|| Senesco’s therapeutic candidate, SNS01-T comprises three components: a DNA plasmid, a small inhibitory RNA (siRNA) and polyethylenimine (PEI). The DNA plasmid expresses eIF5AK50R (human eIF5A containing a lysine to arginine substitution at amino acid position 50) that up-regulates the apoptotic pathways within cancer cells. By RNA inhibition (RNAi), the siRNA down-regulates the production of hypusine eIF5A and by this mechanism suppresses anti-apoptotic proteins, NF-kB, ICAM and pro-inflammatory cytokines, which are proliferation factors for multiple myeloma. PEI is a cationic polymer that promotes self-assembly of nanoparticles with demonstrated enhanced delivery to tissues and protection from degradation in the blood stream.
SNS01-T is the subject of an open IND and an on-going study in multiple myeloma.
Preclinical studies have shown that SNS01-T is able to promote the elimination of cancer cells through multiple validated mechanisms including:
i. Down-regulating NFkB and anti-apoptotic proteins
ii. Up-regulating p53 and pro-apoptotic proteins
iii. Blocking the IL-6 paracrine growth signal among cells in the tumor environment
The DNA plasmid for eIF5AK50R is under the control of the B29 promoter and enhancer, which has been shown to restrict expression to B-cells (Hermanson et al, 1989; Hermanson et al, 1988; Malone et al, 2006). The mode of action of SNS01-T employs an eIF5A-specific siRNA to reduce the pool of hypusinated eIF5A in myeloma cells, while simultaneously producing eIF5AK50R that mimics the lysine protein, but cannot be hypusinated. This approach promotes apoptosis of multiple myeloma cells, while simultaneously depleting cellular levels of hypusinated eIF5A, which normally protects the cells from apoptosis. SNS01-T reduces tumor burden in murine myeloma models without damaging normal tissues.
Hermanson GG, Briskin M, Sigman D and Wall R (1989). Immunoglobulin enhancer and, promoter motifs 5' of the B29 B-cell-specific gene. Proc. Natl. Acad. Sci. U.S.A. 86: 7341–7345.
Hermanson G., Eisenberg D., Kincade P. and Wall R. (1988) B29: a member of the immunoglobulin gene superfamily exclusively expressed on beta-lineage cells. Proc Natl Acad Sci USA 85 : 6890-6894.
Malone CS, Kuraishy AI, Fike FM, Loya RG, Mikkili MR, Teitell MA, Wall R (2006). B29 gene silencing in pituitary cells is regulated by its 3’ enhancer. J Mol Biol 362 : 173-183.