The promise of antisense oligonucleotides in precision medicine

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Antisense oligonucleotides, which target the disease source at the RNA level, have gained a lot of popularity in recent years among drug developers. Not only does this class of drugs offer a highly specific, targeted treatment, but it is also extremely versatile in terms of what types of diseases it can treat, potentially making it extremely advantageous over other types of therapies.

What are antisense oligonucleotides?

First explained in 1978, antisense oligonucleotides are short, single-stranded synthetic fragments of DNA or RNA that bind specifically to the target RNA sequence inside cells and modulate protein expression through several different mechanisms. Ultimately, they block the ability of the RNA to make a protein or work in other ways.

René Rückert, chief operating officer at Isarna Therapeutics, said that antisense oligonucleotides are extremely specific treatments: “It really targets one molecule that could be responsible for one indication for one disease.” They also have what Rückert describes as a “major advantage” over other drug classes such as antibodies, which target molecules that have already been produced by the cell and have also already been released by the cell, meaning that the target molecule could potentially already have done some damage before the therapeutic antibody catches it. In contrast, antisense oligonucleotides hit their target before it can even be produced.

Despite being discovered more than 40 years ago, antisense oligonucleotides are actually still part of an emerging field that is only just starting to garner attention. Their progress had originally been hampered by issues such as inadequate target engagement, insufficient biological activity, and off-target toxic effects. Rückert said: “There are many modifications of antisenses. So to increase the stability, otherwise the pure antisense is what I used in a lab 30 years ago or 25 years ago that was very, very unstable and would never survive an injection in a human body since it was degraded.”

Several improvements have been made in recent years, and Rückert added that there are now plenty of different methods to stabilize them and to add other molecules. This also makes them easier to deliver. “Now, we can do a targeted delivery, and deliver antisense in different ways. You can inject antisense and most of the therapies, I think all of the therapies that are approved at the moment, are injected in some way; subcutaneous or intravenous injection.” He added that there are new studies that also show bioavailability orally, as a tablet.

These modifications, in combination with elucidation of the mechanism of action of antisense oligonucleotides and improved clinical trial design, have provided momentum for the translation of antisense oligonucleotide-based strategies into therapies.

Approved antisense oligonucleotide drugs

The first antisense oligonucleotide drug to be approved was in 1998 when Ionis Pharmaceuticals’ fomivirsen – sold under the brand name Vitravene – was given the green light by the U.S. Food and Drug Administration (FDA). It was indicated for the treatment of cytomegalovirus (CMV) retinitis — a serious infection of the retina that can rapidly lead to blindness — in carriers of human immunodeficiency virus (HIV) exhibiting acquired immune deficiency syndrome (AIDS), who were intolerant of, or had contraindications to, other treatments or were insufficiently responsive to previous treatments.

Despite initial enthusiasm for this drug due to an unmet need in the late 1990s, its success was fleeting, and the drug was withdrawn by the FDA in 2001 because of the emergence of antiretroviral therapy, which reduced the incidence of opportunistic infections in individuals with HIV in the early 2000s. This ultimately left little need for fomivirsen.

Because of the aforementioned issues that plagued their progress until recently, there are not as many approved antisense oligonucleotide treatments on the market as one might expect given the advantages and potential they hold. Since fomivirsen, only 14 other antisense oligonucleotide-based treatments have been approved. The most recent one to reach the market is Biogen’s Qalsody (tofersen), which is indicated to treat patients with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS). The approval was based on a reduction in plasma neurofilament light, a blood-based biomarker of axonal (nerve) injury and neurodegeneration.

“I’m still surprised that not more [have been approved] since, again, the treatment is very specific,” commented Rückert.

Therapeutic applications of antisense oligonucleotides

According to Rückert, antisense oligonucleotides are useful for “basically everything” – although he added that might be a bit biased considering he works in the field. But it is true that they are being tried and tested across a variety of disease areas; the three major ones being central nervous system (CNS) disorders, ophthalmology, and oncology.

CNS disorders

It could be argued that antisense oligonucleotides hold the most promise in CNS disorders, and there is currently a lot of research being done in this area.

For example, in a study published in May, a research team from Tokyo Medical and Dental University (TMDU) explored the use of antisense oligonucleotides to reduce the expression of α-synuclein and improve symptoms in a mouse model of Parkinson’s disease. Parkinson’s disease has shown a link between the abnormal aggregation of α-synuclein and neuronal death. These aggregates are known as Lewy bodies. When the researchers injected antisense oligonucleotides into the left striatum of the models two weeks before inoculation of the mice’s brain with disease-causing fibrils at the same site, a significant decrease of over 90% in Lewy pathology-like neuronal inclusion was observed.

Antisense oligonucleotides have also recently shown promise in treating Huntington’s disease – this time in a more advanced, clinical setting. In June, Wave Life Sciences announced positive results in this indication from its phase 1b/2a clinical trial of its candidate WVE-003, an allele-selective antisense oligonucleotide designed to lower mutant huntingtin (mHTT) protein and preserve healthy, wild-type huntingtin (wtHTT) protein.

In terms of delivery, it is worth noting that, as with any therapy being developed for a CNS indication, delivery to the brain can be a monumental challenge, as the blood-brain barrier protects the brain from ‘harmful’ substances. Antisense oligonucleotides themselves currently require invasive infusion directly into the cerebrospinal fluid.

However, in another bit of advantageous news for antisense drugs, Denali Therapeutics announced last week that it had developed a way to deliver them to the brain more easily by smuggling them across the blood-brain barrier. In studies with mice and macaques, the California-based biotech combined antisense oligonucleotides with their transferrin-targeting transport vehicle platform and successfully knocked down certain gene activity across the brain.

Denali’s transport vehicle platform is an engineered antibody that targets transferrin receptor 1, which normally shuttles iron across the blood-brain barrier. This technology is also the basis for Denali’s lead drug candidate, called DNL310, which is currently in phase 3 trials. Here, iduronate 2-sulfatase enzyme is bound to the transport vehicle and shepherded into cells to treat Hunter syndrome, a rare genetic disorder in which the body does not properly break down certain sugar molecules. Individuals with the disease have mutations in the gene that codes for the iduronate 2-sulfatase enzyme, making it not work properly. DNL310 is currently in phase 3 trials.

Ophthalmology

Antisense oligonucleotides are well-researched in the area of ophthalmology; after all, the first-ever approved drug of its kind was for an eye-related condition.

In fact, Rückert’s company, Isarna Therapeutics, has an antisense oligonucleotide drug in clinical development for wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME), called ISTH0036. The candidate targets transforming growth factor beta (TGF-β), which plays an important role in key biological processes such as cell proliferation, cell differentiation, immune response, and tissue modeling. Because it is chronically elevated in many diseases, including ophthalmic diseases, and is involved in their pathophysiology, it is an extremely versatile drug target throughout the body. In ophthalmology, certain gene variants affecting the TGF-β pathway are expected to lead to a higher risk for patients to suffer from more severe forms of AMD during their lifetime, which suggests that TGF-beta might contribute to disease progression.

Isarna recently presented the first data from its BETTER study, a parallel, two-segment phase 2a clinical study to evaluate ISTH0036 in patients with wet AMD and DME. “It’s a blockbuster indication,” commented Rückert.

Rückert said ISTH0036 works differently from the current gold standard. “Currently, the gold standard in AMD and DME are injections into the eye, intravitreal injections, with drugs on the market for 15 years. They all target the same molecule and they work in the beginning. But all the patients develop fibrosis. And therefore, the vision goes down.

“You may need to have a combination therapy in a few selected patients. But in most of the patients, it works on its own with injection every other month. We could extend it to every three or four months, hopefully. And it really showed some benefit in suppressing the fibrosis and suppressing the development of the fibrosis, which is the key concern, the highest medical need in both AMD and DME, and our first data that we presented look very good.”

The company is currently finalizing its phase 2a trial, in anticipation of a phase 2b or phase 3 study, with a partner.

Oncology

TGF-beta is also a good target for antisense drugs in oncology indications, according to Rückert. “We have very early preclinical data that has been generated many, many years ago. So we’re not actively working on this. But you can also generate antisense against not only messenger RNA, which we know for decades already, but also against microRNA, for example.

“So, miRNA, which is a non-coding RNA, where everyone believed until five years ago that that’s just junk RNA, but it is not. There are very important molecules that regulate transcription and many, many biologic processes. So both the micro and non-transcribing RNA are particularly important in cancer pathology. And therefore, I think it’s the direction where it goes and where many, many options are.”

Secarna Pharmaceuticals is a company that is currently focusing its efforts on developing antisense oligonucleotides for oncology indications – as well as for diabetic nephropathy and inflammatory and fibrotic diseases of the kidney and liver. The company’s preclinical immuno-oncology pipeline is addressing several targets within the ”immunosuppressive cloud”, which enables the tumor to escape immune surveillance and destruction, contributing to resistance to current immunotherapeutic approaches.

Although CNS disorders, ophthalmology, and oncology are the most promising areas involving antisense drugs at this moment in time, as Rückert said, these drugs could potentially treat indications within every disease area if more companies decide to enter the field and test more and more assets.

An opportunity for growth, as more companies join the field

“It took quite a while before the first drug was approved. And again, compared to antibodies, there are probably hundreds or so approved for different therapies, with more than 10 antisense therapies approved and on the market for very few patients and often indications. It’s still a surprise to me, why more companies are not working on this,” commented Rückert.

But he also said that the field is starting to attract more companies: “There are a few companies, so, in particular, Ionis is a company that is mostly focused really on antisense; I would say it’s the market leader that has also drugs on the market. More larger companies are getting into this and it’s a potential for growth, I would say.”

Indeed, Ionis has an antisense pipeline of more than 40 potential first-in-class and/or best-in-class medicines designed to treat a broad range of diseases spanning CNS disorders, cardiovascular diseases, rare diseases, as well as other indications. It has also partnered with AstraZeneca on the development of some of its drugs for indications such as nonalcoholic steatohepatitis (NASH), amyloid transthyretin cardiomyopathy (ATTR-CM), and amyloid transthyretin polyneuropathy (ATTR-PN). Again, this just goes to show the potential antisense oligonucleotides have across other disease areas like fibrosis and cardiovascular disorders.

The future for this class of drugs does look promising. According to Future Market Insights, the global antisense oligonucleotides market is projected to amass revenue of around $5,519 million by 2033, up from $2,913 million in 2023, moving forward with a compound annual growth rate (CAGR) of 6.6% during the forecast period.

Ultimately, the antisense oligonucleotide field could really become one of endless possibilities. “It’s a very interesting field and I would encourage more people to have a look at this in the potential of antisense as a therapy that has very few side effects, that has a very targeted mode of action, and could really improve the therapy for many, many different diseases,” stressed Rückert.