By Doug Macron
Danish pharmaceutical firm Lundbeck this week announced that it is collaborating with the University of Massachusetts Medical School's Neil Aronin to develop an RNAi-based treatment for Huntington's disease, marking the company's first formal effort to develop drugs based on the gene-silencing technology.
Lundbeck "has been exploring RNAi from a research perspective for quite some time and has been monitoring the field," Stevin Zorn, executive vice president of Lundbeck Research USA, told Gene Silencing News. But "this is the first time we've actually invested in the technology."
And although Lundbeck's foray into RNAi drugs is modest compared with some of the investments made by other pharmas, it comes at a time when many of those firms, including Roche and, most recently, Pfizer (related story, this issue), have put the brakes on their commitment to the approach.
Lundbeck has "a commitment to linking biology to diseases," particularly Huntington's disease, Zorn said. Late last year, for instance, the company launched a research initiative to "identify and ultimately commercialize therapies that may slow or halt the progression of the disease … [through] collaborations with academic institutions and companies with promising compounds in development."
Zorn said work by Aronin is "a good match to try to break open this area in a way that could help provide some basic biology information to help link the [huntingtin] protein to the disease and, ultimately, identify a treatment for it."
The specific terms of the collaboration remain undisclosed, but Zorn confirmed that Lundbeck will help fund a study led by Aronin, who has been studying Huntington's disease for decades. In addition, the company will have the option to license technology and discoveries arising from the effort.
Huntington's disease, 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, Aronin believes silencing this mutant form of huntingtin could be a promising treatment strategy.
"Our view is that you go after what is causing the disease, which is the mutant, not the wild type" huntingtin, he told Gene Silencing News. "There is a safety issue [if you target both] because huntingtin has some normal functions, presumably, and you don't want to get rid of something that works.
"Allele-specific [knockdown] theoretically makes more sense," he added.
In 2007, Aronin and colleagues published a paper in The Proceedings of the National Academy of Sciences demonstrating that siRNAs targeting human huntingtin and delivered in adeno-associated viral vectors directly into the striatum could silence the gene, "attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model.”
But for the work planned with Lundbeck, Aronin will use so-called shRNAmirs, which are shRNA sequences contained within an artificial microRNA scaffold.
In 2008, University of Iowa researcher Beverly Davidson, who pioneered the shRNAmir approach, reported in PNAS that these shRNAmirs could help reduce neurotoxicity while still maintaining RNAi silencing in mouse models of Huntington's disease.
While the shRNAmirs Aronin is using differ from those employed by Davidson, "the principle is the same," he said. "They should, in theory, get into the neuron and be expressed for many years … so we don't have to keep giving" treatment.
Initially, Aronin and Lundbeck will evaluate the safety and volume of distribution of the shRNAmirs in vitro. "Hopefully, after a few years, if we can show safety and … we know how many injections we have to give and how much virus, then we might be able to use [a sheep model] that has a huntingtin gene and we can look at the neuropathology more carefully," he said.
Testing the Waters
While the therapeutic potential of RNAi triggered much excitement among big pharmas a few years ago, some of the firms to invest heavily in the technology have since changed course.
Notably, Roche late last year said it was shutting down its in-house RNAi activities amid a broader cost-saving program. And, as first reported by Gene Silencing News, Pfizer plans to close its oligonucleotide therapeutics unit.
But not all pharmaceutical shops have turned away from the technology, including Lundbeck. According to Zorn, the work with Aronin could set the stage for other RNAi programs at the company.
"In some ways, [the collaboration] is helping to blaze a trail," he said.
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