not express the ovalbumin gene, were transfected with the neoantigen construct and the presentation of the ovalbumin CTL epitope SIINFEKL was detected by staining the SIINFEKL/H2-Kb complex with the 25-D1.16 antibody (Figure 1(b), upper panel). Transfection with the poly-neoantigen construct, but not with a control GFP-encoding construct, displayed positive staining for SIINFEKL/H2-Kb complexes. Moreover, after transfection with the neoantigen construct, cells were recognized by the hybridoma T cell line B3Z, which express a TCR specific for SIINFEKL/H2-Kb (Figure 1(b), lower panel).
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
Genetic modification of HSCs can be achieved by both physical and viral methods. HSCs can be transiently modified using physical gene delivery or non-integrating viruses, or stably modified using integrating viruses. Physical modification includes chemical methods such as cationic liposome and polymer transfer of genetic material, as well as electroporation, particle bombardment, ultrasound, and magnetofection. While these methods offer reduced efficiency in comparison to viral gene transduction, their cost-effectiveness, availability, reduced immunogenicity, and lack of DNA construct size limitations ensures further investigation into how to best employ these systems [42]. As LSD treatment likely requires long-term gene expression, little work using these transient delivery systems have been completed in this context. Rather, the majority of gene therapy strategies for the treatment of LSDs use viral vector delivery strategies.