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Genetics and exercise: an introduction
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Claude Bouchard, Henning Wackerhage
Usually, genes can be manipulated most easily in cell culture. Such experiments are termed in vitro (Latin in glass, as in a test tube). In vitro gene manipulation experiments can yield useful information about traits of interest (51) but are generally less productive for the study of more complex traits such as VO2max. In these experiments, researchers use methods such as electroporation, transfection agents or viruses to get gene manipulation agents, such as small interfering RNA (siRNA), short-hairpin RNA (shRNA) or a gene construct into cells and their nuclei, where the gene manipulation agents can then block, reduce or increase the expression of a gene or manipulate the gene itself.
Nucleic Acid-Based, mRNA-Targeted Therapeutics for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
It is quite clear that many of the considerations that apply to the use of traditional antisense DNA molecules and ribozymes will also apply to RNAi whether in the form of siRNA, miRNA, or short hairpin RNA (shRNA) expressed from viral vectors (51). These issues include (1) the ability to deliver these molecules into target cells (52–54), (2) development of chemical modifications that increase intracellular stability of the targeting molecules without compromising ability to hybridize with the mRNA target and disable or destroy it (54–57), (3) develop reliable, reproducible strategies for targeting a desired mRNA, and (4) keep “off target” or unintended silencing to a minimum (49,58–61).
Lung cancer inhalation therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
In this approach, a targeted oligonucleotide that reduces transcription of complementary messenger ribonucleic acid (mRNA) inhibits gene expression (172). Plasmid or viral vector mediated transfer of small interfering RNA (siRNA) or short hairpin RNA (shRNA) precursors was reported in animal models. A chitosan-graft 1.8 K PEI copolymer has the advantage of reducing toxicity of PEI and enhancing transfection efficacy of chitosan (57). In a B16-F10 model of lung metastasis, nebulized PEI-WTI (Wilms tumor gene) RNAi complexes reduced the number and size of lung metastasis, probably through inhibition of angiogenesis (173). Use of poly(amidoamine) (PAMAM) dendrimers (G4NH2) as carriers to complex siRNA efficiently target and silence genes expressed in A549 cells (174).
Polyglutamine spinocerebellar ataxias: emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Andreia Neves-Carvalho, Sara Duarte-Silva, Andreia Teixeira-Castro, Patrícia Maciel
The most encouraging and innovative therapies aiming at silencing the SCA causative genes are RNA-targeting approaches that involve the use of antisense oligonucleotides (ASOs) or virus-mediated delivery of synthetic RNA-interference agents – microRNA (miRNA), short hairpin RNA (shRNA), and small interference RNAs (siRNAs) Figure 1. This can be achieved in an allele-specific manner, by targeting either the PolyQ mutation or a linked single nucleotide polymorphism (SNP), or by targeting both mutant and wild-type (WT) alleles (Reviewed in [8,9]). Preclinical tests of allele-specific strategies for SCA1, SCA2, SCA3, SCA6, and SCA7 showed promise and potential for further clinical advancement, with efficient reduction of gene expression, reduction of mutant protein aggregation, and improvement of neuropathology and motor impairments [10–15].
Choice of nanocarrier for pulmonary delivery of cancer therapeutics
Published in Expert Opinion on Drug Delivery, 2020
Patients with lung cancer are treated with several therapeutic procedures such as surgery, radiotherapy, chemotherapy, and molecular-targeted therapies. Chemotherapy is usually administered to the patients as neo-adjuvant or adjuvant therapy. It is an essential treatment mode especially in advanced lung cancer where metastasis prevails. Gene therapy has been the recent focus of research [2,3]. Small interfering ribonucleic acid (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA) are examples of RNAi-based therapeutics that can either be delivered through systemic administration or local administration to negate the expression of intended gene and cancer. The delivery of RNAi-based therapeutics through systemic administration may bring about adverse effects such as liver toxicity, therapeutic instability, and stimulation of immune response. Pulmonary administration of RNAi-based therapeutics is deemed to be a better delivery approach in targeting the cancer tissue [4].
Lessons learned from lung and liver in-vivo gene therapy: implications for the future
Published in Expert Opinion on Biological Therapy, 2018
Joost van Haasteren, Stephen C. Hyde, Deborah R. Gill
Some of the diseases targeted by ex-vivo gene therapy harbor a mutation that causes a proliferative advantage to cells that have been corrected (such as SCID). This will, in time, cause an amplification of cells that are corrected since they will out-proliferate non-corrected cells. Ultimately, as long as this amplification is not unregulated, this advantage is likely to benefit the treated patient. Such an effect is not readily observed in in-vivo lung or liver gene therapy, but examples do exist, and a proliferative advantage can be established artificially. For example, correcting the common PI*Z mutation of AAT deficiency or inhibiting its expression with a microRNA prevents the accumulation of PI*Z polymers in the hepatocytes and give those cells a survival advantage over non-corrected cells that have a tendency to undergo stress-induced apoptosis [87]. A more synthetic approach was taken by Nygaard and colleagues, who developed a vector that, in addition to expressing a therapeutic transgene, also expressed a short hairpin RNA (shRNA) that protects against a toxic drug [88]. Cells that do not have this vector integrated succumb to the drug and allow cells that do harbor the shRNA to outgrow them and at the same time express the therapeutic transgene.