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Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders

Marlen C. Lauffer, Willeke van Roon-Mom, Annemieke Aartsma-Rus & N=1 Collaborative (Communications Medicine)

January 5, 2024


Antisense oligonucleotides (ASOs) are incredibly versatile molecules that can be designed to specifically target and modify RNA transcripts to slow down or halt rare genetic disease progression. They offer the potential to target groups of patients or can be tailored for individual cases. Nonetheless, not all genetic variants and disorders are amenable to ASO-based treatments, and hence, it is important to consider several factors before embarking on the drug development journey. Here, we discuss which genetic disorders have the potential to benefit from a specific type of ASO approach, based on the pathophysiology of the disease and pathogenic variant type, as well as those disorders that might not be suitable for ASO therapies. We further explore additional aspects, such as the target tissues, intervention time points, and potential clinical benefits, which need to be considered before developing a compound. Overall, we provide an overview of the current potentials and limitations of ASO-based therapeutics for the treatment of monogenic disorders.


Antisense oligonucleotides (ASO) are short oligonucleotides that can bind to RNA in a target-specific manner and ultimately modify protein expressions. These molecules have shown incredible potential in the treatment of genetic disorders and can drastically alter the course of heritable diseases1. By interacting with RNA transcripts in a sequence-specific manner, ASOs can reduce target RNA transcript levels leading to limited expression of the encoding toxic proteins or can alter transcript sequences through splice-modulation to restore protein function where otherwise function would be lost2. These approaches have successfully been employed for multiple genetic disorders, such as spinal muscular atrophy (SMA), homozygous familial hypercholesterolemia, and primary hyperoxaluria type 1. Up to date, 15 oligonucleotides have so far received market authorization in different countries3,4, with several others currently being tested in clinical phase I–III trials, with some edging closer to market approval5,6.

ASOs are of special interest for approximately 8000 rare disorders, where rare by definition is a disease that affects less than 1 in 2000 people in Europe or less than 1 in 200,000 people in the US7,8. The high unmet medical need for developing treatments for rare disease patients is highlighted by the fact that no targeted therapeutics are available for over 90% of these disorders9. Since around 70–80% of rare disorders9 are caused by pathogenic genetic alterations in single genes, ASO-based drugs could provide potentially disease-modifying therapies for many of these conditions. The recent successes of ASO-based therapies, especially the development of individualized treatments and treatments for disorders with only a few known cases, have given hope to the rare disease community10,11.

Depending on the disease-causing mechanism, different ASO approaches may be applicable. As not all genetic diseases are amenable to ASO-based therapy, it is important to consider a multitude of aspects when deciding if an ASO is the most suitable therapeutic option for a given disease. This can be a complex process, and it is easy to overestimate clinical potential. In this regard, it is important to realize the limitations of the different ASO-based strategies, ensure transparent communication with affected individuals and their caregivers, and manage the hopes and expectations that come with new and often experimental treatments.

Here, we provide important considerations in determining the suitability of ASO approaches for different monogenic diseases. Besides the genetic background and pathophysiological mechanism of disease, we take the target tissue, delivery route, timing of intervention, and clinical outcome measures into account. We discuss the types of monogenic disorders that are treatable with the available ASO strategies and point out any potential hurdles that will need overcoming to expand the group of diseases that could become amenable to an ASO intervention.

Mechanisms of action

ASOs are small, single- or double-stranded oligonucleotides that have been chemically modified to increase stability, improve the target affinity and bioavailability, and enhance cellular uptake. Depending on their chemical modifications, ASOs are subdivided into three generations12. ASOs can bind to their target RNA transcript in a sequence-specific manner via Watson–Crick base pairing. They can thus be designed to target distinct sequences or specific genetic variants2. Through this complementary binding, the molecules can alter protein expression by either knocking down transcripts or modifying pre-mRNA splicing, ultimately leading to either a reduction, modification, or restoration of a specific protein. According to their mechanism of action, ASOs can be divided into gapmer antisense oligonucleotides (gapmer ASOs) and small interfering RNAs (siRNAs) with which transcript knockdown can be achieved, and splice switching ASOs (ssASOs) used to modulate pre-mRNA splicing2 (Fig. 1). ASOs that interfere with microRNAs, such as agomirs and antagomirs, are not considered here as these do not address the root cause of monogenic diseases.

Fig. 1: Overview of the action mechanisms of antisense oligonucleotides (ASOs).

Lauffer, M.C., van Roon-Mom, W., Aartsma-Rus, A. et al. Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders. Commun Med 4, 6 (2024).



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