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 Blood, 7 May 2009, Vol. 113, No. 19, pp. 4548-4555.
Prepublished online as a Blood First Edition Paper on March 3, 2009; DOI 10.1182/blood-2008-12-196220.

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IMMUNOBIOLOGY

Antisense-mediated exon skipping to correct IL-12Rβ1 deficiency in T cells

Esther van de Vosse1, Els M. Verhard1, Roelof A. de Paus1, Gerard J. Platenburg2, Judith C. T. van Deutekom2,3, Annemieke Aartsma-Rus3, and Jaap T. van Dissel1

1 Department of Infectious Diseases, Leiden University Medical Center, Leiden; 2 Prosensa Therapeutics BV, Leiden; and 3 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

Patients with Mendelian susceptibility to mycobacterial disease have severe, recurrent life-threatening infections with otherwise poorly pathogenic mycobacteria and salmonellae. The extreme susceptibility is the result of genetic defects in the interleukin-12/interferon-{gamma} (IL-12/IFN-{gamma}) pathway. The infections are difficult to treat, and therapeutic options are limited. We explored the feasibility of antisense-mediated exon skipping as therapy for Mendelian susceptibility to mycobacterial disease with cells from a complete IL-12Rβ1–/– patient. Expression constructs were first studied to determine whether IL12RB1 lacking exon 2 encodes a functional protein. The IL-12Rβ1 expression construct lacking exon 2 was expressed on T cells. On IL-12 or IL-23 stimulation, this construct phosphorylated similar amounts of STAT1, STAT3, and STAT4 and induced similar amounts of IFN-{gamma} compared with a normal IL-12Rβ1 construct. Antisense oligonucleotides (AONs) directed at exon 2 resulted in transcripts lacking exon 2 in both controls' and patients' T cells. In IL-12Rβ1–/– cells, skipping of exon 2 led to expression of IL-12Rβ1 on the cell surface and responsiveness to IL-12. We showed that IL12RB1 lacking exon 2 encodes a functional IL-12Rβ1. We demonstrated that T cells can be highly efficiently transduced with AONs and are amenable to antisense-mediated exon skipping. Furthermore, we showed that exon skipping (partly) corrects the IL-12Rβ1 deficiency in patients' cells.


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