Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome.

ABSTRACT: While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.

SUBMITTER: Lee SE

PROVIDER: S-EPMC6997046 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome.

Lee Sarah E SE Duran-Martinez Monica M Khantsis Sabina S Bianchi Diana W DW Guedj Faycal F

Trends in molecular medicine 20191107 2

While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to i ...[more]

PMID: 31706840

Similar Datasets

Challenges and Opportunities for Grounding Cognition

Project description:According to the grounded perspective, cognition emerges from the interaction of classic cognitive processes with the modalities, the body, and the environment. Rather than being an autonomous impenetrable module, cognition incorporates these other domains intrinsically into its operation. The Situated Action Cycle offers one way of understanding how the modalities, the body, and the environment become integrated to ground cognition. Seven challenges and opportunities are raised for this perspective: (1) How does cognition emerge from the Situated Action Cycle and in turn support it? (2) How can we move beyond simply equating embodiment with action, additionally establishing how embodiment arises in the autonomic, neuroendocrine, immune, cardiovascular, respiratory, digestive, and integumentary systems? (3) How can we better understand the mechanisms underlying multimodal simulation, its functions across the Situated Action Cycle, and its integration with other representational systems? (4) How can we develop and assess theoretical accounts of symbolic processing from the grounded perspective (perhaps using the construct of simulators)? (5) How can we move beyond the simplistic distinction between concrete and abstract concepts, instead addressing how concepts about the external and internal worlds pattern to support the Situated Action Cycle? (6) How do individual differences emerge from different populations of situational memories as the Situated Action Cycle manifests itself differently across individuals? (7) How can constructs from grounded cognition provide insight into the replication and generalization crises, perhaps from a quantum perspective on mechanisms (as exemplified by simulators).

| S-EPMC7528688 | biostudies-literature

Opportunities and challenges for antisense oligonucleotide therapies.

Project description:Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence-specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in the United States and Europe. Nucleotides are chemically modified to protect AONs from degradation, enhance bioavailability and increase RNA affinity. Whereas single stranded AONs can efficiently be delivered systemically, delivery of double stranded AONs requires capsulation in lipid nanoparticles or binding to a conjugate as the uptake enhancing backbone is hidden in this conformation. With improved chemistry, delivery vehicles and conjugates, doses can be lowered, thereby reducing the risk and occurrence of side effects. AONs can be used to knockdown or restore levels of protein. Knockdown can be achieved by single stranded or double stranded AONs binding the RNA transcript and activating RNaseH-mediated and RISC-mediated degradation respectively. Transcript binding by AONs can also prevent translation, hence reducing protein levels. For protein restoration, single stranded AONs are used to modulate pre-mRNA splicing and either include or skip an exon to restore protein production. Intervening at a genetic level, AONs provide therapeutic options for inherited metabolic diseases as well. This review provides an overview of the different AON approaches, with a focus on AONs developed for inborn errors of metabolism.

| S-EPMC7891411 | biostudies-literature

Warfarin pharmacogenetics: challenges and opportunities for clinical translation.

Project description: Not available

| S-EPMC3490409 | biostudies-literature

MiRNA-Based Therapies for Lung Cancer: Opportunities and Challenges?

Project description:Lung cancer is a commonly diagnosed cancer and the leading cause of cancer-related deaths, posing a serious health risk. Despite new advances in immune checkpoint and targeted therapies in recent years, the prognosis for lung cancer patients, especially those in advanced stages, remains poor. MicroRNAs (miRNAs) have been shown to modulate tumor development at multiple levels, and as such, miRNA mimics and molecules aimed at regulating miRNAs have shown promise in preclinical development. More importantly, miRNA-based therapies can also complement conventional chemoradiotherapy, immunotherapy, and targeted therapies to reverse drug resistance and increase the sensitivity of lung cancer cells. Furthermore, small interfering RNA (siRNA) and miRNA-based therapies have entered clinical trials and have shown favorable development prospects. Therefore, in this paper, we review recent advances in miRNA-based therapies in lung cancer treatment as well as adjuvant therapy and present the current state of clinical lung cancer treatment. We also discuss the challenges facing miRNA-based therapies in the clinical application of lung cancer treatment to provide new ideas for the development of novel lung cancer therapies.

| S-EPMC10295928 | biostudies-literature

CAR-T Therapies in Solid Tumors: Opportunities and Challenges.

Project description:Purpose of reviewThis review will discuss the challenges facing chimeric antigen receptor (CAR)-T cell application for solid tumors and opportunities to overcome these obstacles. In addition, this review will examine therapies that are in development for pediatric solid tumors.Recent findingsThe similar success of CAR-T cell treatment for hematological malignancies has not been observed in solid tumors because of the hostile tumor microenvironment and tumor heterogeneity. Most strategies developed to combat these limitations emphasize combinatorial techniques that still require further testing. Preliminary results of multiple clinical trials, including GD2- and HER2-CAR-T cells, are encouraging but must be reproduced and validated on a larger scale. CAR-T cell application in solid tumors remains challenging, and most research is in development. Several clinical trials are ongoing for pediatric solid tumors. Early results are promising but demonstrate the need for CAR-T cell modification to prevent tumor recurrence.

| S-EPMC10110629 | biostudies-literature

Cell-based therapies for rheumatoid arthritis: opportunities and challenges.

Project description:Rheumatoid arthritis (RA) is the most common immune-mediated inflammatory disease characterized by chronic synovitis that hardly resolves spontaneously. The current treatment of RA consists of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, conventional disease-modifying antirheumatic drugs (cDMARDs), biologic and targeted synthetic DMARDs. Although the treat-to-target strategy has been intensively applied in the past decade, clinical unmet needs still exist since a substantial proportion of patients are refractory or even develop severe adverse effects to current therapies. In recent years, with the deeper understanding of immunopathogenesis of the disease, cell-based therapies have exhibited effective and promising interventions to RA. Several cell-based therapies, such as mesenchymal stem cells (MSC), adoptive transfer of regulatory T cells (Treg), and chimeric antigen receptor (CAR)-T cell therapy as well as their beneficial effects have been documented and verified so far. In this review, we summarize the current evidence and discuss the prospect as well as challenges for these three types of cellular therapies in RA.

| S-EPMC9131381 | biostudies-literature

Fluorescence Guidance in Surgical Oncology: Challenges, Opportunities, and Translation.

Project description:Surgical resection continues to function as the primary treatment option for most solid tumors. However, the detection of cancerous tissue remains predominantly subjective and reliant on the expertise of the surgeon. Surgery that is guided by fluorescence imaging has shown clinical relevance as a new approach to detecting the primary tumor, tumor margins, and metastatic lymph nodes. It is a technique to reduce recurrence and increase the possibility of a curative resection. While significant progress has been made in developing this emerging technology as a tool to assist the surgeon, further improvements are still necessary. Refining imaging agents and tumor targeting strategies to be a precise and reliable surgical strategy is essential in order to translate this technology into patient care settings. This review seeks to provide a comprehensive update on the most recent progress of fluorescence-guided surgery and its translation into the clinic. By highlighting the current status and recent developments of fluorescence image-guided surgery in the field of surgical oncology, we aim to offer insight into the challenges and opportunities that require further investigation.

| S-EPMC6724738 | biostudies-literature

Top-down proteomics in health and disease: challenges and opportunities.

Project description:Proteomics is essential for deciphering how molecules interact as a system and for understanding the functions of cellular systems in human disease; however, the unique characteristics of the human proteome, which include a high dynamic range of protein expression and extreme complexity due to a plethora of PTMs and sequence variations, make such analyses challenging. An emerging "top-down" MS-based proteomics approach, which provides a "bird's eye" view of all proteoforms, has unique advantages for the assessment of PTMs and sequence variations. Recently, a number of studies have showcased the potential of top-down proteomics for the unraveling of disease mechanisms and discovery of new biomarkers. Nevertheless, the top-down approach still faces significant challenges in terms of protein solubility, separation, and the detection of large intact proteins, as well as underdeveloped data analysis tools. Consequently, new technological developments are urgently needed to advance the field of top-down proteomics. Herein, we intend to provide an overview of the recent applications of top-down proteomics in biomedical research. Moreover, we will outline the challenges and opportunities facing top-down proteomics strategies aimed at understanding and diagnosing human diseases.

| S-EPMC4100610 | biostudies-literature

GnRH replacement rescues cognition in Down syndrome.

Project description:At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

| S-EPMC7613827 | biostudies-literature

Acute kidney injury: preclinical innovations, challenges, and opportunities for translation.

Project description:BackgroundAcute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice.ObjectiveThis article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice.Sources of informationMEDLINE, ISI Web of Science.FindingsThis paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition.LimitationsThis review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature.ImplicationsTranslation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations.

| S-EPMC4556308 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data