RNA-Focused Drug Development Emerging as a Dominant Treatment Modality

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The surging scientific excitement surrounding RNA therapeutics is a little like realizing you can pick fruit off a tree without cutting it down, or pick a flower without uprooting the plant.

In other words, RNA therapeutics manipulate the translation of genetic instructions as opposed to DNA therapeutics, which target genes – the source of instructions. The former strategy gives researchers easier to reach new targets and more options for treatment modalities in fighting a broad range of illnesses.  

Essentially, RNA therapeutics enter the cell’s cytoplasm ready to take-over its protein manufacturing machinery, whereas DNA therapeutics, such as gene therapy and gene editing technologies, must penetrate the cell’s nucleus to modulate genes and risk altering the genome.

“RNA therapeutics therefore offer a more flexible approach to address a variety of diseases from different angles compared to DNA-based therapeutics,” said MiNA Therapeutics CEO Robert Habib. “Initially, DNA-based approaches were favored in drug development, based on the inadequate delivery technologies for the less stable RNA. However, over the last ten years the field has seen major advances in both delivery technologies and manufacturing capabilities.”

After more than two decades of research, a signal that RNA therapeutics may be ready to realize their potential occurred in 2018 with Alnylam Pharmaceuticals’ approval of Onpattro by the US Food and Drug Administration (FDA) and the European Medicines Agency.

Onpattro, granted Breakthrough Therapy designation by the FDA in 2017, is the first-of-its-kind RNA interference (RNAi) therapeutic for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, a life-threatening genetic disease caused by abnormal levels of amyloid in tissues and organs.

As for what’s in the pipeline, Drug Discovery World reported in 2018 that there were 69 companies developing RNA therapeutics in 315 clinical trials. The journal also observed that forecasts of global sales showed a market exceeding $10 billion by 2024.

To explore the potential and scope of RNA therapeutics, WuXi AppTec Communications spoke with Habib and the leaders of five other companies developing medicines targeting RNA. They are Keith Blundy, Ph.D., CEO of STORM Therapeutics; Michael Gilman, Ph.D., chairman and CEO of Arrakis Therapeutics; Karin Jooss, Ph.D., executive vice president and chief scientific officer of Gritstone Oncology; Patrick Lu, Ph.D., founder, president and CEO of Sirnaomics; and Roel Schaapveld, CEO of InteRNA Technologies. Their complete interviews also are available on this website – http://wxpress.wuxiapptec.com – with links from their names.

WuXi AppTec – a leading global pharmaceutical and biopharmaceutical open access capability and technology platform – assists biotech and pharmaceutical companies from discovery to manufacturing and beyond. An important element of this support involves offering a communications platform to facilitate the exchange of ideas among the most innovative companies and the creative people behind them.


Before the approval of the RNAi therapeutic, Onpattro, earlier RNA drugs on the market were antisense oligonucleotides, which demonstrated the versatility of manipulating genetic instructions to either reduce gene expression of proteins or boost it to treat a broad range of diseases.

For example, Mipomersen, approved in 2013, reduces expression of a protein to treat high cholesterol and Spinraza, approved in 2016, increases production of a deficient protein involved in spinal muscular dystrophy.

As InteRNA’s Schaapveld explains, “It is important to note that the RNA therapeutics field consists of a variety of different approaches that either results in the up- or down-regulation of certain proteins in a cell.”

In addition to antisense and RNAi, which includes short interfering RNA (siRNA) and microRNA (miRNA), other RNA therapeutics include messenger RNA (mRNA), self-amplifying mRNA (samMRNA) and small activating RNA (saRNA).

While these RNA therapeutics employ RNA oligonucleotide molecules, another strategy involves using small molecules as modulators of RNA. Small molecules are one of the most recent emerging RNA-focused therapeutics; and have several advantages over RNA molecules, including oral administration, easier entry into cells and better stability.

To underscore the vast potential of targeting RNA, Arrakis’ Gilman observed that “85% of the human genome is transcribed into RNA” and only 3% translates into proteins, many of which cannot be targeted by existing treatment modalities.

“So, between these undruggable proteins and all the emerging biology of noncoding RNAs there is a lot of disease biology that remains beyond our reach,” Gilman explained. “By directly targeting RNA, we can bring that biology into play for patients.”

STORM’s Blundy added, “Given that all genes are transcribed into RNA and much of the genome is also transcribed into RNA, there is a great potential in targeting disease through altered RNA function, whether RNA is a coding or non-coding RNA.”

Where are we?

The companies profiled here reflect the latest emerging strategies in what many experts believe will become a dominant treatment modality for many diseases.

Arrakis’ approach, among the most recent entries, involves creating chemically-based small molecules to bind to mRNA to treat cancer.  “When we started two years ago,” Gilman said, “most investors we talked to thought we were out of our mind.”

They questioned the possibility of creating small molecules that could successfully bind to RNA because it “is not well structured, it’s floppy, and there’s insufficient sequence variation (only four building blocks compared to twenty on proteins),” Gilman recalled. “It turns out that none of those presumptions are true.”

Arrakis’ approach aims to target some of those “non-druggable proteins,” such as MYC, RAS and other “classic oncogenes and transcription factors” whose roles in cancer are well known.

STORM is also developing small molecules for cancer treatment, but is focusing on RNA epigenetic regulation by targeting enzymes that make RNA modifications and consequently affect RNA and cell function.

“All RNAs, coding and non-coding, are modified post-transcriptionally,” Blundy said. “These modifications are numerous, are enzymatically encoded, often dynamic, and affect RNA structure and function.”

Once a link between a disease and RNA function is identified, one fix, Blundy explained, is correcting the RNA modifications by modulating the encoding enzymes with small molecules.

“Drugging the enzymes,” he suggested, “making functionally important modifications, which we have demonstrated is technically possible, is a less risky approach (than other forms of RNA therapeutics) and one that will progress to proof of concept rapidly.”

While small molecules represent one of the most recent additions to the RNA armamentarium, most of the other medicines are RNA molecules. However, unlike small molecules, which easily slip through the cell membrane because of their low molecular weight, RNA oligonucleotides must be ferried across within some sort of vehicle.

Sirnaomics, for example, is focused on cancer and fibrosis using siRNAi therapeutics, which gains entry to the cell via a polypeptide nanoparticle (PNP).

“This PNP wraps around the siRNAs and serves to protect them from the surrounding environment while in the bloodstream,” said Lu, the company’s CEO. Once inside the cell, the siRNA is released into the cytoplasm to silence the targeted gene expression.

Sirnaomics uses a “dual targeted siRNA drug design,” Lu said, and its lead candidate is a double stranded TGF-β1 (transforming growth factor beta 1) and COX-2 (cyclooxygenase-2) for treatment of non-melanoma skin cancer and liver cancer.

InteRNA is developing miRNA, another form of RNAi, for liver cancer and triple negative breast cancer. The miRNA molecules are delivered into cells by lipid nanoparticles.

“In contrast to classical RNAi approaches,” InteRNA’s Schaapveld said, miRNA “offers the benefit to address a variety of targets within a specific and/or across several disease-associated pathways with one therapeutic.”

He noted, “Our lead candidate, INT-1B3, has shown powerful immune system activation, tumor regression and pronounced long term immunity based on a CD 8+ T cell immune response.”

Rather than interfere with RNA function, MiNA develops RNA medicines, formulated in a liposomal nanoparticle, that activate gene transcription. Small activating RNAs “upregulate intracellular or secreted proteins for therapeutic benefit,” explained MiNA’s Habib, adding that they “have been shown to increase protein levels for both naturally expressed and epigenetically silenced targets.”

The company is focused on immuno-oncology, metabolic diseases and genetic diseases. The saRNA medicines, Habib said, can be directed to restore a cell’s biology including targeting “powerful transcription factors, most of which are undruggable by conventional medicines.”

Yet another form of RNA therapeutic, samRNA, is being used by Gritstone to generate cancer tumor antigens.

The samRNA, delivered by lipid nanoparticles, creates what Gritstone’s Jooss describes as “neoantigen-based immunotherapies.” Once inside cells, the samRNA produces large quantities of tumor antigens – specific to the patient’s cancer – generating a sustained immune system attack.

“The mRNA vector we use,” said Jooss, “comprises RNA that encodes the selected target antigens plus an RNA polymerase. After injection into muscle and uptake into host cells, the RNA is translated into a protein, and the RNA polymerase starts to replicate the originally sourced RNA, amplifying the number of copies within the cells dramatically.”

Gritstone’s samRNA medicines can be manufactured for a specific patient or for many patients who share common tumor neoantigens.

Where are we headed?

Despite what seems like a dizzying array of RNA therapeutics in development, particularly those composed of RNA oligonucleotide molecules, the experts agree there are a variety of hurdles to overcome before the treatments gain their anticipated prominence.

Blundy observed that for RNA therapeutics to become a mainstream modality three major impediments must be solved: better stability; improved pharmacokinetics; and delivery to multiple tissues.

“The progress made to date with new oligonucleotide chemistries and targeting suggests these issues will be solved,” Blundy said.

Lu added, “The next step in the evolution of RNAi as a leading therapeutic will be the ability to safely target organs outside the liver, such as the lung and brain. This will revolutionize disease treatments if the industry can demonstrate similar data sets for non-liver targets as we have seen in liver based diseases.”

To improve characteristics such as stability, potency and deliverability will require better manufacturing processes, Jooss said, and then the technical ability to produce therapies on a commercial scale.

“To emerge as a dominant treatment modality alongside small molecules and antibodies,” said Habib, “means delivering those outcomes to a very large number of patients and only certain RNA technologies are suited to have that kind of impact.”

Another challenge, of course, is advancing the science to close gaps in identifying RNA’s linkage with disease.

“Despite the noteworthy strides forward in uncovering the full potential of RNAs,” said Schaapveld, “there is still a lot to learn and understand.”

One critical component of drug development that does not seem to pose troublesome challenges is regulatory oversight.

“Many recently identified issues were addressed and FDA guidelines have been established,” Lu said. And, he observed, “Unike RNA-based therapies, DNA-based therapies change the genetic outcome of the patient’s cells and require special Recombinant DNA Advisory Committee oversight” in the US.

Schaapveld described the years before 2018 as “a turbulent time for RNA-based technology” with many companies rushing into clinical development and suffering major setbacks.

“The scientific consensus,” he said, “has shifted towards the necessity of a therapeutic approach that addresses multiple components of a (disease) pathway rather than knocking out single genes when developing treatment for multiple types of cancer.”

With the excitement surrounding the approval of Onpattro in the US and Europe in 2018, Schaapveld observed, “2019 could be seen in years to come as the start of a new era for RNA therapeutics.”

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