Intravitreal administration of antisense oligonucleotides: potential of liposomal delivery

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Abstract

Antisense oligonucleotides are short synthetic fragments of genes that are able to inhibit gene expression after being internalized by cells. They can therefore be used as antiviral compounds particularly, for the treatment of ocular viral infections (i.e. Herpes simplex virus or Cytomegalovirus, CMV). Antisense oligonucleotides are however poorly stable in biological fluids and their intracellular penetration is limited. Although oligonucleotides are now currently used in therapeutics for the treatment of CMV by intravitreal injection (Vitravene) their main drawbacks impose to repeat the number of administrations which can be very harmful and damaging. A system that is able to permit a protection of oligonucleotides against degradation and their slow delivery into the vitreous would be more favorable for improving patient compliance. The use of liposomes for intravitreal administration can be very promising since these lipid vesicles are able to protect oligonucleotides against degradation by nucleases and they allow to increase the retention time of many drugs in the vitreous. In this review, the potentialities of liposomes for the intravitreal delivery of oligonucleotides will be discussed.

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Characterization of oligonucleotide transport into living cells.

Mark A. Stein, C Subasinghe, K Mori … (1989)

Addition of antisense oligonucleotides to cell cultures has been used to specifically inhibit gene expression. We have investigated the mechanism by which oligonucleotides enter living cells. These compounds are taken up by cells in a saturable, size-dependent manner compatible with receptor-mediated endocytosis. Polynucleotides of any length are competitive inhibitors of oligomer transport, providing they possess a 5'-phosphate moiety. Using oligo(dT)-cellulose for affinity purification, we have identified an 80-kDa surface protein that may mediate transport. Knowledge of the oligonucleotide transport mechanism should facilitate the design of more effective synthetic antisense oligomers as potential clinical agents.

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Stability and properties of double and triple helices: dramatic effects of RNA or DNA backbone composition.

D Crothers, R. Roberts (1992)

Studies of a series of short oligonucleotide double and triple helices containing either all RNA, all DNA, or a mixture of the two show strand-dependent variation in their stability and structure. The variation in stability for both groups falls over a range of greater than 10 kilocalories per mole. In forming the triple helix, RNA is favored on both pyrimidine strands, whereas DNA is favored on the purine strand. In general, relatively unstable duplexes form particularly stable triplexes and vice versa. Structural data indicate that the strands in hybrid helices adopt a conformation that is intermediate between molecules containing all DNA and all RNA. Thus, RNA-DNA hybrids were not forced into the conformation of the RNA (A-form). The provocative stability of the triplex with an RNA third strand+DNA duplex points to novel antisense strategies and opens the possibility of an in vivo role of these structures. Overall, the data emphasize the fundamental role of sugars in determining the properties of nucleic acid complexes.