Antisense therapy

Half-life and stability

ASO-based drugs employ highly modified, single-stranded chains of synthetic nucleic acids that achieve wide tissue distribution with very long half-lives.^[4][5][6] For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle-free delivery to cells.^[7][8]

In vivo delivery

Phosphorothioate ASOs can be delivered to cells without the need of a delivery vehicle. ASOs do not penetrate the blood brain barrier when delivered systemically but they can distribute across the neuraxis if injected in the cerebrospinal fluid typically by intrathecal administration. Newer formulations using conjugated ligands greatly enhances delivery efficiency and cell-type specific targeting.^[7]

Amyotrophic lateral sclerosis

Tofersen (marketed as Qalsody) was approved by the FDA for the treatment of SOD1- associated amyotrophic lateral sclerosis (ALS) in 2023.^[9] It was developed by Biogen under a licensing agreement with Ionis Pharmaceuticals. In trials the drug was found to lower levels of an ALS biomarker, neurofilament light change, and in long-term trial extensions to slow disease.^[9] Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence.^[10]

Batten disease

Milasen is a novel individualized therapeutic agent that was designed and approved by the FDA for the treatment of Batten disease. This therapy serves as an example of personalized medicine.^[11][12]

In 2019, a report was published detailing the development of milasen, an antisense oligonucleotide drug for Batten disease, under an expanded-access investigational clinical protocol authorized by the Food and Drug Administration (FDA).^[11] Milasen "itself remains an investigational drug, and it is not suited for the treatment of other patients with Batten's disease" because it was customized for a single patient's specific mutation.^[11] However it is an example of individualized genomic medicine therapeutical intervention.^[11][13]

Cytomegalovirus retinitis

Fomivirsen (marketed as Vitravene), was approved by the U.S. FDA in August 1998, as a treatment for cytomegalovirus retinitis.^[14]

Duchenne muscular dystrophy

Several morpholino oligos have been approved to treat specific groups of mutations causing Duchenne muscular dystrophy. In September 2016, eteplirsen (ExonDys51) received FDA approval^[15] for the treatment of cases that can benefit from skipping exon 51 of the dystrophin transcript. In December 2019, golodirsen (Vyondys 53) received FDA approval^[16] for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. In August 2020, viltolarsen (Viltepso) received FDA approval for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.^[17]

Epilepsy of Infancy with Migrating Focal Seizures (EIMFS)

Valeriasen is an investigational antisense oligonucleotide designed to reduce expression of KCNT1, a gene encoding the sodium-activated potassium channel K_Na1.1^[18] Pathogenic gain-of-function variants in KCNT1 are associated with developmental and epileptic encephalopathy, including epilepsy of infancy with migrating focal seizures (EIMFS), a severe early-life epilepsy syndrome characterized by treatment-resistant seizures, developmental impairment, and increased childhood mortality.^[19][20][21] The therapeutic strategy uses an RNase H–activating RNA-targeted therapy to knock down KCNT1 transcript levels rather than correcting a specific variant at the DNA level. In 2026, Nakayama et al reported intrathecal administration of valeriasen in two children with severe KCNT1 p.Arg474His-associated EIMFS under an investigational clinical protocol. Treatment was associated with reductions in seizure frequency and severity, but ventricular enlargement or hydrocephalus was observed in both patients, indicating a potential safety concern for some intrathecally delivered knockdown ASOs.^[18]

A companion human translational study by Golinski et al. investigated the developmental biology and preclinical feasibility of KCNT1 knockdown in utero. The study reported functional K_Na1.1 conductance in prenatal and neonatal human brain tissue, gain-of-function potassium currents in patient-derived excitatory and inhibitory neurons, and that ASO-mediated knockdown altered firing in mid-gestation primary human neurons, supporting the hypothesis that KCNT1-targeted ASO therapy may act on disease-relevant neuronal physiology during early human brain development.^[22]

Familial chylomicronaemia syndrome

Volanesorsen was approved by the European Medicines Agency (EMA) for the treatment of familial chylomicronaemia syndrome in May 2019.^[23][24]

Familial hypercholesterolemia

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia. ^[25][26][27]

Hereditary transthyretin-mediated amyloidosis

Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018.^[28] The application for inotersen was granted orphan drug designation.^[28] It was developed by Ionis Pharmaceuticals and licensed to Akcea Therapeutics. Patisiran (sold under Onpattro) was developed by Alnylam Pharmaceuticals, and also approved for use in the US and EU in 2018 with orphan drug designation.^[29] Its mechanism-of-action is the active substance of small interfering RNA (siRNA), which allows it to interfere with and block the production of transthyretin.^[30] As such, it was the first FDA-approved siRNA therapeutic.^[29]

Spinal muscular atrophy

In 2004, development of an antisense therapy for spinal muscular atrophy began. Over the following years, an antisense oligonucleotide later named nusinersen was developed by Ionis Pharmaceuticals under a licensing agreement with Biogen. In December 2016, nusinersen received regulatory approval from FDA^[31][32] and soon after, from other regulatory agencies worldwide.

Current clinical trials

As of 2020^[update], more than 50 antisense oligonucleotides were in clinical trials, including over 25 in advanced clinical trials (phase II or III).^[7][33]

Preclinical development

Several ASOs are currently being investigated in disease models for Alexander disease,^[37] ATXN2 (gene) and FUS (gene) amyotrophic lateral sclerosis, Angelman syndrome,^[38] Lafora disease, lymphoma, multiple myeloma, myotonic dystrophy, Parkinson's disease,^[39] Pelizaeus–Merzbacher disease,^[40][41] and prion disease,^[42] Rett syndrome,^[43] spinocerebellar Ataxia Type 3.