Antisense oligonucleotides limitations

Bell TA, III Brown JM, Graham MJ, Lemonidis KM, Crooke RM, Rudel LL. Liver-specific inhibition of acyl-coenzyme axholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein BlOO-only low-density lipoprotein receptor-/- mice. Arterioscler Thromb. Vase. Biol. 2006 26 1814-1820. 

Despite the apparent success of antisense oligonucleotide therapy, several limitations of this technology have been manifested, First, the ODN must effectively cross the cell membrane to reach the cytoplasm or nucleus (permeation). Once inside the cell, the ODN must be resistant to degradation (stability). Finally the ODN must be able to bind specifically and with a high affinity to the RNA target to inhibit the desired gene (affinity and specificity) (28,30). 

A number of experimental studies have shown that caspase inhibition reduces ischemic injury [51]. Caspase-3 inhibitors [52], gene deletions of Bid or caspase-3 [53], and the use of peptide inhibitors, viral vector-mediated gene transfer, and antisense oligonucleotides that suppress the expression and activity of apoptosis genes have all been found to be neuroprotective [51]. However, caspase inhibitors do not reduce infarct size in all brain ischemia models, perhaps related to the greater severity of ischemia, limited potency or inability of the agent to cross the blood-brain barrier, relatively minor impact of apoptosis on stroke outcome, and upregulation of caspase-independent or redundant cell-death pathways. Ultimately, it may be necessary to combine caspase inhibitors and other inhibitors of apoptosis with therapies directed toward other pathways, for successful neuroprotection. 

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