Antisense therapy is a form of treatment that uses antisense

oligonucleotides Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids ...

(ASOs) to target

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...

(mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including

ribonuclease H Ribonuclease H (abbreviated RNase H or RNH) is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/ DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearl ...

mediated decay of the pre-mRNA, direct steric blockage, and

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

content modulation through splicing site binding on pre-mRNA. 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.International Nonproprietary Names (INN) for biological and biotechnological substances
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Pharmacokinetics and pharmacodynamics

Half-life and stability

ASO-based drugs employ highly modified, single-stranded chains of synthetic

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...

s that achieve wide tissue distribution with very long half-lives. For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle-free delivery to cells.

''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 Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the Cell (biology), cells, and transports Metabolic waste, metabolic waste products away from th ...

when delivered systemically but they can distribute across the

neuraxis The neuraxis or sometimes neuroaxis is the axis of the central nervous system. It denotes the direction in which the central nervous system lies. During embryological development, the neuraxis is bent by various flexures, contributing to the ma ...

if injected in the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

typically by

intrathecal administration Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain m ...

. Newer formulations using conjugated ligands greatly enhances delivery efficiency and cell-type specific targeting.

Approved therapies

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. 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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA). 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. However it is an example of individualized genomic medicine therapeutical intervention.

Cytomegalovirus retinitis

Fomivirsen Fomivirsen (brand name Vitravene) is an antisense antiviral drug that was used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. It was administered via intraocular injection. It was d ...

(marketed as Vitravene), was approved by the U.S. FDA in August 1998, as a treatment for

cytomegalovirus retinitis Cytomegalovirus retinitis, also known as CMV retinitis, is an inflammation of the retina of the eye that can lead to blindness. Caused by human cytomegalovirus, it occurs predominantly in people whose immune system has been compromised, 15-40% of ...

Duchenne muscular dystrophy

Several

morpholino A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. Its molecular structure contain ...

oligos have been approved to treat specific groups of mutations causing

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...

. In September 2016, eteplirsen (ExonDys51) received FDA approval for the treatment of cases that can benefit from skipping exon 51 of the dystrophin transcript. In December 2019,

golodirsen Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry. The most common ...

(Vyondys 53) received FDA approval 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.

Familial chylomicronaemia syndrome

Volanesorsen was approved by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) for the treatment of familial chylomicronaemia syndrome in May 2019.

Familial hypercholesterolemia

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia.

Hereditary transthyretin-mediated amyloidosis

Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018. The application for inotersen was granted

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

designation. It was developed by Ionis Pharmaceuticals and licensed to Akcea Therapeutics.

Spinal muscular atrophy

In 2004, development of an antisense therapy for

spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...

began. Over the following years, an

antisense oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids ...

later named

nusinersen Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder. Since the condition it treats i ...

was developed by

Ionis Pharmaceuticals Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has 3 commercially approved medicines: Spinraza (Nusinersen), Tegsedi (I ...

under a licensing agreement with

Biogen Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. History ...

. In December 2016, nusinersen received regulatory approval from

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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).

Phase III trials

= Amyotrophic lateral sclerosis

= Tofersen (also known as IONIS-SOD1_{Rx and} BIIB067) is currently being tested in a phase 3 trial for

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(ALS) due to mutations in the

SOD1 Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...

gene. Results from a phase 1/2 trial have been promising. It is being developed by Biogen under a licensing agreement with Ionis Pharmaceuticals.

= 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 Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retinol'' ...

reduction in patients.

= Huntington's disease

= Tominersen (also known as IONIS-HTT_Rx and RG6042) was tested in a phase 3 trial for

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

although this trial was discontinued on March 21, 2021, due to lack of efficacy. It is currently licensed to

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

by Ionis Pharmaceuticals.

Phase I and II trials

Clinical trials are ongoing for several diseases and conditions including: Acromegaly,

age related macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, autosomal dominant retinitis pigmentosa,

beta thalassemia Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cli ...

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

, elevated level of

lipoprotein(a) Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart ...

centronuclear myopathy Centronuclear myopathies (CNM) are a group of congenital myopathies where cell nuclei are abnormally located in the center of muscle cells instead of their normal location at the periphery. Symptoms of CNM include severe hypotonia, hypoxia-requi ...

, coagulopathies,

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

epidermolysis bullosa dystrophica Epidermolysis bullosa dystrophica or dystrophic EB (DEB) is an inherited disease affecting the skin and other organs. "Butterfly child" is the colloquial name for a child born with the disease, as their skin is seen to be as delicate and fragile ...

familial chylomicronemia syndrome Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead t ...

frontotemporal dementia Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...

Fuchs' dystrophy Fuchs dystrophy, also referred to as Fuchs endothelial corneal dystrophy (FECD) and Fuchs endothelial dystrophy (FED), is a slowly progressing corneal dystrophy that usually affects both eyes and is slightly more common in women than in men. Althou ...

hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...

hereditary angioedema Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomitin ...

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

IgA nephropathy IgA nephropathy (IgAN), also known as Berger's disease () (and variations), or synpharyngitic glomerulonephritis, is a disease of the kidney (or nephropathy) and the immune system; specifically it is a form of glomerulonephritis or an inflammati ...

Leber's hereditary optic neuropathy Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predomin ...

multiple system atrophy Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism) and ataxia. This is caused by progr ...

non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

, Stargardt disease, STAT3-expressing

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

Usher syndrome Usher syndrome, also known as Hallgren syndrome, Usher–Hallgren syndrome, retinitis pigmentosa–dysacusis syndrome or dystrophia retinae dysacusis syndrome, is a rare genetic disorder caused by a mutation in any one of at least 11 genes result ...

Preclinical development

Several ASOs are currently being investigated in disease models for

Alexander disease Alexander disease is a very rare autosomal dominant leukodystrophy, which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. The most common type is the infantile form that usually begins duri ...

, ATXN2 (gene) and

FUS (gene) RNA-binding protein FUS/TLS (FUused in Sarcoma/Translocated in LipoSarcoma), also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the ''FUS'' gene. Discovery FUS/TLS was initially identified as a fu ...

Angelman syndrome Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...

Lafora disease Lafora disease is a rare, adult-onset and autosomal recessive genetic disorder which results in Myoclonus#Epilepsy forms, myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by t ...

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...

myotonic dystrophy Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intel ...

Pelizaeus–Merzbacher disease Friedrich Christoph Pelizaeus, Pelizaeus–Ludwig Merzbacher, Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in proteolipid protein 1 (''PLP1''), a maj ...

, and

prion disease Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

, spinocerebellar Ataxia Type 3.

References

External links

Antisense Pharma: Promising Phase IIb Results Of Targeted Therapy With AP 12009 In Recurrent Anaplastic Astrocytoma
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