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European Heart Journal May 2017In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century.... (Review)
Review
In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'. Several drug developments did show a potent Lp(a)-lowering effect but did not make it to endpoint studies, mainly for safety reasons. Currently, three therapeutic approaches are either already in place or look highly promising: (i) lipid apheresis (specific or unspecific for Lp(a)) markedly decreases Lp(a) concentrations as well as cardiovascular endpoints; (ii) PCSK9 inhibitors which, besides lowering LDL cholesterol also decrease Lp(a) by roughly 30%; and (iii) antisense therapy targeting apolipoprotein(a) which has shown to specifically lower Lp(a) concentrations by up to 90% in phase 1 and 2 trials without influencing other lipids. Until the results of phase 3 outcome studies are available for antisense therapy, we will have to exercise patience, but with optimism since never before have we had the tools we have now to prove Koch's extrapolated postulate that lowering high Lp(a) concentrations might be protective against cardiovascular disease.
Topics: Aortic Valve Stenosis; Blood Component Removal; Cardiovascular Diseases; Cholesterol, LDL; Evidence-Based Medicine; Humans; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Lipoprotein(a); Oligonucleotides, Antisense; PCSK9 Inhibitors; Practice Guidelines as Topic; Risk Factors; Vascular Calcification
PubMed: 28329241
DOI: 10.1093/eurheartj/ehx033 -
Experimental Dermatology Jan 2017Genetic disorders affecting the skin, genodermatoses, constitute a large and heterogeneous group of diseases, for which treatment is generally limited to management of... (Review)
Review
Genetic disorders affecting the skin, genodermatoses, constitute a large and heterogeneous group of diseases, for which treatment is generally limited to management of symptoms. RNA-based therapies are emerging as a powerful tool to treat genodermatoses. In this review, we discuss in detail RNA splicing modulation by antisense oligonucleotides and RNA trans-splicing, transcript replacement and genome editing by in vitro-transcribed mRNAs, and gene knockdown by small interfering RNA and antisense oligonucleotides. We present the current state of these therapeutic approaches and critically discuss their opportunities, limitations and the challenges that remain to be solved. The aim of this review was to set the stage for the development of new and better therapies to improve the lives of patients and families affected by a genodermatosis.
Topics: Animals; Gene Knockdown Techniques; Genetic Therapy; Humans; Oligonucleotides, Antisense; RNA; RNA, Messenger; Skin Diseases, Genetic; Trans-Splicing
PubMed: 27376675
DOI: 10.1111/exd.13141 -
European Journal of Internal Medicine Jun 2020Several lines of evidence now attest that lipoprotein[a] (Lp[a]) is a significant risk factor for many cardiovascular disorders. This enigmatic lipoprotein, composed of... (Review)
Review
Several lines of evidence now attest that lipoprotein[a] (Lp[a]) is a significant risk factor for many cardiovascular disorders. This enigmatic lipoprotein, composed of a single copy of apolipoprotein B (apoB) and apolipoprotein[a] (apo [a]), expresses peculiar metabolism, virtually independent from lifestyle interventions. Several therapeutic options have hence been proposed for lowering elevated Lp[a] values, with or without concomitant effect on low density lipoprotein (LDL) particles, mostly encompassing statins, ezetimibe, nicotinic acid, lipoprotein apheresis, and anti-PCSK9 monoclonal antibodies. Since all these medical treatments have some technical and clinical drawbacks, a novel strategy is currently being proposed, based on the use of antisense apo[a] and/or apoB inhibitors. Although the role of these agents in hypercholesterolemic patients is now nearby entering clinical practice, the collection of information on Lp[a] is still underway. Preliminary evidence would suggest that apo[a] antisense therapy seems more appropriate in patients with isolated Lp[a] elevations, while apoB antisense therapy is perhaps more advisable in patients with isolated LDL elevations. In patients with concomitant elevations of Lp[a] and LDL, either combining the two apo[a] and apoB antisense therapies (a strategy which has never been tested), or the combination of well-known and relatively inexpensive drugs such as statins with antisense apo[a] inhibitors can be theoretically suggested. The results of an upcoming phase 3 study with antisense apo[a] inhibitors will hopefully provide definitive clues as to whether this approach may become the standard of care in patients with increased Lp[a] concentrations.
Topics: Blood Component Removal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipoprotein(a); Lipoproteins, LDL
PubMed: 32336611
DOI: 10.1016/j.ejim.2020.04.036 -
Current Opinion in Neurology Oct 2021There has been an explosion of advancement in the field of genetic therapies. The first gene-based treatments are now in clinical practice, with several additional... (Review)
Review
PURPOSE OF REVIEW
There has been an explosion of advancement in the field of genetic therapies. The first gene-based treatments are now in clinical practice, with several additional therapeutic programs in various stages of development. Novel technologies are being developed that will further advance the breadth and success of genetic medicine.Congenital myopathies are an important group of neuromuscular disorders defined by structural changes in the muscle and characterized by severe clinical symptoms caused by muscle weakness. At present, there are no approved drug therapies for any subtype of congenital myopathy.In this review, we present an overview of genetic therapies and discuss their application to congenital myopathies.
RECENT FINDINGS
Several candidate therapeutics for congenital myopathies are in the development pipeline, including ones in clinical trial. These include genetic medicines such as gene replacement therapy and antisense oligonucleotide-based gene knockdown. We highlight the programs related to genetic medicine, and also discuss congenital myopathy subtypes where genetic therapy could be applied.
SUMMARY
Genetic therapies are ushering in an era of precision medicine for neurological diseases. Congenital myopathies are conditions ideally suited for genetic medicine approaches, and the first such therapies will hopefully soon be reaching congenital myopathy patients.
Topics: Genetic Therapy; Humans; Muscle Weakness; Myopathies, Structural, Congenital; Oligonucleotides, Antisense
PubMed: 34267051
DOI: 10.1097/WCO.0000000000000978 -
Journal For Immunotherapy of Cancer Apr 2022The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited... (Clinical Trial)
Clinical Trial
BACKGROUND
The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man.
METHODS
We have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons.
RESULTS
AZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8 T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy.
CONCLUSIONS
Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669).
Topics: Animals; Disease Models, Animal; Forkhead Transcription Factors; Humans; Immunosuppression Therapy; Immunotherapy; Mice; Neoplasms; Oligonucleotides, Antisense; T-Lymphocytes, Regulatory; Tumor Microenvironment
PubMed: 35387780
DOI: 10.1136/jitc-2021-003892 -
The Canadian Journal of Cardiology Dec 2023Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a... (Review)
Review
Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.
Topics: Humans; Cholesterol, LDL; Proprotein Convertase 9; PCSK9 Inhibitors; Cardiovascular Diseases; Antibodies, Monoclonal; Atherosclerosis; Biological Therapy; Vaccines; Anticholesteremic Agents; Angiopoietin-Like Protein 3
PubMed: 37562541
DOI: 10.1016/j.cjca.2023.08.003 -
Pharmaceutics Nov 2021Nucleic acid-based therapeutics have demonstrated their efficacy in the treatment of various diseases and vaccine development. Antisense oligonucleotide (ASO) technology... (Review)
Review
Nucleic acid-based therapeutics have demonstrated their efficacy in the treatment of various diseases and vaccine development. Antisense oligonucleotide (ASO) technology exploits a single-strand short oligonucleotide to either cause target RNA degradation or sterically block the binding of cellular factors or machineries to the target RNA. Chemical modification or bioconjugation of ASOs can enhance both its pharmacokinetic and pharmacodynamic performance, and it enables customization for a specific clinical purpose. ASO-based therapies have been used for treatment of genetic disorders, cancer and viral infections. In particular, ASOs can be rapidly developed for newly emerging virus and their reemerging variants. This review discusses ASO modifications and delivery options as well as the design of antiviral ASOs. A better understanding of the viral life cycle and virus-host interactions as well as advances in oligonucleotide technology will benefit the development of ASO-based antiviral therapies.
PubMed: 34959297
DOI: 10.3390/pharmaceutics13122015 -
Trends in Molecular Medicine Mar 2024Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming... (Review)
Review
Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.
Topics: Humans; Amyotrophic Lateral Sclerosis; Oligonucleotides, Antisense; RNA Splicing
PubMed: 38216448
DOI: 10.1016/j.molmed.2023.12.003 -
Arquivos de Neuro-psiquiatria Jun 2024Neuromuscular diseases (NMD) include a broad group of medical conditions with both acquired and genetic causes. In recent years, important advances have been made in the...
Neuromuscular diseases (NMD) include a broad group of medical conditions with both acquired and genetic causes. In recent years, important advances have been made in the treatment of genetically caused NMD, and most of these advances are due to the implementation of therapies aimed at gene regulation. Among these therapies, gene replacement, small interfering RNA (siRNA), and antisense antinucleotides are the most promising approaches. More importantly, some of these therapies have already gained regulatory approval or are in the final stages of approval. The review focuses on motor neuron diseases, neuropathies, and Duchenne muscular dystrophy, summarizing the most recent developments in gene-based therapies for these conditions.
Topics: Humans; Neuromuscular Diseases; Muscular Dystrophy, Duchenne; Genetic Therapy; Gene Expression Regulation
PubMed: 38325390
DOI: 10.1055/s-0043-1777755 -
Clinical Therapeutics Nov 2023High plasma concentrations of LDL and lipoprotein(a) (Lp[a]) are independent and causal risk factors for atherosclerotic cardiovascular disease (ASCVD). There is an... (Review)
Review
PURPOSE
High plasma concentrations of LDL and lipoprotein(a) (Lp[a]) are independent and causal risk factors for atherosclerotic cardiovascular disease (ASCVD). There is an unmet therapeutic need for high-risk patients with elevated levels of LDL-C and/or Lp(a). Recent advances in the development of nucleic acids for gene silencing (ie, triantennary N-acetylgalactosamine conjugated antisense-oligonucleotides [ASOs] and small interfering RNA [siRNA]) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and Lp(a) offer effective and sustainable therapies.
METHODS
Related articles in the English language were identified through a search for original and review articles in the PubMed database using the following key terms: cardiovascular disease, dyslipidemia, PCSK9 inhibitors, Lp(a), LDL-cholesterol, familial hypercholesterolemia, siRNA, and antisense oligonucleotide and clinical trials (either alone or in combination).
FINDINGS
Inclisiran, the most advanced siRNA-treatment targeting hepatic PCSK9, is well tolerated, producing a >30% reduction on LDL-C levels in randomized controlled trials. Pelacarsen is the most clinical advanced ASO, whereas olpasiran and SLN360 are the 2 siRNAs directed against the mRNA of the LPA gene. Evidence suggests that all Lp(a)-targeting agents are safe and well tolerated, with robust and sustained reduction in plasma Lp(a) concentration up to 70% to 90% in individuals with elevated Lp(a) levels.
IMPLICATIONS
Cumulative evidence from clinical trials supports the value of ASO and siRNA therapies targeting the synthesis of PCSK9 and Lp(a) for lowering LDL-C and Lp(a) in patients with established ASCVD or high risk of ASCVD. Further research is needed to examine whether gene silencing therapy could improve clinical outcomes in patients with elevated LDL and/or Lp(a) levels. Confirmation of the tolerability and cost-effectiveness of long-term inhibition of PCSK9 and Lp(a) with this approach is essential.
Topics: Humans; Proprotein Convertase 9; Cholesterol, LDL; Cardiovascular Diseases; Lipoprotein(a); Oligonucleotides, Antisense; Atherosclerosis; RNA, Small Interfering
PubMed: 37524569
DOI: 10.1016/j.clinthera.2023.07.008