Ramping Up Nucleic Acid Therapy Development

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In the Lab eNewsletter, Pharmaceutical Technology's In the Lab eNewsletter, May 2023, Volume 18, Issue 5

The market potential of nucleic acid-based therapies have been pushed into the spotlight following the success of the COVID-19 vaccines.

With the explosion of RNA-based therapeutics on the scene, development projects are ramping up to bring these and other nucleic acid-based therapeutics to market. But what exactly are nucleic acid-based drugs and what advantages do they hold over conventional therapeutics (biologics and small-molecule)?

Nucleic acids in the spotlight

According to Carl Schoellhammer, PhD, principal at DeciBio Consulting, a US-based life science strategy consulting firm, nucleic acid-based therapeutics are drugs that are made up of a string of nucleotides; these include DNA and RNA-based medicines. These types of therapeutics can act at the genetic level to potentially correct or restore healthy function at the level of a patient’s genes.

Vasant Jadhav, PhD, senior vice-president of Research and head of the RNAi Platform group at Alnylam Pharmaceuticals adds that a common feature of nucleic acid-based therapies is that they are “programmable” drugs; a nucleic acid sequence provides the “code” for the intended target. Examples of approved nucleic acid-based therapies include RNA interference (RNAi), antisense oligonucleotides (ASOs), and the now-familiar messenger RNA (mRNA) therapeutics.

RNAi therapeutics utilize a post-transcriptional gene silencing mechanism in which the active ingredient is double stranded short interfering RNA (siRNA). The siRNA targets and degrades mRNA encoded by a disease-causing or disease-associated gene, explains Jadhav. “RNAi therapeutics leverage a naturally occurring protein complex, called RISC [RNA-induced silencing complex], to accomplish gene silencing,” he states.

Meanwhile, ASOs, also a gene silencing medicine, are composed of single-stranded oligonucleotides that hybridize to target RNA and degrade it by “either recruiting RNAseH [ribonuclease H] (so called gapmer design) or modulate splicing to produce desired mRNA (so called splice switching olignucleotides),” according to Jadhav.

Finally, as has been seen with the COVID-19 vaccines, mRNA therapeutics are experimental genetic medicines in which the mRNA itself is the therapeutic entity; it is introduced with the aim of expressing a functional/therapeutic protein or antigen. However, there are currently no approved mRNA therapeutics outside of the COVID-19 vaccines, Jadhav observes.

Vaccines opened the door

The COVID-19 vaccines are currently the most well-known type of medicine that utilizes a nucleic acid-based active ingredient (i.e., mRNA). However, as described previously, nucleic acid molecules can be used for other types of medicines (e.g., as gene-silencing medicines).

Schoellhammer emphasizes the fact that nucleic acid-based therapeutics “are a powerful set of medicines with the capacity to turn signals on, or off, at a genetic level.” He points out that there are well over 10 nucleic acid-based therapeutics that are approved by regulators. “These medicines are, broadly speaking, divided by the action they take in the body to either turn signals on or off,” he states.

ASOs, as well as siRNAs, for example, target genes to turn them off or limit their expression. And while most of these approved nucleic acid-based therapeutics are for rare diseases (i.e., small patient population), some have been indicated for vast patient populations: Schoellhammer points to a Novartis product, Leqvio (inclisiran), which received approval by FDA for treating a type of high cholesterol in late 2021 (1).

Inclisiran, Schoellhammer explains, is a siRNA medicine that shuts off a signal in the liver, leading to a lowering of lipids. While it is currently approved for a subsegment of individuals with high cholesterol, he expects that the therapeutic could in the future be applied to anyone with high cholesterol, therefore making these medicines mainstream.

“On the other end of these therapies sits mRNA, which tells the body to produce, or turn on, specific proteins that the mRNA encodes for. [Messenger] RNA is like a blueprint, telling our cells how to make certain proteins. If a certain protein is desired, the corresponding mRNA can be made and delivered so the body will produce it,” Schoellhammer adds.

This is how the COVID mRNA vaccine operates; it is a sequence that encodes for a small fragment of the spike protein in the SARS-CoV-2 virus, for example. “When our body’s cells produce this small protein fragment, they recognize it as foreign, and produce an immune response, just as a traditional vaccine does,” Schoellhammer says.

“The pandemic demonstrated the power of this therapeutic and interest has flourished, with 100s of companies working to create new mRNA-based medicines and well over 200 public programs in development,” Schoellhammer continues. “These programs are tackling a diverse set of applications, ranging from oncology through the development of immune-stimulating treatments to help fight the cancer, to other indications leveraging CRISPR [clustered regularly interspaced short palindromic repeats]-based editing whereby the mRNA encodes for the CRISPR machinery.”


A powerful advantage

Nucleic acid-based therapeutics hold a definite advantage over conventional biologics or traditional small-molecule APIs. According to Schoellhammer, one of the greatest benefits of nucleic acid-based medicines is their specificity.

“In the case of those that turn off signals, they must find and bind with the exact complementary sequence in our body to turn it off. This means that other genetic signals can be unaffected. Similarly, for mRNA, the sequence, and therefore the protein it encodes for, is controlled. These features greatly limit any off-target effects that are often seen with small molecules or biologics,” Schoellhammer states.

Compared to small molecules and monoclonal antibodies, nucleic acid medicines, such as RNAi therapeutics work “upstream,” asserts Jadhav, treating diseases at their genetic source—that is, at the RNA/transcript level—rather than by addressing the symptoms/manifestations of the disease. Furthermore, Jadhav adds, “small-molecule drugs and monoclonal antibodies have inherent limitations when it comes to the speed with which they can be developed and the type and breadth of diseases they can be used to treat.”

Jadhav points out that the development of small molecules is an arduous process that relies on understanding the structure of the target disease-causing or disease-associated protein (vs. the genetic sequence that encodes that protein). “Oftentimes the structure of the protein is not known and needs to be solved. Identification of the right small molecule requires screening large libraries of chemical compounds to identify a candidate that can interact with the target protein in a ‘lock and key’ fashion. This is a painstaking process that requires extensive trial and error to achieve efficacy, tolerability, and safety,” he emphasizes.

As far as biologics such as antibodies are concerned, Jadhav explains that, while antibodies as a class of medicines have enjoyed much therapeutic success in the past decade, one of the drawbacks here is the inability to access and act on intracellular protein targets. “In contrast to monoclonal antibodies, nucleic acid medicines, such as RNAi therapeutics, can act on disease-causing or disease-associated proteins that are expressed both on the inside and outside of the cell,” he explains.

Meanwhile, Schoellhammer points out a limitation in nucleic acid-based therapeutic development: nucleic acid-based medicines are difficult to deliver, which is a drawback. To work, he specifies, they must be taken up by the right cell in the right place in the body. At the same time, nucleicacid-based medicines are extremely delicate and susceptible to being destroyed in the bloodstream.

“While this can somewhat limit the indications that scientists are using these medicines to treat, it further helps improve these medicines’ specificity and lack of off-target effects. For example, if one uses an siRNA therapeutic to ‘silence’ a target, dosing someone with more of that siRNA should have little effect. This is not the case for small molecules, such as aspirin, where taking more of it could eventually lead to significant, negative side effects,” Schoellhammer says.

Jadhav, meanwhile, explains that nucleic acid-based therapeutics, such as RNAi-based medicines, leverage a platform technology that gives rise to consistent and predictable drug properties. “This is not the case for small molecules, where each individual small molecule compound is completely unique, both in terms of its design elements and its profile as a drug candidate,” he states.

Supporting precision medicine

Development of nucleic acid-based therapeutics supports the bio/pharma industry’s shift to precision medicine. For instance, there are examples of nucleic acid-based medicines (e.g., RNAi therapeutics) that are approved to treat rare and ultra-rare genetic diseases for which there were no previously available therapeutic options, points out Jadhav. He has observed the therapeutic landscape of rare diseases dramatically evolve in large part due to the development and availability of genetic medicines, which now have the potential to help patients with more common diseases for which treatment options are limited or inadequate.

Schoellhammer says that, because these medicines are based on genetic sequences, they are highly specific. They can be used to treat rare diseases that are caused by a mutation in our genes. He points out that Biogen’s Spinraza (nusinersen), an antisense therapy for treating spinal muscular atrophy, was a significant accomplishment that has drastically improved the quality of life in patients for whom the disease often presents in newborns and is fatal by age two.

“Beyond presently approved nucleic acid medicines, companies are working on using these therapeutics in combination with CRISPR machinery to enable highly precise edits to genetic signals in patients. In theory, this could one day be used to target a drug for a unique individual,” says Schoellhammer.

Adding to the complex tapestry of nucleic acid-based therapeutics are the different moieties, or species of molecule, within the nucleic acid space. According to Schoellhammer, there are several different types based on their action. Within ASO therapies, for example, there are a variety of strategies to control the “degree” of silencing. There are certain therapeutics, such as Spinraza, for example, that are termed “exon-skipping” because, rather than telling the body to turn off a gene completely, these therapeutics instruct the body to skip only a certain part of a gene when producing the corresponding signal, Schoellhammer explains.

He also emphasizes the existence of microRNA (miRNA), which can have a similar effect to that of silencing therapies, guide RNAs (gRNA), which are used to target a desired gene sequence in the body for editing using CRISPR machinery, and, finally, certain types of RNA medicines that utilize naturally occurring machinery in the body to elicit an editing effect on defective genes. The latter is referred to as transfer RNA (tRNA).

“Beyond this, there is an almost endless further segmentation based on chemical modifications made to the nucleic acid therapy to make it more resilient to degradation by our body or make it more efficient in eliciting its desired effect,” Schoellhammer concludes.


1. Novartis. FDA Approves Novartis Leqvio (inclisiran), First-in-Class siRNA to Lower Cholesterol and Keep it Low with Two Doses a Year. Press Release, Dec. 22, 2021.

About the author

Feliza Mirasol is the science editor for BioPharm International.