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RNAi Startup Believes siRNAs Can Treat Extremely Rare Skin Disorder

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As interest in the RNAi drugs sector grows, so does the number of companies entering the playing field. The newest entrant is Santa Cruz, Calif.-based TransDerm, which, with the help of a nonprofit consortium, some well-known academic centers, and a former employer, is trying to use siRNAs to develop therapeutics for an extremely rare skin disorder.

The four-person company was co-founded late last year by CEO Roger Kaspar, who previously served as vice president of biology for Somagenics, a startup focused on developing siRNA libraries and a novel antisense-related gene-silencing technology called RNA lassos (see RNAi News, 4/30/2004).

TransDerm's primary goal, according to Kaspar, is to develop delivery approaches for nucleic acid-based treatments for pachyonychia congenita, a rare autosomal disorder characterized by hypertrophic nail dystrophy and focal palmoplantar keraderma with blisters.

While at Somagenics, Kaspar participated in a symposium sponsored by the International Pachyonychia Congenita Consortium "where a group of physicians and scientists that all had different skills were brought together with the idea of trying to figure out how to come up with a therapeutic as quickly as possible for PC," he told RNAi News this week.


"One thing led to another and finally I told them, 'If you want to put up some money, we'll start a company [with] goals aligned with your goals for the initial couple of years.'"

The investigators sought Kaspar's and Somagenics' help with their PC project, "and I told them I was happy to help … but I couldn't help them the way they wanted me to" given that Somagenics was focused on more widespread diseases such as HIV and hepatitis C.

"One thing led to another and finally I told them, 'If you want to put up some money, we'll start a company [with] goals aligned with your goals for the initial couple of years,'" Kaspar said. An undisclosed angel investor then provided the funding necessary to get TransDerm up and running, and "that's how the whole thing started."

The investor "is basically [a group] that's very interested in seeing a therapeutic be brought to clinic, [and who] realized that it's such a rare disorder • there's only several hundred patients that have been identified worldwide • that if they didn't do something, it was unlikely the NIH or some big company would pick up on this," Kaspar said.

"And yet, this disease is a great disease [for therapeutic intervention] because the molecular targets are well-defined and it [affects] the skin, which is fairly accessible," he added.

During a poster session at the first meeting of the Oligonucleotide Therapeutics Society in New York City last week, Kaspar presented in vitro data on the use of siRNAs to inhibit the mutant genes responsible for PC. Also contributing to the poster data were researchers from Ninewells Medical School in the UK, Rockefeller University, and Johannes Gutenberg-Universitat in Germany.

According to the poster, PC is caused by mutations in genes encoding keratin 6a or keratin 16, "including several recurrent mutations at the N171 site of K6a, which can be deleted (K6a 171del) or mutated at a single nucleotide resulting in an amino acid change (N171K)."

Kaspar and his colleagues demonstrated that a fusion protein comprising "wild-type K6a and YFP reporter results in keratin filaments in transfected human PLC and keratinocyte cells as assayed by fluorescence microscopy. Similar constructs containing the N171K or 171del mutations result in keratin aggregates," the poster notes.

The researchers designed siRNAs to target the mutation sites, and co-transfected them with K6a/YFP constructs (wild-type, N171K, or 171del) into 293 FT cells, the poster states. They found that the inhibitors preferentially targeted mutant K6a mRNA.

Additionally, the researchers saw that K6a mutation-specific siRNAs were able to "rescue aberrant keratin filaments in cells co-transfected with a mixture of K6a-wt/YFP and K6a-mut/YFP plasmids," suggesting that "siRNAs can discriminate single [nucleotide] mutations … [and] that 'designer siRNAs' may allow effective treatment of a host of genetic disorders including PC."

PC is a "dominant-negative disorder, so there's a copy of a bad gene and a copy of a good gene," Kaspar explained. Based on the data thus far, "we think we can knock down the bad gene without affecting the good gene."

He noted that he has also conducted follow-on work using "we call a dominant-negative tissue culture model where we introduce a mixture of the wild-type and mutant [K6a], and both of these are fused to a reporter gene. If we put both of them in [the model], it screws up the keratin filaments. But if we put both of them in the presence of [the siRNA] … the mutant form … is knocked down and only the wild-type is left, and you get very nice keratin filament structures being formed."

With these data in hand, Kaspar said TransDerm is working with Stanford University researcher Chris Contag to test the siRNAs in mice and begin tackling the delivery issue.

"We have a couple of different [delivery] methods" being tested, Kaspar said. "The most direct is just to do intradermal injections. We're also working [in collaboration with Somagenics] on what we call a 'gene cream,' which is a formulation where we introduce our siRNAs or reporter genes and then rub this onto shaved skin of mice. It works pretty well and is obviously something we're interested in making work even better."

He noted that since one of the biggest hurdles PC patients face is walking due to foot pain, TransDerm is initially working on a treatment that can be applied directly to the soles of the feet.

While this work progresses, Kaspar said, TransDerm is trying to schedule a pre-investigational new drug application meeting with US regulators "to find out exactly what they'll require of us to use these things in patients."

He noted that TransDerm is part of the International Pachyonychia Congenita Consortium and collaborates with nonprofit organization PC Project, which is expected to help the company find and enroll patients in a possible clinical trial.

Aside from PC, Kaspar expects that TransDerm's technology could apply to a number of disorders.

"There are about 10,000 different congenital disorders in man, and about 20 percent of them involve the skin," he said. "If we can knock down any gene specifically, which from our tissue culture experiments and early animal work [looks possible], there is a tremendous number of disorders we could go after that are caused by a single gene. Then there are multi-factorial [diseases] such as psoriasis or atopic dermatitis that ought to be amenable to these types of treatments."

• Doug Macron ([email protected])

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