Endostatin Gene Therapy for Cancer

E10A

Gene therapy is a technology which uses DNA as a pharmaceutical agent to supplement or alter genes within an individual as a therapy to treat disease. Marsala's product E10A uses the Endostatin gene to prevent angiogenesis (blood vessel growth), and shut off the nutrient supply to tumors, starving the tumors and leading to tumor shrinkage.

To deliver the endostatin gene to the tumor, the gene is integrated into an adenoviral vector which is then injected into the tumor. The adenoviral vector will infect the tumor cells, delivering the endostatin gene inside the cell. Once inside, the endostatin gene uses the cellular machinery of the tumor cells to produce endostatin protein. Endostatin protein then acts to prevent angiogenesis, shutting off the nutrient supply to the tumor which results in tumor shrinkage.

The creation of new blood vessels, known as angiogenesis, is a critical element in tumour formation and growth. Inhibition of tumour angiogenesis as a therapeutically useful target, fostered an intense search for anti-angiogenic agents. Several angiogenesis inhibitors are currently in preclinical or clinical trials.

Endostatin is a 20 kDa internal fragment of the carboxy terminus of collagen XVIII discovered by Dr. Judah Folkman's group at the Children's Hospital, Boston, an affiliate of the Harvard Medical School. Endostatin inhibits endothelial cell proliferation and angiogenesis and the endogenous angiogenesis inhibitors in the body, endostatin has the broadest anti-cancer spectrum. Antitumour activity of endostatin protein has been demonstrated in various murine and human studies. An N-terminal modified recombinant human endostatin was approved by the State FDA in China for the treatment of nonsmall-cell lung cancer in 2005. 

E10A is a replication-deficient recombinant adenovirus containing a wild-type human endostatin transgene constructed from serotype 5 adenovirus (Ad5), E10A uses an adenovirus to deliver the endostatin gene to various tumours. In Phase-II clinical trials endostatin gene therapy was associated with significant inhibition of primary tumours and their metastases. 

Advantages of E10A over other treatment options include:

• Improved efficacy & safety
• Reduced manufacturing costs 
• Longer half-life 
• Simplified dosing regimen 
• Improved patient compliance

Tumor Angiogenesis

Tumor angiogenesis is a vital process that facilitates tumor growth and survival. It is the process by which a tumor stimulates new blood vessel formation and is a critical step in development that enables tumor expansion, local invasion and dissemination by increasing delivery of oxygen, nutrients, and growth factors. The increased blood vessels also form a route for tumor metastases.

There are naturally occurring proteins that can inhibit angiogenesis. Marsala's gene therapy product E10A uses endostatin, an anti-angiogenic factor, to inhibit angiogenesis and to reduce the supply of blood to the tumor. Deprived of nutrients, tumor growth halts and shrinks.