Our Chemistry Advances

Advancing antisense chemistry has been a central focus of our research efforts. Chemical modifications can improve a drug's stability in the body, its ability to move into certain tissues and cells, its specificity and binding strength for its intended target, its side effect profile and its ability to be metabolized and eliminated from the body. Our scientists have made great advances in chemistries; building upon our first-generation technology to create antisense drugs with enhanced pharmaceutical properties, which we call our second-generation antisense drugs. We continue to advance the chemistry and design of our drugs, and expect to introduce generation 2.5 soon, an even better class of drugs.

Isis' first-generation chemistry

Our first-generation chemistry solved many of the fundamental hurdles for creating oligonucleotide-based drugs and provided a foundation for the majority of our next-generation chemistries. First-generation antisense drugs have a sulfur chemistry modification, known as a phosphorothioate. This modification makes the drug more resistant to degradation, increases stability in the blood stream and in tissues and prevents rapid elimination of the drug from the body.

Isis' second-generation chemistry
(called 2'-O-methoxyethyl or 2'MOE)

Most of the antisense drugs in our pipeline incorporate our second-generation chemistry, which adds our proprietary 2'-O-methoxyethyl (2'MOE) chemistry and makes the drugs RNA-like.

Second-generation drugs are composed of both RNA-like and DNA-like nucleotides, while first-generation drugs are entirely DNA-like. Because RNA hybridizes more tightly to RNA than to DNA, the second-generation drugs have a greater affinity for their RNA targets and, therefore, greater potency. With increased potency, our second-generation drugs are active at lower doses, which decreases the overall cost of therapy.

Second-generation chemistry slows degradation of the drugs by protecting them from nucleases, the molecules responsible for disassembling strands of nucleotides. Slower clearance of the drug from the body allows for less frequent dosing, and offers the potential for more convenient oral delivery.

Beyond second-generation chemistry

Our scientists continue to advance our technology and improve the properties of our drugs. Most recently, we have introduced generation 2.2 drugs that are a product of better screening systems and optimization of the activity of the cellular enzyme, RNase H. By increasing the activity of RNase H, our generation 2.2 drugs have demonstrated increased potency in preclinical studies, which could potentially lead to antisense drugs with lower doses, oral administration and reduced cost-of-goods. Currently, antisense drugs are being studied in many routes of delivery including, aerosol, enema, intrathecal, intravenous, subcutaneous, topical and intravitreal.

We have created a proprietary 'toolbox' of chemical modifications for antisense drugs that strengthen duplex formation with the target RNA and enhance the pharmaceutical properties of antisense drugs. Beyond generation 2.2 chemistry, we are evaluating entirely new types of chemistries, which will be the basis for our next-generation antisense technology, generation 2.5.

Learn more about Antisense Approaches