Form of treatment for genetic disorders and other illnesses
Antisense therapy is a form of treatment that uses antisense
oligonucleotides (ASOs) to target
messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including
ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and
exon content modulation through
splicing site binding on pre-mRNA.[1] Several ASOs have been approved in the United States, the European Union, and elsewhere.
Nomenclature
The common stem for antisense oligonucleotides drugs is -rsen. The substem -virsen designates antiviral antisense oligonucleotides.[2]
Pharmacokinetics and pharmacodynamics
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.[3][4][5] For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit
nuclease degradation enabling vehicle-free delivery to cells.[6][7]
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.[6]
Approved therapies
Amyotrophic lateral sclerosis
Tofersen (marketed as Qalsody) was approved by the FDA for the treatment of
SOD1- associatedamyotrophic lateral sclerosis (ALS) in 2023.[8] 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.[8] Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence.[9]
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.[10][11]
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).[10] 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.[10] However it is an example of
individualized genomic medicine therapeutical intervention.[10][12]
Several
morpholino oligos have been approved to treat specific groups of mutations causing
Duchenne muscular dystrophy. In September 2016,
eteplirsen (ExonDys51) received FDA approval[14] 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[15] 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.[16]
As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in
advanced clinical trials (phase II or III).[27][28]
Phase III trials
Hereditary transthyretin-mediated amyloidosis
A follow-on drug to Inotersen is being developed by Ionis Pharmaceuticals and under license to
Akcea Therapeutics for hereditary transthyretin-mediated amyloidosis. In this formulation the ASO is conjugated to
N-Acetylgalactosamine enabling hepatocyte-specific delivery, greatly reducing dose requirements and side effect profile while increasing the level of
transthyretin reduction in patients.
Huntington's disease
Tominersen (also known as IONIS-HTTRx and RG6042) was tested in a phase 3 trial for
Huntington's disease[29] although this trial was discontinued on March 21, 2021, due to lack of efficacy.[30] It is currently licensed to
Roche by Ionis Pharmaceuticals.
Phase I and II trials
Clinical trials are ongoing for several diseases and conditions including:
^Morcos PA (June 2007). "Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos". Biochemical and Biophysical Research Communications. 358 (2): 521–7.
doi:
10.1016/j.bbrc.2007.04.172.
PMID17493584.
^
abBennett CF, Swayze EE (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annual Review of Pharmacology and Toxicology. 50: 259–93.
doi:
10.1146/annurev.pharmtox.010909.105654.
PMID20055705.
^Bennett CF, Swayze EE (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annual Review of Pharmacology and Toxicology. 50: 259–93.
doi:
10.1146/annurev.pharmtox.010909.105654.
PMID20055705.