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]

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

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">Small interfering RNA</span> Biomolecule

Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20–24 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation.

<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 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 followed by the arms. This can result in trouble standing up. Most are unable to walk by the age of 12. Affected muscles may look larger due to increased fat content. Scoliosis is also common. Some may have intellectual disability. Females with a single copy of the defective gene may show mild symptoms.

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.

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

Deflazacort is a glucocorticoid used as an anti-inflammatory and immunomodulatory agent. It was patented in 1965 and approved for medical use in 1985. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication for Duchenne Muscular Dystrophy.

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">Marathon Pharmaceuticals</span> Former U.S. rare disease drug company

Marathon Pharmaceuticals LLC was a privately held biopharmaceuticals company focused on drugs for people with rare diseases. The Illinois-based company developed and manufactured therapeutics and brought them to market. It employed 100 people in four global locations. In 2017, PTC Therapeutics acquired rights to Marathon Pharmaceuticals' drug Emflaza (deflazacort) for $140 million after criticism about their plan to sell the drug at a list price of $89,000 per year to sufferers despite the fact that the same drug was available in Canada and the UK for around $1,000 per year.

<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 3 commercially approved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen) and has 4 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.

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.

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.

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 medical scientist and professor of medical genetics at the University of Alberta, where he also holds the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. He is best known for his studies of antisense oligonucleotide-based therapeutics for muscular dystrophy that led to the development of an FDA-approved drug viltolarsen. His research interests include precision medicine for muscular dystrophy and genetic diseases. He has co-edited two books both published in the Methods in Molecular Biology series from Humana Press, Springer-Nature, and has published more than 100 refereed papers and patents. He is a member of the editorial boards for the International Journal of Molecular Sciences, Genes, Frontiers in Genome Editing, Frontiers in Physiology, and Nucleic Acid Therapeutics, a member of the Medical and Scientific Advisory Committee of Muscular Dystrophy Canada, and a co-founder of the Canadian Neuromuscular Network (CAN-NMD).

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

Ultragenyx is an American biopharmaceutical company involved in the research and development of novel products for treatment of rare and ultra-rare genetic diseases for which there are typically no approved treatments and high unmet medical need. The company works with multiple drug modalities including biologics, small molecule, gene therapies, and ASO and mRNAs in the disease categories of bone, endocrine, metabolic, muscle and CNS diseases.

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.

References

  1. ↑ 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. PMID   17493584.
  2. ↑ International Nonproprietary Names (INN) for biological and biotechnological substances
  3. ↑ Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997. ISBN   0849385520 ISBN   9780849385520
  4. ↑ Weiss B, Davidkova G, Zhou LW (March 1999). "Antisense RNA technology for studying and modulating biological processes". Cellular and Molecular Life Sciences. 55 (3): 334–58. doi:10.1007/s000180050296. PMID   10228554. S2CID   9448271.
  5. ↑ Goodchild J (2011). "Therapeutic Oligonucleotides". Methods in Molecular Biology. Vol. 764. pp. 1–15. doi:10.1007/978-1-61779-188-8_1. ISBN   978-1-61779-187-1. PMID   21748630.{{cite book}}: Missing or empty |title= (help)
  6. 1 2 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. PMID   20055705.
  7. ↑ Xu L, Anchordoquy T (January 2011). "Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics". Journal of Pharmaceutical Sciences. 100 (1): 38–52. doi:10.1002/jps.22243. PMC   3303188 . PMID   20575003.
  8. 1 2 "Tofersen". The ALS Association. Retrieved 2023-04-25.
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  30. ↑ "Roche drops Huntington's disease trial with once-promising drug tominersen". Reuters. 2021-03-23. Retrieved 2021-03-25.
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  32. ↑ Hagemann, Tracy L.; Powers, Berit; Mazur, Curt; Kim, Aneeza; Wheeler, Steven; Hung, Gene; Swayze, Eric; Messing, Albee (2018). "Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease". Annals of Neurology. 83 (1): 27–39. doi:10.1002/ana.25118. ISSN   1531-8249. PMC   5876100 . PMID   29226998.
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