ISIS Copies Alnylam’s Heart Disease Strategy

Today, ISIS Pharmaceuticals, a company developing antisense therapeutics, announced a collaborative deal with Bristol-Myers Squibb to target PCSK9 for the treatment of hypercholesterolemia. As dicussed in my May 6 post, this is the same gene targeted by the RNAi Therapeutics company Alnylam. Since both antisense and RNAi are nucleic acid-based methods for down-regulating gene expression, I will use today’s news to contrast the two technologies.

Both technologies use short nucleic acids designed to seek out their complementary RNA targets and thereby down-regulate corresponding gene expression. Antisense typically comes in two flavours. One is to target a certain region in the complementary mRNA that should inhibit its translation into protein without destroying the RNA target, the other is to use DNA-based antisense molecules that when paired to their target RNA will trigger RNaseH in the cell to degrade the RNA. Although the latter method takes advantage of an enzyme, the natural function of this enzyme is thought to be mainly involved in facilitating DNA synthesis, and therefore neither of the two strategies takes advantage of an existing gene repression mechanism. By contrast, RNAi makes use of such a pre-existing gene repression mechanism that is catalytic and therefore theoretically more efficient. Accordingly, antibodies and recombinant proteins have demonstrated the power of harnessing biological pathways for therapeutic purposes. In the case of RNAi, this is borne out by the finding that in tissue culture and in vivo, the amount of nucleic acid needed to efficiently knock down a gene is significantly less and gene knockdown generally more specific and predictable for siRNAs compared to antisense molecules. This is important as lower doses and higher specificity should reduce side-effect risk. Furthermore, for certain applications it may be desirable to use DNA directed RNAi induction methods, which is not a viable option for antisense.

But one of the main reasons why I am so excited about RNAi Therapeutics is because of the immense interest in the scientific community to understand and leverage the endogenous functions of RNAi. This not only attracts some of the scientific minds to solve potential bottlenecks, but also public recognition and consequently financial support. The Nobel Prize last year has certainly helped, and it is therefore gratifying to see the governor of Massachussetts announce yesterday a plan to support the biotechnologies in that state, specifically mentioning RNAi Therapeutics as one of the focus areas. Antisense, however, has had a long history of failures which has affected investor confidence and hurt its development. Interestingly, however, a number of issues that led to these failures like medicinal chemistry, delivery, and target selection are quite similar for the development of RNAi Therapeutics, and it is fortunate that RNAi can take advantage of lessons learned in the antisense field. It is therefore maybe not surprising that Alnylam and ISIS have extensively cross-licensed their IP, and given the size of the heart disease market, both drugs should ultimately be able to co-exist on the market. My bet, however, is on RNAi.