Nucleic acid delivery therapy

Chinnery P.E., Taylor R.W., Diekert K., Lill R., Turnbull D.M., Lightow-LERS R.N. Peptide nucleic acid delivery to human mitochondria. Gene Therapy 1999 6 1919-1928. 

Wagner E, Kircheis R, Walker GF (2004) Targeted nucleic acid delivery into tumors new avenues for cancer therapy. Biomed Pharmacother 58 152-161... 

FORMULATIONS AND DELIVERY LIMITATIONS OF NUCLEIC-ACID-BASED THERAPIES... 

Tatiana Segura, Chemical and Biomolecular Engineering Department, University of California, Los Angeles, Los Angeles, California, Formulations and Delivery Limitations of Nucleic-Acid-Based Therapies... 

DDS systems may be ascribed to more than one type, e.g. nanoparticles or microspheres coated with multilayer films. Cationic polymers are extensively used in nucleic acid delivety and the respective delivery systems may also be considered as DDSs. However, since non-viral nucleic acid delivery with a great potential in gene therapy has become such an intensively studied area, it is out of the scope of the present chapter. 

Dendrimers have been investigated as a vector for nucleic acid-based therapies for nearly 20 years, and PAMAM and PPI dendrimers are the two most commonly used kinds that are commercially available.[113-115] Their unique chemical architecture with all primary, secondary, and tertiary amines enabling the proton-sponge effect described above make dendrimers one of the ideal platforms for gene delivery. Furthermore, the close-to-monodispersed chemical structure of dendrimers allows the precise control over their functionalities, which can minimize the unpredictable transfection efficiencies observed in the cases of heterogeneous liposomes and other polymer-based systems.[l 16]... 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, Molema G, Lu PY, Scaria PV, Woodle MC (2004) Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 32 el49... 

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

Theoretically, mutated or nonfunctional genes could be excised and replaced, and new genes with desired functions could be permanently inserted into the genome. Stable integration of an antisense DNA might also be desirable in some circumstances. Because of the technical difficulties associated with the delivery of nucleic acid-based products selectively to specific target cells in vivo, more experimental information is available for ex vivo human gene therapy. 

Written by international experts knowledgeable about many aspects of nucleic acid-based therapeutics, this book will be an essential guide to aspiring scientists interested in the various aspects of nucleic acid-based therapeutics as well as established scientists in the gene therapy field and related disciplines. This book presents a comprehensive account of the structures and physicochemical properties of gene delivery and expression systems, with emphasis on their in vivo applications for the production of therapeutic... 

Gene delivery into eukaryotic cells is commonly performed for research purposes as well as in gene therapy procedures. Cellular membranes do not spontaneously take up ectopic nucleic acid because of the polar nature of the phospholipid bilayer [1] which functions as a natural barrier that prevents entry of most water-soluble molecules such as nucleic acids. In studies of gene or protein function and regulation, manipulation of the intracellular expression level is a fundamental approach. For this reason, multiple methods for delivery of nucleic acids through membranes using chemical, physical, or biological systems have been established in the last 40 years. 

Systemic delivery of cationic polyplexes is a challenging strategy in gene therapy. Polyplexes carrying a positive net charge due to condensation of nucleic acid by polymers such as PEI, oligo(ethylene imine OEI), or PLL encounter several... 

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