Polycystic kidney disease strikes in varying severity. But in bad cases, the normally fist-sized kidney "can reach the size of a football," Katharine Klinger, senior vice president of genetics at Framingham, Mass.-based Genzyme Inc., told BioWorld Today.
The cause of the disorder is clear: It's a genetic disease in which either polycystin-1 or polycystin-2 are mutated. That in turn leads cysts to replace nephrons, the filtering units of the kidneys. Aside from the fluid buildup, that prevents the kidneys from filtering waste.
The cure is less clear. "Right now, there is no therapy for this disease," said Oxana Ibraghimov-Beskrovnaya, a scientific director of cell biology at Genzyme and the senior author of a paper published online ahead of print by Nature on Nov. 22, 2006. In it, Ibraghimov-Beskrovnaya and her colleagues at Genzyme demonstrated that (r)-roscovitine can lead to "long-lasting arrest of polycystic kidney disease," as the authors formulated in their title.
In their work, they were guided by recent research showing that all known proteins that are disrupted in polycystic kidney disease are located in the primary cilia. Those cilia, Ibraghimov-Beskrovnaya told BioWorld Today, function more or less like antennae, and they regulate the cell cycle.
"There is a direct link between primary cilia abnormality and abnormality in the cell cycle," she said.
The scientists tested two different mouse models of polycystic kidney disease, and found that in both cases, roscovitine, which targets cyclin-dependent kinase, inhibited the development of cysts in all parts of the nephron. Investigating the molecular mechanisms of its actions, the Genzyme team found that roscovitine affected several cyclin-dependent kinases, causing cell-cycle arrest, transcriptional inhibition and attenuation of apoptosis.
At this point, the work's goal is mainly to elucidate the molecular mechanisms of polycystic kidney disease, though Klinger, who is a co-author on the paper, said that "obviously, we're looking for a therapeutic path forward eventually."
For its part, roscovitine is in clinical trials; Short Hills, N.J.-based Cyclacel Pharmaceuticals Inc. announced last June that it was beginning multicenter randomized Phase IIb trials investigating the use of r-roscovitine, also known as seliciclib or CYC202, for the treatment of non-small-cell lung cancer.
Composition-of-matter patents for both roscovitine and purified r-roscovitine are licensed exclusively to Cyclacel. In fact, Cyclacel CEO Spiro Rombotis told BioWorld Today that the company also has the license to a broader patent covering purine derivatives that inhibit cyclin-dependent kinases, so "we own the entire chemical space" in the area. As for commercializing a chemical that is available via the Aldrich catalogue, Rombotis said that "you can buy any patented drug from suppliers" for research purposes, as long as it is not administered to humans.
Cyclacel and Genzyme are collaborating on the use of seliciclib in kidney disease; Cyclacel announced in September 2005 that it had granted Genzyme an exclusive option to license two preclinical stage cyclin-dependent kinase inhibitors for further development in renal diseases and certain related conditions.
Rombotis said that his company was unaware of the data now published in Nature at the time the deal was struck, but "evidently, Genzyme was interested in picking up access to compounds they were studying."
The Nature paper comes more or less on the heels of a paper in the October 2006 issue of Nature Medicine, in which researchers from the University of Edinburgh in Scotland and University College London showed that in both inflammatory lung disease and arthritis, r-roscovitine induced apoptosis in inflammatory neutrophils and independently enhanced the neutrophils' clearance by macrophages.
"That data, seen together with the Nature paper, are quite striking," Rombotis said, "because it is rare for an anticancer agent to have effects outside oncology."