Targeting bcr-abl transcripts with siRNAs in an imatinib-resistant chronic myeloid leukemia patient: challenges and future directions.

Within the recent years, RNA interference (RNAi) has become an almost standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential therapeutic use. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. This chapter describes the in vivo application of targeted non-virally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome positive chronic myeloid leukemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic hematopoietic stem cell transplantation. A remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells was found. In vivo siRNA application was well tolerated without any clinically adverse events. The current findings imply that the clinical application of synthetic siRNA is feasible and safe and has real potential for genetic-based therapies using synthetic non-viral carriers.