Traversa Therapeutics has filed for bankruptcy after failing to secure the financing it needed to continue advancing its core RNAi delivery technology, Gene Silencing News has learned.
However, a portion of that technology is now being shopped around by Traversa co-founder Scott Petersen, who is on the lookout for an industry partner interesting in bringing him on board to continue its development.
Traversa was founded in mid-2006 to commercialize a delivery technology — created in the lab of University of California, San Diego, researcher Steven Dowdy — that combines protein transduction domains linked with a double-stranded RNA binding domain.
According to Traversa, an siRNA coated with the so-called PTD-DRBD molecules binds to cell surface proteoglycans, which stimulates macropinocytosis. The RNAi agent then enters the cell inside a macropinosome, at which point the pH inside the vesicle drops and the siRNA is released from the PTD-DRBD molecules into the cytoplasm.
Traversa initially found some success, closing a $5 million Series B financing round in 2009 (GSN 4/2/2009), inking a deal that same year to market the PTD-DRBD technology for research applications with Integrated DNA Technologies (GSN 6/4/2009), and forging a research arrangement with Sanofi-Aventis in 2010 (GSN 3/25/2010).
However, the company's funding eventually dried up, and additional capital was not forthcoming.
“Although the siRNA delivery science at Traversa worked well, it took longer to pharmaceuticalize than initially anticipated, which, unfortunately, chronologically coincided” with the departure of several big pharma players from the RNAi field, Dowdy told Gene Silencing News in an e-mail. “Traversa was not well positioned for the new business environment.”
While Traversa was up and running, it was working not only on the PTD-DRBD technology, but a related delivery approach that was invented by Petersen while he was a post-doc in Dowdy's lab and advanced through in vitro testing while he was director of chemistry at Traversa.
Dubbed siRNN, the delivery method involves directly modifying the phosphate backbone of an oligo such as an siRNA in order to mask its negative charge, which prevents its passing through the cell membrane.
“The siRNN technology builds the oligonucleotide from scratch ... one monomer at a time,” installing reversible phosphate-protecting groups at any position along the oligo's backbone, Petersen explained to Gene Silencing News on the sidelines of the Tides: Oligonucleotide and Peptide Research, Technology, and Product Development conference in Las Vegas earlier this month. “Starting with the monomers, we just grow from the 3' to the 5' direction using a standard Caruthers method … with standard reagents for doing the coupling, the deprotection, and the rest of the chemistry involved in elongation.”
The modified molecules are then joined to cell-penetrating peptides or other localization moieties to facilitate cellular targeting.
Petersen described the technology as “a multi-stage rocket: a cell-penetrating peptide [or localization agent] brings the siRNN to the cell and the charge neutralization on the backbone allows it to penetrate the membrane.
“Once it is inside of the cell, all of those components fall off and leave just the wild-type 2'-modified oligo construct to interact with RNase H or the RISC complex, depending on what the oligo is and the target you're going after,” he said. Notably, the oligos do not require a delivery vehicle.
Petersen said that roughly 20 percent of Traversa's budget went to funding the siRNN approach, but that the company had kept it under wraps as it established the relevant intellectual property.
That IP essentially consists of US patent application No. 20110294869, entitled “Self-Delivering Bio-Labile Phosphate-Protected Pro-Oligos for Oligonucleotide-Based Therapeutics and Mediating RNA Interference.”
Petersen is listed as the sole inventor on the application, and it is assigned to Traversa, but he said that he has acquired its full rights following the company's bankruptcy filing and is maintaining them in a holding company called LipoSciences.
“Traversa had access to the technology when I was there … [and] helped me to refine the invention,” he said. “Now that they've gone under … I'm trying to take that technology to a larger company that's interested in developing it.”
Petersen said that while he's considering all possibilities for moving the siRNN technology forward, ideally he would partner with a firm that would bring him on board to handle its further development. “This work is going to take significant funding and it's not something I can bootstrap on my own without VC or without a partner,” he said.
“We've moved this technology far enough along that it's ready to go to the next stages,” which include optimization of the cell-penetrating peptide side and of the number and placement of the protecting groups. “I'm [also] going to need to evaluate whether the nuclease stability is high enough … and then move [the technology] into in vivo” testing.
Thus far, work with the siRNN system has been strictly in cell culture, although the data have been promising, Petersen said, with final experiments at Traversa showing between 87 percent and 94 percent target knockdown with “very little cytotoxicity.”
“I generated all the reagents to go to the next step, and that experiment was sitting in the refrigerator when I left Traversa,” Petersen said. “It is very frustrating.”