Antisense therapy

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- associated amyotrophic 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]

Cytomegalovirus retinitis

Fomivirsen (marketed as Vitravene), was

approved by the U.S. FDA in August 1998,
as a treatment for cytomegalovirus
retinitis.[13]
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[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]

Familial chylomicronaemia syndrome

Volanesorsen was approved by the

European Medicines Agency (EMA) for the
treatment of familial chylomicronaemia
syndrome in May 2019.[17][18]

Familial hypercholesterolemia

In January 2013 mipomersen (marketed

as Kynamro) was approved by the FDA for
the treatment of homozygous familial
hypercholesterolemia. [19][20][21]
Hereditary transthyretin-mediated
amyloidosis

Inotersen received FDA approval for the

treatment of hereditary transthyretin-
mediated amyloidosis in October 2018.[22]
The application for inotersen was granted
orphan drug designation.[22] 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.[23] Its
mechanism-of-action is the active
substance of small interfering RNA
(siRNA), which allows it to interfere with
and block the production of
trasnthyretin.[24] As such, it was the first
FDA-approved siRNA therapeutic.[23]

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[25][26] and
soon after, from other regulatory agencies
worldwide.

Investigational therapies

Current clinical trials

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:

Acromegaly, age related macular

degeneration, Alzheimer's disease,
amyotrophic lateral sclerosis, autosomal
dominant retinitis pigmentosa, beta
thalassemia, cardiovascular disease,
elevated level of lipoprotein(a),[31]
centronuclear myopathy, coagulopathies,
cystic fibrosis, Duchenne muscular
dystrophy, diabetes, epidermolysis bullosa
dystrophica, familial chylomicronemia
syndrome, frontotemporal dementia,
Fuchs' dystrophy, hepatitis B, hereditary
angioedema, hypertension, IgA
nephropathy, Leber's hereditary optic
neuropathy, multiple system atrophy, non-
alcoholic fatty liver disease, Parkinson's
disease, prostate cancer, Stargardt
disease, STAT3-expressing cancers, Usher
syndrome.

Preclinical development

Several ASOs are currently being

investigated in disease models for
Alexander disease,[32] ATXN2 (gene) and
FUS (gene) amyotrophic lateral sclerosis,
Angelman syndrome,[33] Lafora disease,
lymphoma, multiple myeloma, myotonic
dystrophy, Parkinson's disease,[34]
Pelizaeus–Merzbacher disease,[35][36] and
prion disease,[37] Rett syndrome,[38]
spinocerebellar Ataxia Type 3.
See also

Antisense
Antisense mRNA
Locked nucleic acid
Morpholino
Oligonucleotide synthesis
Peptide nucleic acid
RNA interference (which uses double-
strand RNA)

References

1. Morcos PA (June 2007). "Achieving

targeted and quantifiable alteration of