Targeted Genetics this week announced that it has acquired exclusive rights to the preclinical Huntington’s disease program it had been working on since 2005 with Merck subsidiary Sirna Therapeutics.
The deal gives Targeted Genetics its first in-house RNAi drug program, which Executive Vice President and CSO Barrie Carter said would likely reach clinical testing some time in late 2009 — a timeline the company is confident about in light of newly published data showing that a major toxicity hurdle associated with the use of shRNAs in the brain could be overcome by incorporating an artificial microRNA expression system.
Under the terms of the arrangement with Sirna, Targeted Genetics received a license to undisclosed intellectual property held by Merck that “may [be] necessary to develop and commercialize” an expressed RNAi-based drug for the disease.
Additionally, Merck has assigned to Targeted Genetics a licensing agreement Sirna signed with the University of Iowa related to an ongoing collaboration to develop RNAi treatments for Huntington’s disease.
In exchange, Targeted Genetics will pay Sirna an undisclosed royalty on sales of products arising from the Huntington’s disease program. Additional terms were not disclosed.
“This moves all of the key pieces of this program to Targeted Genetics and gives us exclusive rights and direct involvement with the University of Iowa to expedite the program," Targeted Genetics President and CEO Stewart Parker said in a statement. "This program is our primary proof of concept in the area of expressed RNAi, which we believe could present multiple product opportunities."
The company, however, is still evaluating those opportunities, a process that involves deciding the “relevant places where RNA interference can be used [and] the particular places where [the company’s adeno-associated viral vector] delivery systems have an advantage,” Carter noted.
He added that Targeted Genetics expects to “define one or more other targets” that will be added to the RNAi pipeline this year.
In early 2005, Sirna announced that it had formed a collaboration to combine its own siRNA expertise with Targeted Genetics’ AAV vector-based delivery systems (see RNAi News, 1/14/2005), building off of an existing alliance the RNAi shop had forged with University of Iowa researcher Beverly Davidson (see RNAi News, 6/11/2004).
Despite promising data from Davidson’s lab on using RNAi to treat the disease, Merck decided to drop the program after it acquired Sirna two years later (see RNAi News, 1/4/2007) because it did not fall within the big pharma’s areas of interest — a fate also shared by Sirna’s one-time hair-removal drug program (see RNAi News, 1/24/2008).
“What we’re looking at is [partially] knocking down … the level of the mutant protein while not totally eliminating the wild-type allele. Because of that, we need to do some pretty extensive studies in … the mouse model of Huntington’s to show that we can, in fact, get that knockdown and not have any untoward effects or cause earlier onset of disease.”
Nonetheless, Targeted Genetics remained interested enough in the Huntington’s disease program to bring it in-house, in part because the nature of the condition makes it a good candidate for expressed RNAi agents.
“Huntington’s is a brain disease, [and] it’s not going to be easy to either deliver oligonucleotides across the blood-brain [barrier] or do repeated injections,” Carter said. As such, an expressed RNAi approach, such as one incorporating Targeted Genetics’ AAV vectors, seems promising.
AAV vectors “persist for extraordinary lengths of time, particularly in non-dividing cells like neurons,” Carter said. “So we can expect to do a one-time delivery and express RNAi knockdown by using short hairpin RNA.”
Also contributing to Targeted Genetics’ confidence in the program are recently released data showing that significant toxicity associated with shRNA delivery to the brain can be overcome.
Huntington's disease, which is a member of a class of disorders known as polyglutamine diseases, is caused by the expansion of a CAG repeat in exon 1 of the gene huntingtin. Based on this, silencing this mutant form of huntingtin could be a promising treatment strategy.
However, this week a team of University of Iowa researchers led by Davidson, along with colleagues at Targeted Genetics, reported that shRNAs targeting human Huntington’s disease and mouse Huntington’s disease homolog mRNAs, as well as control shRNAs, triggered significant neurotoxicity in a mouse model.
According to the paper, which appeared this week in the early edition of this week’s Proceedings of the National Academy of Sciences, a “buildup of antisense RNAs and subsequent off-target silencing of unintended mRNAs” was likely the cause of the toxicity.
To address this issue, the investigators moved the shRNA sequences into an artificial microRNA scaffold, which “significantly reduced neurotoxicity … with no sacrifice in gene-silencing efficacy,” they wrote in PNAS. “We correlated this positive effect to lower steady-state levels of mature antisense RNAs processed from the artificial [miRNA] relative to” the shRNAs not placed in the scaffold.
To Carter, who was a co-author on the PNAS paper, the miRNA scaffold approach, which will be incorporated into its Huntington’s disease clinical candidate, eliminates perhaps the biggest preclinical issue that was facing the program.
Still, questions about the overall safety of an RNAi-based treatment for the disease need to be addressed before human trials can begin, he stressed.
“Huntington’s is a dominant disease, so we’re trying to knock down the mutant allele,” he explained. Since it is not possible to design an RNAi molecule capable of distinguishing the mutant form of huntingtin from its wild-type counterpart given the small difference between the two, however, this kind of treatment will also knock down the normal allele.
This may not be a major issue since “it is not clear that the huntingtin gene has highly important functions in adult life. It’s important in [childhood] development, but in adults it is not clear that you need a full complement of normal huntingtin gene to function,” Carter said.
“What we’re looking at is [partially] knocking down … the level of the mutant protein while not totally eliminating the wild-type allele,” he said. “Because of that, we need to do some pretty extensive studies in … the mouse model of Huntington’s to show that we can, in fact, get that knockdown and not have any untoward effects or cause earlier onset of disease.”
He noted that animal studies have show than even a 50 percent knockdown of the mutant huntingtin gene can have a significant therapeutic benefit.
Additionally, Targeted Genetics intends to follow-up this mouse work in non-human primates — a project that will likely run into next year, he said. “Having done all that, I think we’ll be ready to move toward clinical trials.”
One other RNAi company, Alnylam Pharmaceuticals, is developing a treatment for Huntington’s disease in collaboration with medical device giant Medtronic (see RNAi News, 1/10/2008). Alnylam has not, however, provided a timeline for when its drug may reach human trials.