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RXi Data Shows Long-Term CNS Delivery of siRNA Can Slow ALS Progression in Mouse

Researchers from the University of Massachusetts Medical School late last month published data showing that chemically modified siRNAs targeting a mutant gene associated with familial amyotrophic lateral sclerosis could slow the progression of the disease in a mouse model when delivered via long-term infusion.
Treatment with the siRNAs also extended survival in the mice, according to the findings, which appeared in the online version of the Journal of Biological Chemistry.
“Based on this work, we believe that long-term administration of chemically modified RNAi compounds to the central nervous system has potential promise for the treatment of inherited ALS … and other chronic central nervous system disorders," RXi President and CEO Tod Woolf said in a statement.
Under a deal signed in January 2007, the company holds the rights to all therapeutic RNAi technology developed at UMMS for three years, including the technology described in JBC (see RNAi News, 1/18/2007).
In the paper, a research team led by UMMS investigators and RXi advisors Tariq Rana, who is also a co-founder of RXi, and Zuoshang Xu explored the use of continuous, long-term administration of SOD1-targeting siRNAs in a mouse model of ALS.
“Previous studies have shown that short hairpin RNAs delivered by gene therapy can trigger RNAi against mutant SOD1 and other disease genes and slow the disease progression in animal models,” the researchers wrote. “However, clinical application of this approach is hampered by its potential toxicity and its difficulty in stopping the therapy if adverse effects develop,” such as the shRNA-associated toxicities described by Stanford University researcher Mark Kay last year (see RNAi News, 5/25/2006).
While direct delivery of siRNAs could sidestep this issue, the oligos have difficulty crossing the blood-brain barrier when administered peripherally, they noted. Further, they cautioned that recent data showing that siRNAs conjugated to a peptide from rabies virus can enter the central nervous system has not yet been proven to be safe or effective for repeated or long-term administration.
“An alternative method is to deliver siRNA directly into the CNS, which circumvents” the blood-brain barrier, they wrote.
To do so, Rana, Xu, and colleagues delivered their siRNAs into mice intrathecially over a 28-day period using an implantable catheter and osmotic pump — a delivery approach they noted is “practical in humans” despite the disadvantages of requiring surgery to implant the delivery system and the long-term wearing of the devices.
At one week, they observed “dramatic knockdown” of SOD1 in mice receiving siRNA treatment at rates of 100 to 400 micrograms a day.

“Previous studies have shown that short hairpin RNAs delivered by gene therapy can trigger RNAi against mutant SOD1 and other disease genes and slow the disease progression in animal models. However, clinical application of this approach is hampered by its potential toxicity and its difficulty in stopping the therapy if adverse effects develop.”

“However, infusion at these high doses was not feasible for long-term administration because the animals develop signs of toxicity,” the researchers wrote. Lower doses of 4, 8, and 16 micrograms a day were tolerated and effective for knocking down SOD1 in a dose-dependent manner over the full 28 days of the experiments.
Yet the “overall therapeutic efficacy in this study is relatively modest,” the investigators conceded, noting that SOD1 knockdown was about 15 percent at the 4 microgram dose.
They attributed this to the “relatively low” doses of siRNAs administered over the course of the study; the fact that treatment was initiated at the onset of disease, which is most likely when treatment would be administered in a clinical setting but “relatively late in disease progression” in the model used; and because treatment only lasted 28 days, which “does not cover the entire disease period.”
In addition, the researchers wrote that therapeutic gene silencing is “extremely challenging” in the ALS model they examined because the mice carry more than 20 copies of human mutant SOD1 transgene and express about 17 times of the mutant gene over the endogenous SOD1 level, and because the disease is “dramatically” accelerated in the mouse model versus human ALS.
Portions of the JBC data had previously been disclosed by RXi in various corporate presentations, including one given at last year’s BIO CEO and Investor meeting (see RNAi News, 2/15/2007).
ALS at RXi
ALS is a neurological disorder characterized by the degeneration of motor neurons. The most common form of the disease, sporadic ALS, accounts for 90 to 95 percent of all ALS cases but has no known causes. The other form, familial ALS, accounts for the remaining 5 to 10 percent of cases and is triggered by gain-of-toxicity mutations in the superoxide dismutase 1 gene, or SOD1.
Given its genetic basis, familial ALS has been a target of interest for a number of people working with RNAi. However, CytRx was one of the first RNAi companies to begin examining the potential of the gene-silencing technology to treat the disease, striking alliances with various academic institutions, including UMMS, as early as 2003 (see RNAi News, 10/17/2003).  
Although CytRx officials had at one time predicted that the company’s RNAi-based ALS therapy would reach the IND stage by the end of 2004, the company’s interest in the therapeutic potential of RNAi flagged as it refocused onto small-molecule drugs, including one for ALS (see RNAi News, 5/20/2005).
But in the hands of CytRx spinoff RXi, the ALS program, along with all of CytRx’s other RNAi drug efforts, has taken center stage. According to Woolf, RXi is currently converting the siRNAs described in the JBC paper into the company’s proprietary format, “which we have found to be better tolerated in animal studies.”
Woolf told RNAi News in an e-mail this week that the company has not released any new information regarding the status of the ALS program beyond what it has publicly stated earlier this year.
About a month ago, in conjunction with the initiation of public trading of RXi stock, Woolf said during a conference call that the company is aiming at submitting its first IND some time next year but did not specify which of its preclinical programs would yield a regulatory filing (see RNAi News, 3/13/2008).
Still, at last year’s BIO CEO conference he indicated that the ALS program was one of the company’s most advanced drug-development efforts (see RNAi News, 2/15/2007). RXi is also working in the fields of cancer, type II diabetes, and obesity.
However, at that time Woolf also indicated that forging a corporate alliance before the end of 2008 was a key priority for RXi, suggesting that the interests of a potential partner may influence the company’s choice for its lead drug program.

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