Targeting RNA in the Nervous System: The Rise of Antisense and RNA Therapeutics

Key Takeaways

• RNA therapeutics regulate gene expression by targeting RNA transcripts rather than proteins, enabling highly sequence-specific treatment strategies.

• Antisense oligonucleotides are among the most advanced RNA therapeutic platforms for neurological disease, with approved treatments for spinal muscular atrophy and SOD1-associated amyotrophic lateral sclerosis.

• Additional RNA modalities, including siRNAs and other RNA-targeting approaches—are expanding the therapeutic landscape for neurological and neuromuscular disorders.

• The ability to design oligonucleotide therapies around specific genetic variants has opened the door to individualized “N-of-1” treatment strategies for rare neurological diseases.

• Major scientific challenges remain, particularly in delivering RNA therapeutics effectively to the central nervous system and identifying which diseases are most amenable to RNA-based intervention.

RNA-based therapeutics have emerged as a growing class of medicines designed to alter gene expression by targeting RNA molecules directly. Rather than interacting with proteins after they are produced, these approaches intervene earlier in the biological process by binding RNA transcripts and modifying how genetic information is translated into proteins.

Several distinct modalities fall under the umbrella of RNA therapeutics. Among the most prominent are antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), aptamers, and other RNA-based strategies. These approaches differ in their mechanisms and delivery strategies, but they share a common principle: the ability to regulate gene expression by targeting RNA sequences through complementary binding.

Neurological diseases have become a particularly important focus for RNA therapeutics. Many disorders affecting the nervous system arise from well-defined genetic mutations or disruptions in gene expression, making them suitable targets for sequence-directed interventions. Because RNA-targeting drugs operate through sequence recognition rather than conventional protein binding, they can in principle be designed to address specific genetic drivers of disease.

By intervening at the RNA level, these therapies offer a way to modify or suppress the production of disease-associated proteins before they accumulate or exert toxic effects. This ability to influence gene expression upstream of protein production has positioned RNA therapeutics as a promising strategy for addressing neurological diseases with clear genetic origins or molecular drivers.

ASOs are the most established classes of RNA therapeutics currently being explored in neurology. These molecules consist of short synthetic strands of nucleic acids designed to bind specific RNA transcripts through complementary base pairing. By targeting RNA directly, ASOs provide a means of regulating gene expression at a stage that precedes protein production.¹

Once bound to their target RNA, ASOs can influence gene expression through several distinct mechanisms. In some cases, binding triggers degradation of the target RNA, reducing the production of disease-associated proteins. In other contexts, ASOs can block or redirect the cellular machinery responsible for processing RNA transcripts, allowing them to restore the expression of functional proteins or alter the structure of the resulting protein product. Another widely studied approach involves modifying RNA splicing patterns, enabling the selective inclusion or exclusion of specific RNA segments during transcript processing.¹

These mechanistic possibilities give ASOs considerable flexibility as a therapeutic platform. Because their activity depends on sequence recognition rather than interaction with a specific protein structure, ASOs can theoretically be designed to target a wide range of disease-associated transcripts. This feature has proven particularly valuable for genetic diseases in which the underlying mutation is well defined, as therapeutic oligonucleotides can be tailored to the specific RNA sequence involved. As a result, antisense technologies have become a prominent area of research in the development of treatments for neurological disorders with clear molecular drivers.

Although ASOs have become the most visible RNA-based therapeutic strategy in neurology, they represent only part of a broader and increasingly diverse set of RNA-targeting technologies. RNA therapeutics encompass multiple modalities that operate through different mechanisms but share the underlying ability to regulate gene expression by interacting with RNA transcripts.

Among these approaches are siRNAs, which induce degradation of target messenger RNA through RNA interference pathways. Other RNA-based strategies include aptamers, which are short nucleic acid sequences that fold into structures capable of binding specific molecular targets, as well as emerging mRNA-based therapeutics and vaccine platforms. Each modality offers distinct opportunities for modulating gene expression or influencing cellular pathways relevant to disease.

As these technologies have matured, clinical development programs have begun to expand across several RNA-based modalities targeting neurological and neuromuscular diseases. While antisense oligonucleotides remain a central focus of many programs, siRNA therapeutics have also entered clinical development for disorders affecting the nervous system.²

This expanding pipeline reflects growing interest in RNA-based approaches as tools for addressing genetic diseases of the nervous system. By targeting RNA transcripts rather than protein structures, these therapies can be adapted to address a range of conditions in which disease mechanisms are tied to specific genetic mutations or dysregulated gene expression.

One of the earliest and most prominent RNA therapeutics developed for neurological disease is nusinersen, marketed as Spinraza. Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA), a genetic neuromuscular disorder characterized by degeneration of motor neurons. The therapy works by targeting RNA transcripts associated with the survival motor neuron pathway and is indicated for both pediatric and adult patients with SMA.

Administration of nusinersen requires direct delivery into the central nervous system. The drug is given intrathecally through lumbar puncture, allowing the oligonucleotide therapy to reach the cerebrospinal fluid and spinal cord where the disease process occurs.

Another ASO developed for neurological disease is tofersen, marketed as Qalsody. This therapy is approved for adults with amyotrophic lateral sclerosis (ALS) associated with mutations in the SOD1 gene. Like nusinersen, tofersen is delivered intrathecally to enable access to the central nervous system, where the therapeutic oligonucleotide can target disease-associated RNA transcripts.

The drug received accelerated approval based on evidence that treatment reduced levels of plasma neurofilament light chain, a biomarker associated with neuronal injury. This biomarker-based pathway reflects growing interest in the use of molecular indicators to support regulatory decisions in diseases where traditional clinical endpoints can take years to emerge.

RNA therapeutics have also been developed for neurological complications of hereditary transthyretin-mediated amyloidosis, a genetic disorder in which misfolded transthyretin protein accumulates and damages peripheral nerves.

Two RNA-targeting drugs are approved for polyneuropathy associated with this disease. Inotersen (Tegsedi) is an ASO designed to reduce production of transthyretin by targeting its RNA transcript. Patisiran (Onpattro), by contrast, uses a small interfering RNA mechanism to suppress transthyretin expression through RNA interference pathways. Although these therapies employ different RNA-based mechanisms, both aim to lower production of the disease-causing protein by targeting its RNA precursor.

One of the most distinctive features of ASO therapeutics is the potential for highly individualized treatment design. Because ASOs function through sequence recognition, it is possible to develop oligonucleotides that target specific genetic variants present in a single patient. This capability has raised the prospect of creating customized therapies for rare diseases driven by unique or extremely uncommon mutations.³

A widely discussed demonstration of this concept involved the development of a patient-specific ASO for a child with a rare neurodegenerative disorder caused by a unique genetic mutation. In that case, researchers designed and administered a customized oligonucleotide therapy tailored to the patient’s specific variant, illustrating the potential for rapid therapeutic design when a clear genetic driver of disease can be identified.⁴

Despite the promise of individualized ASO therapies, important limitations remain. Not all genetic variants are suitable targets for antisense approaches, and the feasibility of treatment depends on factors such as mutation type, gene structure, and the biological consequences of altering RNA processing.⁵

Researchers are therefore working to develop systematic methods for identifying patients who may benefit from splice-switching ASO therapies. Recent work has proposed frameworks for prospectively evaluating genetic variants to determine whether they are amenable to oligonucleotide intervention, helping guide decisions about when individualized RNA therapies may be feasible.³

Despite the growing number of RNA therapeutics entering clinical development, delivering these molecules to the central nervous system (CNS) remains one of the most significant challenges in the field. Many RNA-based drugs must reach neurons or other cells within the brain or spinal cord to achieve their therapeutic effect. However, the blood–brain barrier (BBB) restricts the movement of many molecules from the bloodstream into neural tissue, limiting the effectiveness of conventional systemic drug delivery approaches.⁶

This biological barrier presents particular difficulties for nucleic acid–based therapies like ASOs and siRNAs. Because these molecules are relatively large and susceptible to degradation, specialized delivery strategies are often required to ensure that sufficient drug concentrations reach the relevant CNS tissues. As a result, many RNA therapeutic development programs have focused on delivery approaches that bypass or circumvent the BBB rather than attempting to cross it directly.⁶

One strategy that has been adopted for several approved therapies involves direct administration into the cerebrospinal fluid. Intrathecal delivery allows RNA therapeutics to reach the spinal cord and other regions of the CNS by introducing the drug through lumbar puncture rather than relying on systemic circulation. This approach has been used for multiple antisense therapies targeting neurological disease. Both nusinersen, approved for spinal muscular atrophy, and tofersen, approved for amyotrophic lateral sclerosis associated with SOD1 mutations, are administered intrathecally to facilitate delivery to the CNS and enable therapeutic concentrations of the oligonucleotide drug to reach disease-relevant tissues.

Clinical development activity in RNA therapeutics continues to expand across multiple neurological and neuromuscular diseases. While antisense oligonucleotides remain a central focus of many programs, other RNA-based approaches, such as siRNAs, are also entering clinical development for disorders affecting the nervous system. This diversification reflects increasing confidence that RNA-targeting strategies can be adapted to address a variety of disease mechanisms linked to abnormal gene expression. As these programs advance, RNA therapeutics are being explored across a growing set of genetically defined conditions. The ability to design sequence-specific drugs targeting disease-associated transcripts allows researchers to pursue treatment strategies for disorders that were previously difficult to address using traditional small-molecule or protein-based therapies.

The emergence of RNA-based medicines has also created new opportunities for personalized therapeutic approaches. Advances in genomic sequencing have made it easier to identify the specific genetic variants responsible for many rare neurological diseases. In parallel, improvements in oligonucleotide design have made it possible to develop therapeutic molecules that precisely target those variants at the RNA level. These capabilities have raised the possibility that RNA therapeutics could support increasingly individualized treatment strategies, particularly for rare disorders in which conventional drug development pathways are difficult to pursue. The development of frameworks for identifying variants that may be amenable to splice-switching antisense therapies represents one effort to systematize this approach and determine when individualized interventions may be feasible.

Despite this progress, several scientific challenges remain. One of the most persistent barriers is the difficulty of delivering RNA therapeutics effectively to the central nervous system. As discussed earlier, the BBB restricts access to neural tissues, and many current therapies rely on specialized delivery approaches to reach disease-relevant cells. Another challenge involves determining which diseases and genetic variants are most suitable for RNA-based intervention. While antisense and other RNA therapeutics offer powerful tools for modifying gene expression, their applicability depends on the underlying biology of each condition. Ongoing research is therefore focused on identifying the genetic and molecular contexts in which RNA-targeting strategies are most likely to produce meaningful clinical benefit.

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3. Kim, Jinkuk, et al. “A framework for individualized splice-switching oligonucleotide therapy.” Nature. 619: 828–836 (2023).

4. Kim, Jinkuk, et al. “Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.” N. Engl. J. Med. 381: 1644–1652 (2019).

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