HD Insights™

Volume 3

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HD INSIGHTS Meet the Company VITAL SIGNS NAME: Isis Pharmaceuticals HEADQUARTERS: Carlsbad, California STOCK PRICE AS OF 8/21/12: $13.67 52 WEEK RANGE: $6.25 - $14.05 MARKET CAPITALIZATION AS OF 8/21/12: $1.4 billion EMPLOYEES: Approximately 340 Dr. C. Frank Bennett Isis Pharmaceuticals is a biotechnology company that develops therapeutic agents that target and modulate RNA. Isis's primary platform is exploiting antisense oligonucleotide technology to selectively reduce the expression of a target RNA. Co-founder and Senior Vice President of Research, Dr. C. Frank Bennett, spoke with HD Insights about Isis's RNA-based targeting in HD. Edited excerpts from the discussion are below. INSIGHTS: Can you tell us a little bit about Isis? BENNETT: The focus of the company since its inception has been on novel therapeutic agents that target RNA. We use a technology called antisense oligonucleotides (ASOs) that uses short synthetic nucleic acid analogs designed to bind to a target RNA via Watson-Crick base pairing. Once our ASOs bind to the target RNA, they can then be a part of a range of mechanisms to modulate the RNA. For the Huntington disease (HD) Project, the primary mechanism that we're exploiting is through an enzyme called RNase H. RNase H selectively degrades the RNA that is bound by the oligonucleotide. Wherever the oligonucleotide binds, it recruits RNase H to that RNA, and the RNase degrades the RNA. The oligonucleotides are then recycled within the cell. This is a novel catalytic mechanism that we are using to very selectively reduce the expression of a target RNA. In this case, we're targeting RNA that is expressed by the huntingtin gene. INSIGHTS: Since most humans have two copies of the huntingtin gene and in HD-affected individuals only one allele has the CAG expansion, how can you target the production of mutant huntingtin and not wild-type huntingtin? BENNETT: We're taking several different mechanistic approaches. The most advanced project we are using does not distinguish between wild-type and mutant huntingtin. Our pre-clinical research, performed in collaboration with Dr. Don Cleveland at University of California San Diego, suggests there are no deleterious effects associated with reducing wild-type huntingtin, and published research supports our understanding that wild-type huntingtin protein is essential for normal development before birth, but has a largely undefined role in adults. So we are counting on humans having some tolerance for reduced expression of both mutant and wild-type huntingtin. However, we also have two different approaches that we're using to get selectivity in case it's needed. One approach is a project with Dr. Michael Hayden and his colleagues at the University of British Columbia, in which we are targeting single nucleic-type polymorphisms that co-associate with the expanded CAG triplet on the mutant allele. We are able to distinguish a single nucleotide- change, which causes the loss of the mutant allele while sparing the wild-type allele. In our preclinical studies we have been able to demonstrate a greater than 50-fold selectivity of the mutant versus wild-type, based upon that same nucleotide- change. The caveat is that there are a number of haplotypes that all have expansions of repeats, so a single drug would at best treat about 50 percent of HD patients. Multiple drugs must be available to treat all the patients who would be amenable to this therapy. 8 Another approach is to use all the oligonucleotides that bind to the expanded CAG repeat itself. Working with another collaborator, Dr. David Corey, at University of Texas Southwest Medical Center, we have shown that the expansion of that CAG repeat provides more binding sites for the oligonucleotide. Using this technology, we are able to distinguish between wild-type CAG repeat links and the expanded CAG repeat that occurs in a disease. This technology has an advantage that could treat a larger number of patients with a single drug, but there is also concern because other genes have CAG repeats. We are currently working to identify or characterize the risk of the CAG targeting approach versus the polymorphism approach. Copyright © Huntington Study Group 2012. All rights reserved. HD Insights, Vol. 3

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