https://www.cell.com/cell/pdf/S0092-8674(19)31007-4.pdf

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.

Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.

/pdf/advances-in-oligonucleotide-drug-delivery-nuahdv9tzv.pdf

Advances in oligonucleotide drug delivery

Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded antisense oligonucleotide (ASO) drugs representing four chemical classes, two mechanisms of action and four routes of administration have been approved for commercial use, including the first RNA-targeted drug to be a major commercial success, nusinersen. Although all the approved drugs are for use in patients with rare diseases, many of the ASOs in late- and middle-stage clinical development are intended to treat patients with very common diseases. ASOs in development are showing substantial improvements in potency and performance based on advances in medicinal chemistry, understanding of molecular mechanisms and targeted delivery. Moreover, the ASOs in development include additional mechanisms of action and routes of administration such as aerosol and oral formulations. Here, we describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications. We also consider strategic issues such as target selection and provide perspectives on the future of the field.

Antisense technology: an overview and prospectus

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to therapies targeting downstream processes To translate ASO-based therapies into a clinical success, it is crucial to overcome the challenges associated with off-target side effects and insufficient biological activity In this regard, several chemical modifications and diverse delivery strategies have been explored In this review, we systematically discuss the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs Further, we highlight the recent advances made in development of ASO-based drugs with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications We also discuss various promising ASO-based drug candidates in the clinical trials, and the outstanding opportunity of emerging microRNA as a viable therapeutic target for future ASO-based therapies

https://www.mdpi.com/2077-0383/9/6/2004/pdf

Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development.

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.

/pdf/huntington-disease-new-insights-into-molecular-pathogenesis-494a9qvew5.pdf

Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities.

Background Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTR...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1900907

Targeting Huntingtin Expression in Patients with Huntington’s Disease

Background HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production. Design/methods In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent DSMB review of safety, PK and target engagement prior to dose escalation. Results IONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed. Conclusions ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD. Study Supported By: Ionis Pharmaceuticals

Effects of IONIS-HTTRX (RG6042) in Patients With Early Huntington's Disease, Results of the First Htt-lowering Drug Trial

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Targeting Huntingtin Expression in Patients with Huntington’s Disease

Effects of IONIS-HTTRX (RG6042) in Patients With Early Huntington's Disease, Results of the First Htt-lowering Drug Trial