Basic cell biology investigations into how lipase breaks down cell walls in plants laid the foundation for Senesco Technologies.
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.
Preclinical studies at Senesco showed that upregulation of factor 5A recruits messenger RNAs that code for proteins such as p53, caspases, and cytokine receptors. Simultaneously, factor 5A downregulates proliferative proteins such as bcl-2 and VEGF. Senesco’s overall strategy for creating clinical treatments is to increase factor 5A inside cancer cells, thereby boosting apoptosis to destroy tumors.
When first synthesized in cells, factor 5A contains the amino acid lysine, which DHS converts to the unusual amino acid hypusine. Researchers at Senesco discovered that the lysine form of factor 5A is proapoptotic, whereas the hypusine form of the protein inhibits proinflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), gamma interferon, TNF-alpha, and the transcription factor NF-kB. Several new drugs on the market target these proinflammatory cytokines.
Senesco scientists coupled a nanoparticle with a small inhibitory RNA (siRNA) that shuts down both the lysine and hypusine forms of Factor 5A in endogenous tissues, thereby blocking production of proinflammatory cytokines. An added plasmid, which encodes the lysine form of factor 5A, turns on apoptotic pathways within cancer cells.
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.
Senesco’s factor 5A technology also may control apoptosis and inflammation associated with infectious and chronic diseases. Researchers in William Scheld’s laboratory at the University of Virginia School of Medicine, Charlottesville, infected mice with a lethal dose of nasally administered H1N1 mouse influenza. Then they treated the mice with the siRNA against Factor 5A. Among mice treated with the siRNA, 52% survived, compared to 14% of mice that did not receive the siRNA.
In other experiments, mice were given a lethal dose of lipopolysaccharide (LPS). All the mice died within 48 hours from dramatic increases in proinflammatory cytokines, a condition similar to sepsis.
Among mice treated with the siRNA before or after LPS, 100% survived. The siRNA against factor 5A also protects transplanted pancreatic islet cells from cytokine-induced death. These preclinical results suggest that targeting factor 5A may benefit a variety of diseases such as lung inflammation and diabetes, according to Dondero.