Small molecules, peptides, 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 — the first of a two-part series — we’ll dig up the different types of nucleic acids and unearth mRNA-based therapeutics in development.

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.

• 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), and Thymidine (T).

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

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 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. This would be more efficient and enable therapeutic proteins to be introduced directly inside cells or embedded 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.

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 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 challenging. 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 more stable and chemically modified mRNA (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.

Moderna Therapeutics (Cambridge, MA) has received nearly $2 billion to fund ongoing mRNA drug development. In 2022, FDA approved mRNA-based Moderna COVID-19 vaccines, mRNA-1273 (Spikevax), mRNA-1273.214, and mRNA-1273.222. The company now has various products in Phase I clinical studies. Some of these are vaccine candidates against different strains of COVID-19, influenza virus, Nipah virus, and Zika virus. Moderna, In partnership with Merck (Kenilworth, New Jersey), is also working on developing mRNA cancer vaccines. 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.

Another drug,  AZD8601, for which Moderna initiated Phase II clinical trials — in partnership with AstraZeneca (Cambridge, UK) — is a mRNA that codes for the protein known as a 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 also focused on mRNA vaccines, with a therapeutic prostate cancer vaccine, CV9104,  in Phase II clinical studies. Therapeutic vaccines train the patient’s immune system to recognize specific cancer-associated proteins, priming immune cells to attack the tumor that bears those proteins. CureVac also has a mRNA-based rabies vaccine candidate, CV7202, and a COVID-19 Vaccine candidate, CV0501, in Phase I clinical studies. The company also has several more infectious disease and therapeutic cancer vaccines in preclinical development.

Other companies to watch in this space include:

• BioNTech (Mainz, Germany): The company is conducting Phase II studies on a mRNA-based therapeutic vaccine, BNT 111, for melanoma; and therapeutic cancer vaccines for head and neck cancer. It also has vaccine candidates for prostate and ovarian cancer currently in Phase I clinical trials. 
• Arcturus (San Diego, CA): Phase II development of mRNA drugs, including LUNAR OTC-mRNA drug to treat ornithine transcarbamylase deficiency disorder. 
• RaNA (Cambridge, MA): Preclinical development of mRNA drugs to treat protein deficiency disorders.

mRNA drugs show much promise, and we will continue to follow this area for new developments closely.

Nucleic acid-based therapeutics, particularly mRNA drugs, are carving a niche in the pharmaceutical landscape. Their potential to revolutionize treatments for various diseases, from infectious diseases to cancer, is immense. Companies like Moderna and CureVac lead the charge with significant investments and promising clinical trials. However, the journey from theory to reality is fraught with challenges, from the instability of the mRNA molecule to the complexities of delivery. Despite these hurdles, the advancements in this field are promising, and the future of mRNA therapeutics looks bright. As research progresses and more products enter clinical trials, we can anticipate a new era of personalized and efficient treatments that harness the power of our own cells.

1. What makes nucleic acid-based drugs different from other therapeutics?

Unlike small molecules, peptides, and biologic drugs, nucleic acid-based drugs specifically target genetic material, offering a unique approach to treating a wide range of diseases.

2. Why is mRNA gaining so much attention in the pharmaceutical world?

mRNA therapeutics offer a way to provide the information contained in mRNA directly to the patient’s ribosomes, allowing the patient’s cells to produce the therapeutic protein. This method is more efficient and can introduce therapeutic proteins directly inside cells.

3. What are the main challenges faced by mRNA-based therapeutics?

The challenges include the instability of the mRNA molecule, potential immune responses to foreign mRNA, and difficulties in delivering the therapy to cells.

4. How did Moderna leverage mRNA technology in the fight against COVID-19?

Moderna developed mRNA-based COVID-19 vaccines, such as mRNA-1273 (Spikevax), which have received FDA approval. They have several other products in various phases of clinical trials.

5. Are there other companies making significant strides in mRNA therapeutics?

Yes, apart from Moderna, companies like CureVac, BioNTech, Arcturus, and RaNA are actively involved in the development of mRNA drugs and vaccines.

6. What is the future outlook for mRNA therapeutics?

mRNA drugs have shown significant promise. As research advances and more products undergo clinical trials, we can expect groundbreaking treatments that could redefine the way we approach various diseases.