Nucleic Acid Therapeutics

Small molecule, peptide, and biologic drugs aren’t the only players in the game of drug development. A fourth class of therapeutics differs from all three of these: nucleic acid-based drugs. These drugs are rising in prominence due to their potential to specifically target a wide range of diseases, including various types of cancer, autoimmune, and infectious diseases. Companies like Moderna (Cambridge, MA) are garnering unprecedented investor interest, while improvements in delivery methods have increased the efficacy of nucleic acid-based therapies.

In this WEEKLY — the first of a two part series — we’ll dig up the different types of nucleic acids and unearth mRNA-based therapeutics in development.

Term of the Week: Nucleic Acid

Nucleic acids are long chains of repeating units of nucleotides. Nucleotides are made up of a phosphate group, a sugar group, and a base.

There are two types of nucleic acids: DNA and RNA. The nucleotides (or building blocks) of these two varieties of nucleic acids are quite similar, but there are marked differences.


  • The deoxyribose is a more chemically stable sugar group because “deoxyribose” lacks the highly reactive oxygen atom.
  • Two individual strands of linked nucleotides join together to make the double helix by forming complementary base pairs — “A” complements “T” and “C” complements “G.”
  • Bases include Adenine (A), Cytosine (C), Guanine (G), Thymidine (T).


  • The ribose sugar group is a less chemically stable sugar group because “ribose” has a highly reactive oxygen atom.
  • RNA is typically single stranded.
  • Bases include Adenine (A), Cytosine (C), Guanine (G), Uracil (U).


Why mRNA?

You probably recognize DNA as the molecule of heredity, and may recall that it provides cells with the instructions for making proteins. Enter messenger RNA (mRNA) — the literal messenger that relays the DNA instruction to the ribosome where the protein-making process takes place.

So, why all this talk about mRNA? Well, protein therapeutics — the injectable protein-based drugs discussed last week — have revolutionized the treatment of a range of diseases, from diabetes to cancer to autoimmune disorders. However, they are time consuming and expensive to produce. Cells must be engineered to develop the desired protein, then grown in large (thousands of liters) tanks. Finally, the therapeutic protein must be painstakingly purified away from other proteins and cellular debris in the cell.

What if we could eliminate the huge biomanufacturing tanks and just have the patient make the therapeutic protein using their own cells? That is the idea behind mRNA therapeutics — figure out a way to provide the information contained in mRNA directly to the patient’s ribosomes and let the patient’s cells do the work. Not only would this be more efficient, it would also enable therapeutic proteins to be introduced directly inside cells or embed into the cell membrane. Recall that protein therapeutics injected into the bloodstream are too large to enter cells and are limited to interacting with proteins on the surface of cells or in the blood.

Theory vs. Reality

Like much in biotech, the concept of mRNA-based therapeutics is elegant in theory, yet rough in reality.

  • Reason 1: The relative instability of the mRNA molecule itself; mRNA traveling through the bloodstream would typically be degraded by nucleases — enzymes that break down nucleic acids.
  • Reason 2:  “Foreign mRNA” coming from outside of the cell could trigger an immune response; our immune systems have evolved to recognize foreign mRNA as bad.
  • Reason 3: Delivery of mRNA therapy is difficult. Right now the approach that appears to be having the most success is encasing the mRNA in a lipid nanoparticle for delivery to cells.

Bringing mRNA drugs to market involves designing chemically modified mRNA that is more stable (resistant to nucleases) and less visible to immune cells than unmodified mRNA. These modified mRNA molecules are called “nucleotide analogs” because they are similar but different from naturally occurring nucleotides.

In The Pipeline

Moderna Therapeutics (Cambridge, MA) has received nearly $2 billion to fund ongoing mRNA drug development. The company now has five different products in Phase I clinical studies. Four of these are vaccine candidates: two against different strains of influenza virus, one against Zika virus, and one against an undisclosed target in partnership with Merck (Kenilworth, New Jersey). A mRNA-based vaccine uses lipid nanoparticles to deliver the instructions for making a particular viral protein to a cell. The cell then makes the viral protein and displays segments of it on its surface, activating an immune response to fight infection.

The fifth drug for which Moderna has initiated clinical trials — in partnership with AstraZeneca (Cambridge, UK) — is a mRNA that codes for the protein known as vascular endothelial growth factor, or VEGF. This protein promotes the growth of blood vessels, and may help to improve blood supply in cardiac tissue after a heart attack, or in diabetic wound healing.

CureVac (Tubingen, Germany) is focused on mRNA vaccines as well, with a prostate cancer therapeutic vaccine in Phase II clinical studies. Therapeutic vaccines train the patient’s immune system to recognize a specific cancer associated protein, priming immune cells to attack the tumor that bears those proteins. CureVac also has a mRNA-based rabies vaccine in Phase I clinical studies, with several more infectious disease and therapeutic cancer vaccines in preclinical development.

Other companies to watch in this space include:

  • BioNTech (Mainz, Germany): Phase I studies completed on a mRNA-based therapeutic vaccine for melanoma; preparing to enter clinical studies on therapeutic cancer vaccines for head and neck cancer and personalized vaccines.
  • Arcturus (San Diego, CA): Preclinical development of mRNA drugs to treat protein deficiency disorders.
  • RaNA (Cambridge, MA): Preclinical development of mRNA drugs to treat protein deficiency disorders.

mRNA drugs show much promise and we will continue to closely follow this area for new developments. Next week, we’ll continue our discussion of nucleic acid-based therapeutics as we look at additional types of RNA and DNA based drugs.

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