Treatment of malignant gliomas with TGF-β2 antisense oligonucleotides

Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta 2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 mu M versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.