Antisense therapy

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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.

Contents

Nomenclature

The common stem for antisense oligonucleotides drugs is -rsen. The substem -virsen designates antiviral antisense oligonucleotides. [2]

Antisense Oligonucleotide Development

Developments in ASO modification are separated into three generations [3] . Generation one is called backbone-modified and focuses on the phosphodiester group of the nucleotide. This impacts inter-nucleotide binding. These modifications led to better distribution, reduced urinary excretion, and prolonged residence time of the ASOs in the cell. Some examples of first generation modifications include the addition of a phosphorothioate group (PS), methyl group, or nitrogen. The most common is the phosphorothioate group (PS) in which the oxygen atoms of a phosphodiester group are replaced with sulfur atoms, greatly improving efficacy and reducing degradation. Generation two is sugar-modified, focused on the ribose sugar of the nucleotide. This generation saw improved binding affinity while reducing degradation. Some examples of generation two modifications are the substitution of R group with morpholine group (MO) and the usage of phosphorodiamidate morpholino oligomer (PMO) and thiomorpholine oligomer (TMO) as linkages between the ribose sugar and phosphodiester group in the backbone. Generation three is nucleobase-modified, the least common type of modification. These modifications enhanced binding affinity and cell penetration while reducing degradation and off-target effects. Examples include the introduction of G-clamps, pseudoisocytosine, and the substitution of bases with amine, thione, halogen, alkyl, alkenyl, or alkynyl groups [4] .

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. [5] [6] [7] For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle-free delivery to cells. [8] [9]

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. [8]

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. [10] 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. [10] Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence. [11]

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. [12] [13]

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). [12] 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. [12] However it is an example of individualized genomic medicine therapeutical intervention. [12] [14]

Cytomegalovirus retinitis

Fomivirsen (marketed as Vitravene), was approved by the U.S. FDA in August 1998, as a treatment for cytomegalovirus retinitis. [15]

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 [16] 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 [17] 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. [18]

Familial chylomicronaemia syndrome

Volanesorsen was approved by the European Medicines Agency (EMA) for the treatment of familial chylomicronaemia syndrome in May 2019. [19] [20]

Familial hypercholesterolemia

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia. [21] [22] [23]

Hereditary transthyretin-mediated amyloidosis

Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018. [24] The application for inotersen was granted orphan drug designation. [24] 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. [25] 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. [26] As such, it was the first FDA-approved siRNA therapeutic. [25]

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 [27] [28] 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). [29] [30]

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 [31] although this trial was discontinued on March 21, 2021, due to lack of efficacy. [32] 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), [33] 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, [34] ATXN2 (gene) and FUS (gene) amyotrophic lateral sclerosis, Angelman syndrome, [35] Lafora disease, lymphoma, multiple myeloma, myotonic dystrophy, Parkinson's disease, [36] Pelizaeus–Merzbacher disease, [37] [38] and prion disease, [39] Rett syndrome, [40] spinocerebellar Ataxia Type 3.

See also

Related Research Articles

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 fragments of nucleic acids can be manufactured as single-stranded molecules with any user-specified sequence, and so are vital for artificial gene synthesis, polymerase chain reaction (PCR), DNA sequencing, molecular cloning and as molecular probes. In nature, oligonucleotides are usually found as small RNA molecules that function in the regulation of gene expression, or are degradation intermediates derived from the breakdown of larger nucleic acid molecules.

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.

<span class="mw-page-title-main">Morpholino</span> Chemical compound

A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule used in molecular biology to modify gene expression. Its molecular structure contains DNA bases attached to a backbone of methylenemorpholine rings linked through phosphorodiamidate groups. Morpholinos block access of other molecules to small specific sequences of the base-pairing surfaces of ribonucleic acid (RNA). Morpholinos are used as research tools for reverse genetics by knocking down gene function.

Sarepta Therapeutics, Inc. is a medical research and drug development company with corporate offices and research facilities in Cambridge, Massachusetts, United States. Incorporated in 1980 as AntiVirals, shortly before going public the company changed its name from AntiVirals to AVI BioPharma soon with stock symbol AVII and in July 2012 changed name from AVI BioPharma to Sarepta Therapeutics and SRPT respectively. As of 2023, the company has four approved drugs.

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

Drisapersen is an experimental drug that was under development by BioMarin, after acquisition of Prosensa, for the treatment of Duchenne muscular dystrophy. The drug is a 2'-O-methyl phosphorothioate oligonucleotide that alters the splicing of the dystrophin RNA transcript, eliminating exon 51 from the mature dystrophin mRNA.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

<span class="mw-page-title-main">Ionis Pharmaceuticals</span> Biotechnology company

Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has three commercially approved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen), and has four drugs in pivotal studies: tominersen for Huntington's disease, tofersen for SOD1-ALS, AKCEA-APO(a)-LRx for cardiovascular disease, and AKCEA-TTR-LRx for all forms of TTR amyloidosis.

<span class="mw-page-title-main">Nusinersen</span> Medication used for spinal muscular atrophy

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.

<span class="mw-page-title-main">Custirsen</span> Chemical compound

Custirsen, with aliases including custirsen sodium, OGX-011, and CC-8490, is an investigational drug that is under clinical testing for the treatment of cancer. It is an antisense oligonucleotide (ASO) targeting clusterin expression. In metastatic prostate cancer, custirsen showed no benefit in improving overall survival.

<span class="mw-page-title-main">Golodirsen</span> Medication for Duchenne muscular dystrophy

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

<span class="mw-page-title-main">Inotersen</span> Pharmaceutical drug

Inotersen, sold under the brand name Tegsedi, is a 2'-O-(2-methoxyethyl) (2'-MOE) antisense oligonucleotide medication used for the treatment of nerve damage in adults with hereditary transthyretin-mediated amyloidosis. The sequence is TCTTG GTTACATGAA ATCCC, where C is methylated C, and the first and third section are MOE-modified.

<span class="mw-page-title-main">Viltolarsen</span> Pharmaceutical drug

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

<span class="mw-page-title-main">Cure Rare Disease</span>

Cure Rare Disease is a non-profit biotechnology company based in Boston, Massachusetts that is working to create novel therapeutics using gene therapy, gene editing and antisense oligonucleotides to treat people impacted by rare and ultra-rare genetic neuromuscular conditions.

Toshifumi (Toshi) Yokota is a biomedical scientist and professor of medical genetics at the University of Alberta, holding the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. Yokota is widely recognized for pioneering work in antisense therapy for muscular dystrophy and other genetic diseases, which led to the development of viltolarsen, an FDA-approved treatment for Duchenne muscular dystrophy (DMD). With over 100 peer-reviewed publications and several patents, Yokota has made significant contributions to the field of precision medicine. Yokota also co-edited three volumes in the Methods in Molecular Biology series by Humana Press, Springer-Nature and serves on editorial boards of multiple scientific journals.

<span class="mw-page-title-main">Casimersen</span> Medication

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.

Gapmers are short DNA antisense oligonucleotide structures with RNA-like segments on both sides of the sequence. These linear pieces of genetic information are designed to hybridize to a target piece of RNA and silence the gene through the induction of RNase H cleavage. Binding of the gapmer to the target has a higher affinity due to the modified RNA flanking regions, as well as resistance to degradation by nucleases. Gapmers are currently being developed as therapeutics for a variety of cancers, viruses, and other chronic genetic disorders.

ncRNA therapy

A majority of the human genome is made up of non-protein coding DNA. It infers that such sequences are not commonly employed to encode for a protein. However, even though these regions do not code for protein, they have other functions and carry necessary regulatory information.They can be classified based on the size of the ncRNA. Small noncoding RNA is usually categorized as being under 200 bp in length, whereas long noncoding RNA is greater than 200bp. In addition, they can be categorized by their function within the cell; Infrastructural and Regulatory ncRNAs. Infrastructural ncRNAs seem to have a housekeeping role in translation and splicing and include species such as rRNA, tRNA, snRNA.Regulatory ncRNAs are involved in the modification of other RNAs.

<span class="mw-page-title-main">Eplontersen</span> Medication

Eplontersen, sold under the brand name Wainua, is a medication used for the treatment of transthyretin-mediated amyloidosis. It is a transthyretin-directed antisense oligonucleotide. It was developed to treat hereditary transthyretin amyloidosis by Ionis Pharmaceuticals and AstraZeneca.

Stephen Donald Wilton, also known as Steve Wilton, is an Australian molecular biologist and academic, serving as the Foundation Professor of Molecular Therapy at Murdoch University and adjunct professor at the University of Western Australia (UWA). He also fulfills dual roles as a Director at the Perron Institute for Neurological and Translational Science and deputy director at Murdoch's Centre for Molecular Medicine and Innovative Therapeutics (CMMIT).

References

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