Antisense oligonucleotides: the next frontier for treatment of neurological disorders

  title={Antisense oligonucleotides: the next frontier for treatment of neurological disorders},
  author={Carlo Rinaldi and Matthew J. A. Wood},
  journal={Nature Reviews Neurology},
Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs… 

Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development

This review systematically discusses the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs, with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications.

Development of Antisense Oligonucleotide Gapmers for the Treatment of Dyslipidemia and Lipodystrophy.

This chapter focuses on the clinical applications of gapmer AOs for genetic dyslipidemia and lipodystrophy.

The powerful world of antisense oligonucleotides: From bench to bedside

Through pioneering examples, this review shows the versatility of the mechanisms of action that provide ASOs with the potential capacity to achieve custom treatment, revolutionizing personalized medicine.

Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases

Antisense oligonucleotides hold great therapeutic potential for numerous other inherited retinal diseases with common deep-intronic and dominant gain-of-function mutations, and would complement viral vector-mediated gene augmentation which is generally limited by the size of the transgene and to the treatment of recessive diseases.

Development of Antisense Oligonucleotide Gapmers for the Treatment of Huntington's Disease.

This chapter focuses on the modified gapmer AOs for the treatment of HD, a promising therapeutic approach for Huntington's disease, a devastating disorder affecting the motor and cognitive abilities.

Nano drug delivery systems for antisense oligonucleotides (ASO) therapeutics.

A perspective on oligonucleotide therapy: Approaches to patient customization

The present review is a congregated effort to present the past and present of OTs and the current efforts to make OTs for plausible future therapeutics, and deliberates on a newly emerging approach to personalized treatment for patients with rare and fatal diseases with OT.

Antisense oligonucleotides for neurodegeneration

It is hoped that ASO-based approaches will provide effective diseasemodifying therapies for HD and similar neurodegenerative diseases soon.

Development and Clinical Applications of Antisense Oligonucleotide Gapmers.

This chapter will cover the development of mipomersen and inotersen in clinical trials, along with advancement in gapmer treatments for cancer, triglyceride-elevating genetic diseases, Huntington's disease, myotonic dystrophy, and prion diseases.



Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA

Many of the more commonly used antisense oligonucleotides (ASOs) chemistries are discussed, as well as the different mechanisms of action that can result from these specific chemical modifications.

Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy.

This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy.

Targeting RNA to treat neuromuscular disease

Recent advances in the development of antisense oligonucleotides and other promising novel approaches, including the induction of readthrough nonsense mutations are reviewed.

Antisense oligonucleotide therapy for neurodegenerative disease.

Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis caused by a mutation in SOD1, suggesting that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.

Clinical pharmacokinetics of second generation antisense oligonucleotides

A limited but growing database on chronic dosing of second generation ASOs, across various patient and special populations, and also with non-systemic local delivery approaches, will help further characterize the clinical PK properties of these compounds and better quantify the extent and sources of any observed PK variability and potential impact on clinical response.

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

An advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration following a systemic route with peptide delivery.

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers

Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, it is shown that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain.