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Chasing US Lead, Japan s GeneCare Takes Aim at Cancer With RNA Interference-Based Therapeutics

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As the world’s second-largest pharmaceutical market, it should come as no surprise that Japan is home to a wide variety of drug developers. And just like in the US, the world’s biggest drugs market, the majority of Japanese pharmas are focused on small molecules.

However, as the potential of RNA interference grows, so, too, does the number of Japanese companies exploring the gene-silencing technology as a therapeutic modality. One of these is GeneCare Research Institute, which claims to be Japan’s only RNAi-based drug developer.

GeneCare was founded in December 2000 by a group of scientists working at a Japanese government- and private-sector-sponsored research consortium called AGene Research Institute, Yasuhiro Furuichi, president, CEO, and co-founder of the company told RNAi News last week.

AGene was set up to investigate the cellular mechanisms behind aging and the genetic disease Werner syndrome, which is characterized by premature aging and a predisposition to malignancies, he said. The consortium had a 7-year term, after which certain of its research was out-licensed to GeneCare.

According to GeneCare, the gene responsible for Werner syndrome, called WRN, encodes a protein that was shown to act as a DNA helicase with exonuclease activity. WRN is a member of the RecQ helicase gene family, which also includes RecQ1, Bloom syndrome gene (BLM), Rothmund-Thomson syndrome gene (RTS), and RecQ5.

Mutations in BLM and RTS are known to be behind two tumor-prone genomic disorders, while the company’s own research has found that expression of RecQ1, BLM, WRN, and RTS helicases are highly up-regulated in both tumor cells and rapidly growing normal cells.

“From this research, we had a hint [about how] to tackle the cancer problem,” Furuichi said, and the company began screening for small-molecule inhibitors of the RecQ helicase family members.

It was around this time, however, that data demonstrating the efficacy of RNAi began showing up in peer-reviewed journals, and GeneCare started trying to silence the DNA helicase genes with siRNAs. “We found that [RNAi] really works well at low concentrations, and when comparing small-molecule inhibitors with the effect of siRNAs, we thought maybe siRNAs are a … better way to [solve] this problem,” he said.

With that, the company turned its attention to developing siRNAs, becoming “the only company in Japan that is explicitly [using] RNAi technology [as the basis] for new drugs,” according to Furuichi. “There may be some other company coming [onto the field], but I haven’t seen it yet.”

(As reported by RNAi News, Japan’s Otsuka Pharmaceutical has said that it is exploring the use of RNAi to treat disease, although the company is primarily a small-molecule developer [see RNAi News, 12/5/2003].)

The Research

GeneCare researchers found that siRNAs against WRN and RecQ1 were able to suppress the growth of cultured HeLa cells, as well as induce apoptosis in tumor-derived cells including those from lung, liver, breast, skin, and renal tumors, the company said.

In in vivo experiments, siRNAs against either of the two DNA helicases were injected with polyethyleneimine around the tumor tissue into human A549 lung tumor cell-bearing nude mice. The result was that tumor growth was significantly suppressed, with the RecQ1 siRNA showing particularly efficacy. GeneCare noted that similar results were seen with siRNAs injected intravenously with polyethyleneimine, although the company does not expect polyethyleneimine to be the best delivery system for an RNAi-based therapy.

With these data, GeneCare is now in the process of identifying the best siRNA sequence for targeting RecQ1, which it is focusing it’s initial efforts on developing as a cancer treatment. The company expects to have identified this sequence in the first half of 2005, and to have a systemic delivery system validated before year-end.

The company plans to wrap-up pre-clinical development of a drug candidate during 2006 in order to be ready for phase I testing in 2007.

GeneCare, however, is a small firm with only about 31 employees, and Furuichi noted that the company is on the prowl for a big pharma partner that will help fund the clinical development of an siRNA drug. That search, which has been expanded from just Japanese drug makers to include American and European ones as well, is currently ongoing, he said.

To help it make its case to potential collaborators, GeneCare has assembled an intellectual property estate that just got a little bigger this month through a licensing deal with Alnylam Pharmaceuticals.

According to GeneCare, it has applied for patents on several helicases belonging to the RecQ family including WRN and RecQ1, with specific claims on the use of siRNAs against the helicases into order to induce tumor-specific apoptosis. GeneCare also became the first company to strike an IP licensing arrangement under Alnylam’s InterfeRx program (see RNAi News, 12/19/2003). Alnylam said that GeneCare took an exclusive license to develop and sell RNAi drugs against two DNA helicase genes associated with cancer, but specific details of that deal remain undisclosed.

Despite its focus on RNAi, GeneCare has also identified a group of genes that it calls “tumor-specific apoptosis-inducing genes.” About 80 these TsAIGs are believed to play a role in DNA repair and genome stabilization, and siRNAs against these genes have been found to induce apoptosis in tumors. GeneCare is looking for partners interested in using the TsAIGs as targets for small-molecule cancer drug discovery.

Additionally, GeneCare is conducting an anti-inflammatory drug-discovery project. The company is currently looking for a partner interested in developing these small molecules into clinically applicable drugs.

— DM

 

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