Intracerebral and Intrathecal Infusion of the TGF-β2-Specific Antisense Phosphorothioate Oligonucleotide AP 12009 in Rabbits and Primates: Toxicology and Safety

Abstract

Here, we provide first evidence that long-term continuous infusion of highly purified antisense phosphorothioate oligodeoxynucleotides (S-ODN) into brain parenchyma is well tolerated and thus highly suitable for in vivo application. AP 12009 is an S-ODN for the therapy of malignant glioma. It is directed against human transforming growth factor-beta (TGF-beta2) mRNA. In the clinical setting, AP 12009 is administered intratumorally by continuous infusion directly into the brain tumor. In view of this clinical application, the focus of our data is on local toxicology studies in rabbits and monkeys to evaluate the safety of AP 12009. AP 12009 was administered either by intrathecal bolus injection into the subarachnoidal space of the lumbar region of both cynomolgus monkeys and rabbits or by continuous intraparenchymatous infusion directly into the brain tissue of rabbits. Intrathecal bolus administration of 0.1 ml of 500 microM AP 12009 showed neither clinical signs of toxicity nor macroscopically visible or histomorphologic changes. After a 7-day intraparenchymatous continuous infusion of 500 microM AP 12009 at 1 microl/h in rabbits, there was no evidence of toxicity except for local mild to moderate lymphocytic leptomeningoencephalitis. Additionally, AP 12009 showed good tolerability in safety pharmacology as well as in acute toxicity studies and 4-week subchronic toxicity studies in mice, rats, and monkeys. This favorable safety profile proves the suitability of AP 12009 for local administration in brain tumor patients from the point of view of toxicology.

TGF-beta in neural stem cells and in tumors of the central nervous system

“…Consequently, the modulation of TGF-beta2 and associated pathways is the focus of current preclinical and clinical development. Initial clinical studies with intratumoral infusion of TGF-beta2 antisense molecules to suppress the levels of TGF-beta 2 have provided evidence for the clinical value of such strategies (Schlingensiepen et al 2005(Schlingensiepen et al , 2006. Alternatively, the targeting of TGF-beta1 and TGF-beta2 expression by RNA interference has also been evaluated in preclinical models (Friese et al 2004).…”

New Therapeutic Strategies in Gliomas Treatment

“…During tumorigenesis, TGF-increases extracellular matrix invasion and induces escape of tumor from immunosurveillance. In this study antisense compound AP 12009 (antisense oligonucleotide anti TGF-2 mRNA) enhanced the immune cell mediated cytotoxic antitumor response against tumor cells (Hau et al, 2007;Schlingensiepen, 2005Schlingensiepen, , 2006. Schneider et al have examined a "double-punched" approach to overcome the escape of glioblastoma cells to the immune surveillance, through an active specific immunization (ASI) with Newcastle-Disease-Virus infected tumor cells and blocked the TGF-production by delivery of TGF-antisense oligonucleotides using polybutyl cyanoacrylate NPs.…”

Transforming growth factor-beta: A target for cancer therapy

“…AP 12009 was selected for clinical investigation based on pre-clinical data showing anti-tumor activity and a favorable toxicity profile (Schlingensiepen et al, 2005).…”