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Published online 17 May 2004

Nucleic Acids Research, 2004, Vol. 32, No. 9 2695-2706
© 2004 Oxford University Press

Identification and functional validation of PNAs that inhibit murine CD40 expression by redirection of splicing

Andrew M. Siwkowski, Leila Malik, Christine C. Esau, Martin A. Maier, Edward V. Wancewicz, Klaus Albertshofer, Brett P. Monia, C. Frank Bennett and Anne B. Eldrup*

Department of Medicinal Chemistry, ISIS Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, CA, 92008, USA

*To whom correspondence should be addressed. Tel: +1 760 603 3852; Fax: +1 760 603 4654; Email: aeldrup{at}isisph.com
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

Received February 6, 2004; Revised and Accepted April 14, 2004

Cognate recognition between the CD40 receptor and its ligand, CD154, is thought to play a central role in the initiation and propagation of immune responses. We describe the specific down regulation of cell surface associated CD40 protein expression by use of a peptide nucleic acid (PNA) antisense inhibitor, ISIS 208529, that is designed to bind to the 3' end of the exon 6 splice junction within the primary CD40 transcript. Binding of ISIS 208529 was found to alter constitutive splicing, leading to the accumulation of a transcript lacking exon 6. The resulting protein product lacks the transmembrane domain. ISIS 208529-mediated CD40 protein depletion was found to be sequence specific and dose dependent, and was dependent on the length of the PNA oligomer. CD40-dependent induction of IL-12 in primary murine macrophages was attenuated in cells treated with ISIS 208529. Oligolysine conjugation to the PNA inhibitor produced an inhibitor, ISIS 278647, which maintained its specificity and displayed efficacy in BCL1 cells and in primary murine macrophages in the absence of delivery agents. These results demonstrate that PNA oligomers can be effective inhibitors of CD40 expression and hence may be useful as novel immuno-modulatory agents.


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