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Keeping a Low Profile, Gradalis Aims to Move RNAi Cancer Rx Into Clinic This Year

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As strides are made in addressing oligonucleotide delivery challenges, cancer has increasingly become a promising indication for RNAi-based drug candidates.
 
A number of companies have been openly working in the field, such as Calando Pharmaceuticals, which last week announced that it had begun dosing patients in a phase I study of its siRNA-based cancer therapy CALAA-01 (see RNAi News, 6/5/2008).
 
But one company, Dallas, Texas-based Gradalis, has been advancing its own RNAi-based cancer therapy toward the clinic in a quieter fashion and is poised to begin testing the drug in humans possibly before the end of the year.
 
According to John Nemunaitis, Gradalis co-founder and executive director of the Mary Crowley Medical Research Center, the company completed a $10 million Series A financing round “a little more than a year ago,” and has used the money to build a research staff of about 10 PhDs and hire lab technicians and support personnel.
 
Because the Series A investments were made entirely by private investors, “we haven’t had any need to be very visible [and] … we’ve tried to stay very low on the radar screen,” he said. ”At some point, we’ll move forward with more visibility, but [not] right now.
 
“We haven’t even created a website,” he noted.
 
Still, representatives from the company have been making the rounds at scientific conferences, and Nemunaitis presented some preclinical data from the company’s most advanced RNAi drug effort at last month’s American Society of Gene Therapy annual meeting in Boston.
 
At the event, Nemunaitis reported on a process he and colleagues at Mary Crowley developed to identify cancer-relevant molecular targets by analyzing tumor samples from individual cancer patients.
 
“When a cancer is resected, as part of the … [initial] process of identifying the tumor … we microdissect the malignant and normal tissue,” he told RNAi News last week. “We [then] do a complete quantitative genomic and proteomic assessment of that tissue. From there, we compare the normal and malignant signals.
 
“Quite often, the normal and malignant signals are very similar with most mRNA and protein signals,” Nemunaitis noted. “But you’ll find the critical mass of signals that are distinctly different in the cancer as opposed to the normal [tissue], and that’s where we focus.”
 

“We haven’t had any need to be very visible [and] … we’re tried to stay very low on the radar screen. We haven’t even created a website.”

The researchers then bioinformatically prioritize the signals that are “uniquely malignant … and have a function that has something to do with the malignant process,” such as survival or tumor spread, he said. “Basically, we identify what we think is the most significant target in a cancer patient … and focus our therapeutic attack on that target.”
 
Details about this identification process were published last year in Cancer Gene Therapy.
 
Using tissue samples from about 150 patients with various solid tumors, Nemunaitis said at ASGT that he and his research team pinpointed Stathmin-1, a protein involved in microtubule formation that has been linked to abnormal cell proliferation when mutated, as the most promising target for therapeutic intervention.
 
“Stathmin-1 in several patients was identified as the primary signal,” he said. Further, in patients where it was not the primary signal, “it was significantly expressed … giving us confidence that if we successfully move forward an RNAi therapeutic against [it], we would not only have an opportunity to impact those patients with the highest priority signal, but it would probably also be a potentially usable therapy in other patients [in whom the protein] is significantly elevated.”
 
To knock down Stathmin-1, investigators at Gradalis developed a plasmid construct capable of expressing a bi-functional shRNA that triggers both cleavage-dependent and cleavage-independent RISC-mediated inhibition of target mRNA.
 
In in vitro testing, the shRNA construct was able to demonstrate Stathmin-1 knockdown of 90 percent to 98 percent in a variety of tumor cells, Nemunaitis said at ASGT. “We also correlated that knockdown with both apoptosis and [tumor] cell kill.”
 
Currently, Gradalis is conducting animal efficacy and toxicology testing of the shRNA drug, “and we are hopeful [we will be able] to move into the clinic before January,” he told RNAi News.
 
Work remains to be done before any human testing can begin, however, specifically in regards to the ever-present delivery hurdle facing most RNAi-based therapeutics.
 
“We have five different delivery vehicles [developed both in-house and by other groups] that we’re looking at,” Nemunaitis said. “We’ve definitely identified a cationic liposome that we think gives us good activity, but … we haven’t 100 percent settled on the delivery vehicle yet.” He declined to elaborate.
 
At the same time, Gradalis is advancing a number of non-RNAi programs including a gene-replacement therapy for the rare inflammatory muscle disease hereditary inclusion body myositis.
 
Still, Nemunaitis said that the company’s “primary focus is RNAi,” and work developing shRNAs against other cancer targets is ongoing.
 
Although a number of small-molecule and antibody-based targeted cancer therapies are already on the market, he told RNAi News that Gradalis is focusing most of its efforts on the gene-silencing technology because of its ability to knock down a target with high specificity.
 
“Some of the targeted therapies that are out there have multiple mechanisms by which they mediate the anti-cancer effect,” he explained. “RNAi tends to work via a very specific, well-characterized mechanism … and you can generate RNAi [agents] to cancer cells that have as little as a point mutation.”
 
“The critical thing is that it needs to be developed in the right patient … not just a whole population,” he added. “In that setting, if you look at RNAi approaches side-by-side with small molecules and antibodies, you tend to have a higher potency … because of the specificity [to] the target mRNA as opposed to the protein target.”

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