Marcel Gubler
F. Hoffmann-La Roche Ltd, Switzerland
Title: Kidney cell assays for in vitro safety profiling of single stranded oligonucleotides
Biography
Biography: Marcel Gubler
Abstract
Chronic treatment of patients with classical low molecular weight drugs like aminoglycoside antibiotics, antivirals and immune-suppressants are known to induce kidney toxicities. Particularly molecules with high renal clearance
can accumulate in proximal tubule epithelial cells (PTECs) of the kidney cortex where high tissue concentrations induce damage to tubular structures and may lead to loss of organ function. Similar toxicities have also been observed with other drug modalities such as for example some single stranded oligonucleotides (SSOs). SSOs represent a class of novel drugs to
modulate gene expression in many diff erent diseases for which there is no adequate treatment currently available. In order to secure development of renal safe drugs, we have established assays with animal and human primary as well as immortalized PTECs for profi ling of nephrotoxic reference compounds side-by-side with SSOs that had previously been tested in rats for signs of organ damage. Using assays of cell function, viability, and death, we have been able to clearly discriminate safe from toxic molecules. Overall, the observed eff ects were similar across PTECs derived from animals and humans and correlated with the in vivo fi ndings for the molecules tested in rats. Th us, we believe that our cellular assays will be useful for rapid in vitro profiling of SSOs for selection of safe compounds on human cells prior to clinical testing.
