Senesco and the Factor 5A1 gene

Senesco is a small research-based company specializing in “genetic technologies designed to regulate cell death.”  A company that started out with focus on commercial agriculture, it has been exploring a proprietary gene, Factor 5A1, that might well also have a role in treating human diseases, particularly cancers.  The story of Senesco is interesting because it illustrates the serendipity that can lead to drug discovery, because it describes a research company that has no research labs, because it points to another gene that could be a key to curing certain cancers, and because after five years the possible cancer therapy is still in a preclinical stage tested only on small animals.

The trade publication Gen featured a story this week, Senesco Attempts to Exploit Cell Death, which tells the early history of the company.  “At the University of Waterloo, Ontario, John Thompson, Ph.D., now Senesco’s CSO, discovered that lipase is regulated by two genes that work together to control senescence in plants. Because the finding held promise for extending the life of plants, Sascha Fedyszyn co-founded Senesco in 1998 to explore agricultural applications. A few years later, company researchers learned that the same senescence cascade in plants operates in humans, too. “That was the start of our life science work,” says Fedyszyn, vp, corporate development. — Senesco scientists found that two genes—eukaryotic translation initiation Factor 5A and deoxyhypusine synthase (DHS)—are powerful regulators of programmed cell death, known as apoptosis in human cells and senescence in plant cells. Although cell death is a normal function, premature apoptosis leads to inflammatory conditions, cancer, and tumor growth.”

The company outsources its research.  “To take greatest advantage of our early stage discoveries, we have formed a highly focused and efficient R&D department headed by John Thompson, Ph.D., the inventor of our technology. This R&D takes place at several highly regarded academic institutions around North America. While most early-stage biotechnology companies spend millions on R&D, we are conducting top-notch research with relatively minimal cash burn by utilizing these institutions(ref).” 

The company maintains relationships with a number of agricultural product firms.  “Agricultural research and development programs continue through licensing and joint ventures with agricultural biotechnology companies such as Monsanto, Bayer Crop Science, and Scotts. Efforts are under way to improve corn, soybeans, rice, cotton, bananas, canola, turf grass, and ornamental plants(ref).”

Relating to the life sciences area, “Senesco’s technology is based on the discovery that Factor 5A1, one of two human genes encoding eucaryotic translation initiation Factor 5A, regulates apoptosis as well as certain execution genes, pro-inflammatory cytokines, receptors and transcription factors and therefore plays a key role in cell death and inflammation. We believe that Factor 5A1 is a novel and potentially powerful therapeutic target for a broad range of apoptotic diseases, including inflammatory/ischemic diseases and cancers(ref).” 

In plain language, the following from the company’s web site says that Factor 5A1 kills cancer cells without affecting normal cells.  “Factor 5A1 functions as a shuttle protein, selectively translocating mRNAs required for apoptosis and cytokine function from the nucleus to cytosolic ribosomes for translation. Our preclinical studies have shown that Factor 5A1 kills cancer cells through both the intrinsic (p53) and the extrinsic (cell death receptor) pathways. We have specifically shown that Factor 5A1 regulates the expression of p53, caspases, TNFR1 (TNFa receptor) and the IFN-gamma receptor, and that it also negatively regulates bcl-2 and telomerase. Our studies to date have shown that Factor 5A1 may be non-toxic to normal cells, presumably because of its function as a shuttle protein. Normal cells are not actively expressing mRNAs of cell death genes, and therefore the Factor 5A1 protein, even if present in normal cells, is non-functional(ref).”

According to the Gen article “The company’s first drug candidate based on this combination therapy, SNS-01, targets multiple myeloma. The cytokines IL-1, IL-6, and NF-kB are known to contribute to the proliferation of this disease. The design of SNS-01 “provides a perfect combination for killing multiple myeloma cells,” says Richard Dondero, Senesco’s vp of R&D. Multiple myeloma is not only a cancer, but also a disease of the immune system with a proinflammatory side. “Our technology lends itself to that,” Dondero says. — Collaborators at the Mayo Clinic tested SNS-01 in in-vitro experiments and on mice. Within two weeks of intravenous delivery of SNS-01, “tumor reduction was visible, and some multiple myeloma tumors were even completely eradicated within six weeks,” says Dondero. Senesco plans to file an IND application for SNS-01 in the treatment of multiple myeloma early in 2010.”

Promotion or inhibition of Factor 5A1 may also serve other therapeutic purposes and Senesco’s experiments with therapies  based on Factor 5A1  go back at least five years.   For example, according to a 2004 report Factor 5A1 may be useful for controlling glaucoma. “By inhibiting Factor 5A1, Senesco blocked TNF-alpha-induced apoptosis by 80% in lamina cribrosa cells of the human optic nerve head. — TNF-alpha is strongly upregulated in the optic nerve head of the glaucomatous eye, and TNF-alpha-induced apoptosis appears to be an important determinant of the progressive neurodegeneration characteristic of glaucoma. Thus, inhibition of TNF-alpha-induced apoptosis may reduce damage to the optic nerve during glaucoma.”  Another 2004 report indicated Proprietary gene Factor 5A1 induces atopsis in lung cancer tumors of mice. 

It will be interesting to see whether Senesco will be successful in moving treatments involving the targeting of Factor 5A1 into clinical trials and, if so, how long it will take for this to happen.