Genasense® reduces the expression of Bcl-2 protein using a technology known as “antisense”. This technology is based on modified strands of DNA that are designed to reduce the levels of a single protein. Virtually any protein can be targeted by antisense. Genta has focused almost 20 years of research on a protein known as Bcl-2 – a target generally considered a critical regulator of the life and death of cancer cells. A successful attack on Bcl-2 may yield a transformational outcome result in cancer patients.
The genes of all cells, which are comprised of DNA, normally unfold and transcribe a product known as messenger RNA (mRNA). Then, the mRNA translates a specific protein. This process is highly regulated by other epigenetic, post-transcriptional, and post-translational processes. In drug discovery, Genta scientists isolated the specific mRNA that encodes the Bcl-2 protein and then – by conducting a “message walk” – we isolated a large number of candidate antisense drugs by building strands of modified DNA that typically ranged in length from 12 to 22 bases. The molecule known as Genasense proved to be the most active in this discovery process.
As a modified form of DNA, Genasense – which is 18 bases in length – binds via Watson-Crick base pairing to its complementary region in the Bcl-2 mRNA. As shown in the figure below, the resulting DNA/RNA duplex is recognized by the body as “foreign”, and a normal defense mechanism is triggered. In this process, an enzyme known as RNAse H is recruited, which destroys the bound mRNA – thus eliminating the ability to produce Bcl-2 protein – but releases the antisense DNA (Genasense) that is then free to bind to other mRNA. Thus, the repetitive bind/destroy/release sequence is highly potent due to this self-amplifying characteristic.
• Scientific proof of principle for antisense technology
• Targets a critical protein that is highly expressed in most types of cancer
• Completed Phase 3 clinical trials with clearly identified responsive patient populations
