Aptamers as a targeting moiety in two deals

CAMBRIDGE, Mass.—In two related developments, Archemix Corp. has entered into collaborative agreements with miRagen Therapeutics Inc. to ferry its microRNA therapies via aptamer conjugates to achieve intracellular delivery and subsequent microRNA targeting, and Dicerna Pharmaceuticals to deliver its siRNA.

Aptamers are synthetically-derived oligonucleotides, or short nucleic acid sequences, that bind to protein targets with high affinity and specificity and can be designed to have a specified duration of action. Archemix will jointly pursue research and development efforts with both of its partners. In addition, miRagen and Dicerna both have an option to negotiate for exclusive rights to further develop and commercialize certain aptamer-RNA therapeutics generated during the collaboration.

First-generation RNA therapeutics have been plagued with dosing and delivery problems that aptamer conjugates may solve.

"Targeting and delivery of nucleic acid drugs are challenges in the field, and aptamers are an exciting class of agents that can potentially address these issues," says Dr. William S. Marshall, president and CEO of miRagen. He notes that his company and Archemix have developed a highly defined research plan. First, Archemix will characterize aptamers for miRagen to manipulate and use as models. A traditional joint research committee will be charged with moving the activity forward.

"We'll use a phased approach to demonstrate activity in vitro with key disease models," Marshall notes. The focus will be cardiovascular and muscular diseases.

"The principle is to use aptamers as a targeting moiety," says Archemix's Dr. Page Bouchard, senior vice president of discovery and preclinical development, and he notes that the principle has been reasonably well demonstrated in published reports of various research collaborations. Now it's time to take the potential of aptamers to the next level, he states.

Archemix will identify aptamers, and miRagen and Dicerna will be responsible for the payload. The Archemix/miRagen and Archemix/Dicerna teams will then develop conjugates. Aptamers are "fairly agnostic" to therapeutic areas, Bouchard says. In contrast to miRagen's focus on cardiovascular and muscular diseases, he notes that Dicerna will be looking at cancer and broader applications.

Dr. James C. Jenson, CEO and co-founder of Dicerna, explains that first-generation RNA therapeutics were based on a 21 nucleotide model because initial research in fruit flies indicated that longer molecules wouldn't work. In 2006, Dr. John Rossi—Dicerna's other founder—found out that in mammalian cells they do work, and in fact, have significantly better properties. Not only is the molecule larger, but it also enters the RNAi pathway upstream from where miRNAs enter. The target is not the risk complex itself, but the dicer molecule.

"Being processed by the dicer, we gain extraordinary advances in potency," Jenson claims. "In respect to the KRAS target, we have two dozen molecules with single-digit picomolar potency. In addition, the gene silencing is catalytic so that a dosing paradigm similar to monoclonal antibodies of perhaps every two weeks can be envisioned."

An even bigger advantage, he says, is that the longer molecule (27-mers), have "handles to which we can attach a variety of targeting moieties—aptamers, peptides, small molecules and others."

Recently, Rossi published a paper that highlighted the binding of GP120 within T-cells, which normally don't take up siRNA at all. By attaching an aptamer, the siRNA complex is hauled into the T-Cell, the dicer clips and the siRNA "does its thing," as Jenson puts it.

In contrast to siRNA, miRNAs silence whole-gene complexes, not a single gene. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, miRNAs represent potential drug targets of unprecedented power. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression.