Personalised Medicine Using N-of-1 Trials: Overcoming Barriers to Delivery.
Ontology highlight
ABSTRACT:
SUBMITTER: Chalmers I
PROVIDER: S-EPMC6956166 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Personalised Medicine Using N-of-1 Trials: Overcoming Barriers to Delivery.
Chalmers Iain I Smeeth Liam L Goldacre Ben B
Healthcare (Basel, Switzerland) 20191105 4
In this paper we discuss the value of N-of-1 trials in personalising health care. We describe the challenges faced in implementing N-of-1 trials in the United Kingdom's National Health Service and suggest how making greater use of these personalised trials might be facilitated. ...[more]
Similar Datasets
Project description:Negatively charged tissues are ubiquitous in the human body and are associated with a number of common diseases yet remain an outstanding challenge for targeted drug delivery. While the anionic proteoglycans are critical for tissue structure and function, they make tissue matrix dense, conferring a high negative fixed charge density (FCD) that makes drug penetration through the tissue deep zones and drug delivery to resident cells extremely challenging. The high negative FCD of these tissues is now being utilized by taking advantage of electrostatic interactions to create positively charged multi-stage delivery methods that can sequentially penetrate through the full thickness of tissues, create a drug depot and target cells. After decades of work on attempting delivery using strong binding interactions, significant advances have recently been made using weak and reversible electrostatic interactions, a characteristic now considered essential to drug penetration and retention in negatively charged tissues. Here we discuss these advances using examples of negatively charged tissues (cartilage, meniscus, tendons and ligaments, nucleus pulposus, vitreous of eye, mucin, skin), and delve into how each of their structures, tissue matrix compositions and high negative FCDs create barriers to drug entry and explore how charge interactions are being used to overcome these barriers. We review work on tissue targeting cationic peptide and protein-based drug delivery, compare and contrast drug delivery designs, and also present examples of technologies that are entering clinical trials. We also present strategies on further enhancing drug retention within diseased tissues of lower FCD by using synergistic effects of short-range binding interactions like hydrophobic and H-bonds that stabilize long-range charge interactions. As electrostatic interactions are incorporated into design of drug delivery materials and used as a strategy to create properties that are reversible, tunable and dynamic, bio-electroceuticals are becoming an exciting new direction of research and clinical work.
| S-EPMC7425807 | biostudies-literature
Project description:Intracellular delivery of therapeutic proteins has increased advantages over current small-molecule drugs and gene therapies, especially in therapeutic efficacies for a broad spectrum of diseases. Hence, developing the protein therapeutics approach provides a needed alternative. Here, we designed a mesoporous silica nanoparticle (MSN)-mediated protein delivery approach and demonstrated effective intracellular delivery of the denatured superoxide dismutase (SOD) protein, overcoming the delivery challenges and achieving higher enzymatic activity than native SOD-conjugated MSNs. The denatured SOD-conjugated MSN delivery strategy provides benefits of reduced size and steric hindrance, increased protein flexibility without distorting its secondary structure, exposure of the cell-penetrating peptide transactivator of transcription for enhanced efficient delivery, and a change in the corona protein composition, enabling cytosolic delivery. After delivery, SOD displayed a specific activity around threefold higher than in our previous reports. Furthermore, the in vivo biosafety and therapeutic potential for neuron therapy were evaluated, demonstrating the biocompatibility and the effective antioxidant effect in Neuro-2a cells that protected neurite outgrowth from paraquat-induced reactive oxygen species attack. This study offers an opportunity to realize the druggable possibility of cytosolic proteins using MSNs.
| S-EPMC9896485 | biostudies-literature
Project description:(1) Background: Personalised medicine (PM) is an innovative way to produce better patient outcomes by using an individualised or stratified approach to disease and treatment rather than a collective approach to treating patients. PM is a major challenge for all European healthcare systems. This article aims to identify the needs of citizens in terms of PM adaptation, as well as to provide insights into the barriers and facilitators categorised in relation to key stakeholders of their implementation. (2) Methods: This article presents data obtained from the survey "Barriers and facilitators of Personalised Medicine implementation-qualitative study under Regions4PerMed (H2020) project". Semi-structured questions were included in the above-mentioned survey. The questions included both structured and unstructured segments in an online questionnaire (Google Forms). Data were compiled into a data base. The results of the research were presented in the study. The number of people who participated in the survey can be considered an insufficient sample size for statistical measurement. In order to avoid collecting unreliable data, the questionnaires were sent to various stakeholders of the Regions4PerMed project, which includes members of the Advisory Board of the Regions4PerMed Project, but also speakers of conferences and workshops, and participants in these events. The professional profiles of the respondents are also diverse. (3) Results: The insights on what would help in the adaptation of Personal Medicine to citizen needs have been categorised into 7 areas of need: education; finances; dissemination; data protection/IT/data sharing; system changes/governmental level; cooperation/collaboration; public/citizens. Barriers and facilitators have been categorised into ten key stakeholders of the implementation barriers: government and government agencies; medical doctors/practitioners; healthcare system; healthcare providers; patients and patient organisations; medical sector, scientific community, researchers, stakeholders; industry; technology developers; financial institutions; media. (4) Conclusions: Barriers to the implementation of Personalised Medicine are observed across Europe. The barriers and facilitators mentioned in the article need to be effectively managed in healthcare systems across Europe. There is an urgent need to remove as many barriers as possible and create as many facilitators as possible to implement personalized medicine in the European system.
| S-EPMC9965772 | biostudies-literature
Project description:The exploitation of nanosized materials for the delivery of therapeutic agents is already a clinical reality and still holds unrealized potential for the treatment of a variety of diseases. This review discusses physiological barriers a nanocarrier must overcome in order to reach its target, with an emphasis on cancer nanomedicine. Stages of delivery include residence in the blood stream, passive accumulation by virtue of the enhanced permeability and retention effect, diffusion within the tumor lesion, cellular uptake, and arrival at the site of action. We also briefly outline strategies for engineering nanoparticles to more efficiently overcome these challenges: Increasing circulation half-life by shielding with hydrophilic polymers, such as PEG, the limitations of PEG and potential alternatives, targeting and controlled activation approaches. Future developments in these areas will allow us to harness the full potential of nanomedicine.
| S-EPMC6928054 | biostudies-literature
Project description:Despite four decades of research in intra-articular drug delivery systems (DDS) and two decades of advances in disease-modifying osteoarthritis drugs (DMOADs), there is still no clinically available disease-modifying therapy for osteoarthritis (OA). Multiple barriers compromise intra-articular DMOAD delivery. Although multiple exciting approaches have been developed to overcome these barriers, there are still outstanding questions. We make several recommendations that can help in fully overcoming these barriers. Considering OA heterogeneity, we also propose a patient-centered, bottom-up workflow to guide preclinical development of DDS-based intra-articular DMOAD therapies. Overall, we expect this review to inspire paradigm-shifting innovations for developing next-generation DDS that can enable clinical translation of intra-articular DMOADs.
| S-EPMC8840969 | biostudies-literature
Project description:Physiological barriers encountered in the clinical translation of cancer nanomedicines inspire the community to more deeply understand nano-bio interactions in not only tumor microenvironment but also entire body and develop new nanocarriers to tackle these barriers. Renal clearable nanocarriers are one kind of these newly emerged drug delivery systems (DDSs), which enable drugs to rapidly penetrate into the tumor cores with no need of long blood retention and escape macrophage uptake in the meantime they can also enhance body elimination of non-targeted anticancer drugs. As a result, they can improve therapeutic efficacies and reduce side effects of anticancer drugs. Not limited to anticancer drugs, diagnostic agents can also be achieved with these renal clearable DDSs, which might also be applied to improve the precision in the gene editing and immunotherapy in the future.
| S-EPMC8696951 | biostudies-literature
Project description:Gaining insight into the mechanisms of signal transduction networks (STNs) by using critical features from patient-specific mathematical models can improve patient stratification and help to identify potential drug targets. To achieve this, these models should focus on the critical STNs for each cancer, include prognostic genes and proteins, and correctly predict patient-specific differences in STN activity. Focussing on colorectal cancer and the WNT STN, we used mechanism-based machine learning models to identify genes and proteins with significant associations to event-free patient survival and predictive power for explaining patient-specific differences of STN activity. First, we identified the WNT pathway as the most significant pathway associated with event-free survival. Second, we built linear-regression models that incorporated both genes and proteins from established mechanistic models in the literature and novel genes with significant associations to event-free patient survival. Data from The Cancer Genome Atlas and Clinical Proteomic Tumour Analysis Consortium were used, and patient-specific STN activity scores were computed using PROGENy. Three linear regression models were built, based on; (1) the gene-set of a state-of-the-art mechanistic model in the literature, (2) novel genes identified, and (3) novel proteins identified. The novel genes and proteins were genes and proteins of the extant WNT pathway whose expression was significantly associated with event-free survival. The results show that the predictive power of a model that incorporated novel event-free associated genes is better compared to a model focussing on the genes of a current state-of-the-art mechanistic model. Several significant genes that should be integrated into future mechanistic models of the WNT pathway are DVL3, FZD5, RAC1, ROCK2, GSK3B, CTB2, CBT1, and PRKCA. Thus, the study demonstrates that using mechanistic information in combination with machine learning can identify novel features (genes and proteins) that are important for explaining the STN heterogeneity between patients and their association to clinical outcomes.
| S-EPMC8467693 | biostudies-literature
Project description:Unbiased genetic approaches, especially genome-wide association studies, have identified novel genetic targets in the pathogenesis of asthma, but so far these targets account for only a small proportion of the heritability of asthma. Recognition of the importance of disease heterogeneity, the need for improved disease phenotyping, and the fact that genes involved in the inception of asthma are likely to be different from those involved in severity widens the scope of asthma genetics. The identification of genes implicated in several causal pathways suggests that genetic scores could be used to capture the effect of genetic variations on individuals. Gene-environment interaction adds another layer of complexity, which is being successfully explored by epigenetic approaches. Pharmacogenetics is one example of how gene-environment interactions are already being taken into account in the identification of drug responders and non-responders, and patients most susceptible to adverse effects. Such applications represent one component of personalised medicine, an approach that places the individual at the centre of health care.
| S-EPMC4768462 | biostudies-literature
Project description:Randomized clinical trials are considered the milestones of clinical research in oncology, and guided the development and approval of new compounds so far. In the last few years, however, molecular and genomic profiling led to a change of paradigm in therapeutic algorithms of many cancer types, with the spread of different biomarker-driven therapies (or targeted therapies). This scenario of "personalized medicine" revolutionized therapeutic strategies and the methodology of the supporting clinical research. New clinical trial designs are emerging to answer to the unmet clinical needs related to the development of these targeted therapies, overcoming the "classical" structure of randomized studies. Innovative trial designs able to evaluate more than one treatment in the same group of patients or many groups of patients with the same treatment (or both) are emerging as a possible future standard in clinical trial methodology. These are identified as "master protocols", and include umbrella, basket and platform trials. In this review, we described the main characteristics of these new trial designs, focusing on the opportunities and limitations of their use in the era of personalized medicine.
| S-EPMC8618758 | biostudies-literature
Project description:BackgroundThe use of new technology has the potential to increase participation rates in dietary studies and improve the validity of collected dietary data. However, to evaluate the usability of developed dietary methods, qualitative studies of participants' experiences and perceptions are needed.ObjectiveTo explore adolescents' experiences using a newly developed mobile phone dietary assessment app, with a focus on factors that could affect their recording of dietary intake.MethodsFocus group interviews were conducted with 75 participants who had used a newly developed mobile phone dietary assessment app in a quantitative evaluation study. The interviews were analyzed using qualitative content analysis and the theoretical framework of Self Determination Theory was applied.ResultsThe adolescents' use of the mobile phone dietary assessment app was characterized by their struggle to overcome several perceived barriers. Facilitators that helped adolescents complete the method were also identified. Motivation was found to be an important facilitator, and intrinsically motivated participants completed the method because they found it fun to use. The autonomous extrinsically motivated participants completed the method for the greater good, in order to contribute to the study. The controlled extrinsically motivated participants completed the method to get a reward or avoid punishment. Amotivated participants did not complete the method. More motivated participants were assumed to be more able to overcome barriers and needed less facilitators.ConclusionsFuture studies that examine the recording of food intake should include systematic efforts that aim to minimize identified barriers and promote identified facilitators. Further research should specifically aim at studying methods for (and effects of) increasing intrinsic motivation by supporting autonomy, competence, and relatedness among adolescents asked to participate in dietary studies.
| S-EPMC4982910 | biostudies-literature