Pre-Clinical DevelopmentThe potency of "silencing RNA" in acting as a novel class of cellular inhibitor in a natural endogenous biological pathway opens new opportunities in biomedical and pharmaceutical research.
The potency of "silencing RNA" in acting as a novel class of cellular inhibitor in a natural endogenous biological pathway opens new opportunities in biomedical and pharmaceutical research. For the successful pharmacological translation of RNAi into a drug, several obstacles need to be overcome. A viable RNAi therapeutic must meet some requirements: cell-type-selective siRNA delivery; pharmacological activity; and challenges in chemistry & manufacturing before moving into clinical development. Silence Therapeutics' candidate Atu027, a chemically stabilized siRNA carried by a cationic liposomal moiety, meets all the above discussed prerequisite and become one of the few viable RNAi therapeutics currently in clinic development.
Development of Atu027: An RNAi Therapeutic for Oncology
Silence Therapeutics' pioneering work on the clinical development program Atu027 clearly illustrates the translation of a scientific discovery into an innovative drug. Silence Therapeutics recognized the necessity of appropriate formulation for application in the body in order to ensure functional siRNA delivery in the target cells. This became realized by the development of suitable liposomal moieties as carrier (AtuPLEX®) for functional siRNA delivery. Pre-clinical studies with Atu027 demonstrated the RNAi-mediated dose-dependent suppression of the PKN3 target gene after repeated intravenous infusions (Aleku et al. 2008a, Santel et al. 2010). These pharmacodynamic studies were accompanied by pharmacokinetic and toxicological studies in order to determine a practical dosage in the clinic. Our drug candidate Atu027 is currently being tested in an escalation Phase-I clinical trial for demonstrating safety in patients with advanced cancer disease.
Atu027 is a four component containing novel RNAi therapeutic composed of AtuRNAi®-type siRNA (targeting PKN3) within a liposomal formulation. The underlying liposomal formulation being Silence's proprietary AtuPLEX®; which ensure the applicability of Atu027 in the patient's bloodstream and delivers RNAi of the target gene PKN3 in the vascular endothelium.
Our pre-clinical studies unraveled the utilization of liposomal siRNA based on AtuPLEX®; technology in vivo and its activity in the vascular endothelium of the vasculature. This cellular target structure of all blood vessels often becomes affected at the onset and during progression of many diseases. In cancer, angiogenesis (the growth of new blood vessel) leads to the development of a malformed tumor vasculature which supplies the tumor with oxygen and nutrition, helping cancer cells to further grow and ultimately spread. Beyond the abnormal function of the endothelium in tumor vessels, the cancer patient's vasculature becomes permeable in order to facilitate cancer cell colonization at organs site where metastasis occurs. Atu027 can target the "vascular bed" within the patient's body in a way that prevents this critical biological process to take place.
PKN3 in cancer
Silence discovery research focused on identifying novel target genes critical for carcinogenesis and metastasis. The proprietary PKN3 gene (Protein Kinase N3) was originally identified at Silence Therapeutics as a downstream target of activated PI-3 kinase signaling (Leenders et al. 2004).
Numerous scientific reports demonstrate the central role of this signaling pathway in coordinating multiple cell functions in cancer and endothelial cells during malignant growth and angiogenesis.
The PKN3 target gene turned out to be a key factor for cancer progression and metastasis. Its function in the endothelium appears also critical during the different steps of metastasis, since PKN3 might integrate incoming signaling cues for coordinated cellular functions, such as cell adhesion and contact formation, cell shape remodeling, cytoskeletal fluidity, and migration.
"Atu027, a liposomal siRNA, is a novel RNAi therapeutic for cancer therapy suppressing PKN3 gene expression in endothelial cells of the vasculature. In cultured human endothelial cells (HUVEC), Atu027 mediated downregulation of PKN3 led to increased levels of the adhesion protein vascular endothelial (VE)-cadherin. The different levels of VE-cadherin protein are depicted in this image in a color-coded manner reflecting highest VE-cadherin levels as red colored membrane staining.
The authors show that Atu027 treatment modulates the vascular endothelium in a way that metastasis through the blood vessels to the lung is effectively inhibited." Clin Cancer Res November 15, 2010.
Pre-clinical development of Atu027
Multiple studies highlighted the importance of PKN3 during cancer progression and dissemination (Aleku et al., 2008a; Santel et al. 2010). Our research on PKN3 gene function in endothelial cells in vitro and in vivo delineated this target gene as a key regulator of metastasis and cancer progression. Accordingly, Silence proposed that inhibition of PKN3 expression through Atu027 treatment in vivo may result in the reduction or modulation of endothelial functions interfering with tumor formation and metastasis. Pre-clinical experiments in various cancer models supported the idea that Atu027 particularly inhibits the dissemination and progression of metastasis to adjacent lymph nodes and the lung. This antimetastatic activity can be attributed to changes in the function and organization of the vascular and lymphatic vessels due to depletion of endothelial PKN3 expression.
Atu027 will interfere with the metastatic cascade and may offer a novel alternative treatment option for the prevention of metastatic disease and progression in cancer patients.
Partnered Clinical Development Programs
Our partners in the pharmaceutical industry trust in Silence Therapeutics proprietary AtuRNAi® technology for developing their own siRNA-based therapeutics clinical programs in the area of ophthalmology as well as kidney injury and transplantation. Clinical trials carried out with these molecules (see Pipeline) demonstrated so far the safety of this class of nucleic acid therapeutics in the tested clinical settings.