Antisense Drugs Make Sense for Neurological Diseases.
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ABSTRACT:
SUBMITTER: Bennett CF
PROVIDER: S-EPMC8682074 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The introduction of genetics revolutionized the field of neurodegenerative and neuromuscular diseases and has provided considerable insight into the underlying pathomechanisms. Nevertheless, effective treatment options have been limited. This changed recently when antisense oligonucleotides (ASOs) could be translated from in vitro and experimental animal studies into clinical practice. In 2016, two ASOs were approved by the United States US Food and Drug Administration (FDA) and demonstrated remarkable efficacy in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). ASOs are synthetic single-stranded strings of nucleic acids. They selectively bind to specific premessenger ribonucleic acid (pre-mRNA)/mRNA sequences and alter protein synthesis by several mechanisms of action. Thus, apart from gene replacement, ASOs may therefore provide the most direct therapeutic strategy for influencing gene expression. In this review, we shall discuss basic mechanisms of ASO action, the role of chemical modifications needed to improve the pharmacodynamic and pharmacokinetic properties of ASOs, and we shall then focus on several ASOs developed for the treatment of neurodegenerative and neuromuscular disorders, including SMA, DMD, myotonic dystrophies, Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease.
| S-EPMC5971383 | biostudies-literature
Project description:PURPOSE OF REVIEW:Colorectal cancer (CRC) screening is recommended to reduce CRC mortality. This review outlines key factors to consider when recommending screening, including disease burden, screening benefits and harms, and remaining knowledge gaps. RECENT FINDINGS:In response to increasing rates of CRC incidence among younger (age <?50 years) adults, the American Cancer Society published guidelines in May 2018 recommending average-risk CRC screening beginning at age 45 (vs. 50) years. Rates of young-onset CRC have increased in the USA since the early 1990s. However, there is very little empirical evidence of screening effectiveness in younger adults, and few studies have reported harms of routine screening in this age group. Further, we know little about the natural history of CRC in younger adults. Uncertainty surrounding the efficacy of CRC screening in younger adults suggests the benefits may be small. Precision cancer screening-or modified screening regimens based on risk-may improve the balance of screening benefits and harms beyond conventional age-based strategies.
| S-EPMC6657498 | biostudies-literature
Project description:Background and objectivesFew empiric studies evaluate the effects of regionalization on pancreatic cancer care.MethodsWe queried the National Cancer Database to identify patients undergoing pancreaticoduodenectomy for clinical stage I/II pancreatic adenocarcinoma between 2006 and 2015. Facilities were categorized by annual pancreatectomy volume. Textbook oncologic outcome was defined as a margin negative resection, appropriate lymph node assessment, no prolonged hospitalization, no 30-day readmission, no 90-day mortality, and timely receipt of adjuvant chemotherapy. Multivariable regression adjusted for comorbid disease, pathologic stage, and facility characteristics was used to evaluate the relationship between facility volume and textbook outcome.ResultsSixteen thousand six hundred and two patients underwent pancreaticoduodenectomy; 3566 (21.5%) had a textbook outcome. Operations performed at high volume centers increased each year (45.8% in 2006 to 64.2% in 2015, p < 0.001) as did textbook outcome rates (14.3%-26.2%, p < 0.001). Surgical volume was associated with textbook outcome. High volume centers demonstrated higher unadjusted rates of textbook outcome (25.4% vs. 11.8% p < 0.01) and increased adjusted odds of textbook outcome relative to low volume centers (odds ratio: 2.39, [2.02, 2.85], p < 0.001). Textbook outcome was associated with improved overall survival independent of volume.ConclusionsRegionalization of care for pancreaticoduodenectomy to high volume centers is ongoing and is associated with improved quality of care.
| S-EPMC8799483 | biostudies-literature
Project description:The plastid psbB operon is composed of the psbB, psbT, psbH, petB and petD genes. The psbN gene is located in the intergenic region between psbT and psbH on the opposite DNA strand. Transcription of psbN is under control of sigma factor 3 (SIG3) and psbN read-through transcription produces antisense RNA to psbT mRNA. To investigate on the question of whether psbT gene expression might be regulated by antisense RNA, we have characterized psbT sense and antisense RNAs. Mapping of 5' and 3'-ends by circular RT-PCR and /or 5'-RACE experiments reveal the existence of two different sense and antisense RNAs each, one limited to psbT RNA and a larger one that covers, in addition, part of the psbB coding region. Sense and antisense RNAs seem to form double-stranded RNA/RNA hybrids as indicated by nuclease digestion experiments followed by RT-PCR amplification to reveal nuclease resistant RNA. Western immunoblotting using antibodies made against PSBT protein and primer extension analysis of different plastid mRNA species and psbT antisense RNA suggest that sequestering of psbT mRNA by hybrid formation results in translational inactivation of the psbT mRNA and provides protection against nucleolytic degradation of mRNA during photooxydative stress conditions.
| S-EPMC3141253 | biostudies-other
Project description:Antisense transcription is widespread in genomes. Despite large differences in gene size and architecture, we find that yeast and human genes share a unique, antisense transcription-associated chromatin signature. We asked whether this signature is related to a biological function for antisense transcription. Using quantitative RNA-FISH, we observed changes in sense transcript distributions in nuclei and cytoplasm as antisense transcript levels were altered. To determine the mechanistic differences underlying these distributions, we developed a mathematical framework describing transcription from initiation to transcript degradation. At GAL1, high levels of antisense transcription alter sense transcription dynamics, reducing rates of transcript production and processing, while increasing transcript stability. This relationship with transcript stability is also observed as a genome-wide association. Establishing the antisense transcription-associated chromatin signature through disruption of the Set3C histone deacetylase activity is sufficient to similarly change these rates even in the absence of antisense transcription. Thus, antisense transcription alters sense transcription dynamics in a chromatin-dependent manner.
| S-EPMC5810148 | biostudies-literature
Project description:BackgroundA significant number of genes in mammalian genomes are being found to have natural antisense transcripts (NATs). These sense-antisense (S-AS) pairs are believed to be involved in several cellular phenomena.ResultsHere, we generated a catalog of S-AS pairs occurring in the human and mouse genomes by analyzing different sources of expressed sequences available in the public domain plus 122 massively parallel signature sequencing (MPSS) libraries from a variety of human and mouse tissues. Using this dataset of almost 20,000 S-AS pairs in both genomes we investigated, in a computational and experimental way, several putative roles that have been assigned to NATs, including gene expression regulation. Furthermore, these global analyses allowed us to better dissect and propose new roles for NATs. Surprisingly, we found that a significant fraction of NATs are artifacts produced by genomic priming during cDNA library construction.ConclusionWe propose an evolutionary and functional model in which alternative polyadenylation and retroposition account for the origin of a significant number of functional S-AS pairs in mammalian genomes.
| S-EPMC1868933 | biostudies-literature
Project description:Transcriptome profiling studies suggest that a large fraction of the genome is transcribed and many transcripts function independent of their protein coding potential. The relevance of noncoding RNAs (ncRNAs) in normal physiological processes and in tumorigenesis is increasingly recognized. Here, we describe consistent and significant differences in the distribution of sense and antisense transcripts between normal and neoplastic breast tissues. Many of the differentially expressed antisense transcripts likely represent long ncRNAs. A subset of genes that mainly generate antisense transcripts in normal but not cancer cells is involved in essential metabolic processes. These findings suggest fundamental differences in global RNA regulation between normal and cancer cells that might play a role in tumorigenesis.
| S-EPMC3286925 | biostudies-literature
Project description:The B-cell lymphoma 2 (Bcl-2) family, comprised of pro- and anti-apoptotic proteins, regulates the delicate balance between programmed cell death and cell survival. The Bcl-2 family is essential in the maintenance of tissue homeostasis, but also a key culprit in tumorigenesis. Anti-apoptotic Bcl-2, the founding member of this family, was discovered due to its dysregulated expression in non-Hodgkin's lymphoma. Bcl-2 is a central protagonist in a wide range of human cancers, promoting cell survival, angiogenesis and chemotherapy resistance; this has prompted the development of Bcl-2-targeting drugs. Antisense oligonucleotides (ASO) are highly specific nucleic acid polymers used to modulate target gene expression. Over the past 25 years several Bcl-2 ASO have been developed in preclinical studies and explored in clinical trials. This review will describe the history and development of Bcl-2-targeted ASO; from initial attempts, optimizations, clinical trials undertaken and the promising candidates at hand.
| S-EPMC8778715 | biostudies-literature
Project description:Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.
| S-EPMC9058873 | biostudies-literature
Project description:Polyphenol oxidases (PPOs) catalyze the oxidation of phenolics to quinones, the secondary reactions of which lead to oxidative browning and postharvest losses of many fruits and vegetables. PPOs are ubiquitous in angiosperms, are inducible by both biotic and abiotic stresses, and have been implicated in several physiological processes including plant defense against pathogens and insects, the Mehler reaction, photoreduction of molecular oxygen by PSI, regulation of plastidic oxygen levels, aurone biosynthesis and the phenylpropanoid pathway. Here we review experiments in which the roles of PPO in disease and insect resistance as well as in the Mehler reaction were investigated using transgenic tomato (Lycopersicon esculentum) plants with modified PPO expression levels (suppressed PPO and overexpressing PPO). These transgenic plants showed normal growth, development and reproduction under laboratory, growth chamber and greenhouse conditions. Antisense PPO expression dramatically increased susceptibility while PPO overexpression increased resistance of tomato plants to Pseudomonas syringae. Similarly, PPO-overexpressing transgenic plants showed an increase in resistance to various insects, including common cutworm (Spodoptera litura (F.)), cotton bollworm (Helicoverpa armigera (Hübner)) and beet army worm (Spodoptera exigua (Hübner)), whereas larvae feeding on plants with suppressed PPO activity had higher larval growth rates and consumed more foliage. Similar increases in weight gain, foliage consumption, and survival were also observed with Colorado potato beetles (Leptinotarsa decemlineata (Say)) feeding on antisense PPO transgenic tomatoes. The putative defensive mechanisms conferred by PPO and its interaction with other defense proteins are discussed. In addition, transgenic plants with suppressed PPO exhibited more favorable water relations and decreased photoinhibition compared to nontransformed controls and transgenic plants overexpressing PPO, suggesting that PPO may have a role in the development of plant water stress and potential for photoinhibition and photooxidative damage that may be unrelated to any effects on the Mehler reaction. These results substantiate the defensive role of PPO and suggest that manipulation of PPO activity in specific tissues has the potential to provide broad-spectrum resistance simultaneously to both disease and insect pests, however, effects of PPO on postharvest quality as well as water stress physiology should also be considered. In addition to the functional analysis of tomato PPO, the application of antisense/sense technology to decipher the functions of PPO in other plant species as well as for commercial uses are discussed.
| S-EPMC6149088 | biostudies-other