The scope of all RNA/DNA Medicines encompasses numerous technology platforms and mechanisms of action and the challenges of appropriate tissue and cellular uptake.
The focus of Genta’s RNA/DNA Medicines program is on the use of Antisense technology to reduce the expression of targeted proteins known to have critical functions in the development and progression of cancer and resistance to cancer therapies.
Most late-stage cancers are systemic diseases. Antisense technology is the only DNA/RNA medicine with the demonstrated capacity to exert therapeutic effects after systemic administration. We are constantly developing new methods to maximize the uptake of antisense into target tumor tissues and ultimately into tumor cells.
The basic concepts of how antisense works are shown in the following figures.
Proteins
Proteins are fundamental molecular machines of life. They are responsible for most cellular functions, including maintenance of structure, growth regulation, signaling processes and metabolism. The blueprint for all proteins, known as “genes”, is encoded in the DNA present in all cells . In order for the information encoded in DNA to become a protein, an intermediate step is required, whereby the DNA is transcribed into RNA and then the RNA is translated into a protein.
Antisense Drug Mechanism
Antisense drugs are small, chemically modified strands of DNA called oligonucleotides are engineered in a sequence that is exactly “opposite” or complementary to the coding (sense) sequence of a target mRNA (hence the term “antisense”) for the purpose of binding to the target mRNA. Upon binding to the mRNA a duplex is formed. This duplex recruits an enzyme which degrades the mRNA portion of the duplex, thereby inhibiting the production of the intended protein. The antisense portion of the duplex is then released for further binding to a new mRNA.
Antisense Technology
The antisense molecule in Genta’s Bcl-2 program is chemically modified by the substitution of sulfur for one of the non-bridging oxygen atoms in each phosphate linkage of the oligonucleotide backbone. The sulfur modification produces the “phosphorothioate” backbone, and confirs numerous desirable properties: increased resisistance to breakdown in the body, enhanced tissue uptake, and prolonged circulation. Phosphorothioate oligonucleotides are the most widely studied, clinically characterized oligonucleotides available.
Advantages of Antisense Therapy
- High gene-target specificity
- Selective knockout of single critical target
- Reduced likelihood of side-effects
With high selectivity, there are two important characteristics that will determine how useful an antisense molecule may be as a treatment for human disease: the technical aspects of oligo design, and the criticality of the protein target. Over the past decade, the technical aspects of the oligo design have been successfully addressed by Genta scientists and others, such that this issue is largely resolved. Thus, the central remaining issue is whether the target that is chosen for antisense attack plays a key role in the biology of a complex human disease.
Targeting Bcl-2
This figure shows c comparison of Genasense® (G3139) to a large number of other antisense oligonucleotides targeting Bcl-2. The data are a direct confirmation that Genasense® is superior to other oligonucleotide leads against this critical therapeutic target gene.
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Technologies
, the company's first approved drug, and a novel oral formulation of this 