Make Way For RNA Based Therapies

The up hill battle of RNA therapeutics to the clinic continues despite extensive use in research. Recall from high school biology that RNA translates DNA code into a language ribosomes can understand in order to make proteins required by the cell.

Fighting the good fight are antisense, RNAi, and microRNA. With their high specificity and relative low manufacturing cost, these technologies may be tomorrow’s biotech sweetheart. In fact, chances are good that previously “undruggable” targets (that cannot be accessed by small or large molecule drugs) are within arm’s reach. However, the main hurdle continues to be delivery—getting the RNA drug where it needs to be, in high enough concentrations, to be effective.

This WEEKLY examines the similarities and differences between the RNA therapeutics winding their way through the clinic and into the marketplace.

Putting The Sense Into Antisense

The on again, off again love affair with antisense therapeutics—that has been going on for over a decade—was renewed in 2013 thanks to the FDA approval of Isis Pharmaceuticals’ (Carlsbad, CA) antisense therapy Kynamro for the treatment of familial hypercholesterolemia.

Antisense drugs are short, synthetic pieces of nucleic acid whose sequence is complementary to the mRNA that codes for a disease-associated protein. When the antisense drug enters a patient’s cells, it binds to the disease-causing mRNA. This binding triggers an enzyme called RNAse H to destroy the antisense-mRNA duo (double-stranded RNA is seen as a mistake and destroyed). Without the mRNA, the disease-associated protein simply is not made—stopping malignancy in its tracks. Kynamro targets apolipoprotein B, a key component of LDL cholesterol, to lower cholesterol levels.

Over the past decade, the tumultuous love affair saw several antisense drugs fail due to lack of efficacy and drug delivery problems. By targeting the right tissues (the most promising targets are in the liver) and developing more stable formulations, Isis and others expect to see more successes. Check out the antisense drugs in clinical development:

Antisense Drugs In The Clinic


RNAi To The Rescue

Like antisense, RNAi takes advantage of naturally occurring cellular pathways to target and destroy double-stranded RNA (dsRNA) to block the expression of a disease-associated protein.

To activate the pathway, researchers introduce a double-stranded or “hairpin” shaped RNA. The enzyme DICER cuts up the hairpin to produce a “short interfering RNA” (siRNA). The siRNA binds to a second enzyme called RNA-induced silencing complex (RISC), the siRNA/RISC complex then attaches to a disease-associated mRNA. Now, double-stranded, RISC destroys both RNA strands—siRNA and mRNA—and the disease is stopped. The RNAi therapeutics in clinical development are listed below:

RNAi Drugs In The Clinic

micro RNA In The Mix

Antisense and RNAi are both synthesized in the lab and delivered to patients to decrease the expression of a disease-associated protein. MicroRNA (miR), on the other hand, is a type of dsRNA made by cells to regulate gene expression. Like RNAi, miR  is processed by enzymes DICER and RISC into single-stranded RNA capable of binding to disease-associated mRNA with a complementary sequence. Since microRNAs only bind to one end of the mRNA, each miR is able to regulate multiple target mRNAs.

MiRs are noteworthy because their expression is significantly altered in many disease states—the patient either makes too many or too few. If the patient is not making enough of a particular miR, the therapeutic approach is to deliver so-called “miR-mimetics”—synthetic versions of the naturally-occurring miR in diseases. The MicroRNA pipeline is summarized below:

MiR Drugs In The Clinic

Regulating The Regulome

Enzymes such as RNAse H and DICER exist in our cells to regulate gene expression. Enter the regulome: the unknown world where the full complexity of these RNA disrupting pathways is beginning to be deciphered. Stay tuned as RNA technology continues an avant-garde approach to disbanding disease—a promising story worth watching.



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