Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story.
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ABSTRACT:
SUBMITTER: Burton A
PROVIDER: S-EPMC7987260 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated.
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Project description:SIL1 acts as a co-chaperone for the major ER-resident chaperone BiP and thus plays a role in many BiP-dependent cellular functions such as protein folding control and unfolded protein response. Whereas increase of BiP upon cellular stress conditions is a well-known phenomenon, elevation of SIL1 under stress conditions was thus far solely studied in yeast and different studies indicated an adverse effect of SIL1 increase. This is seemingly in contrast with the beneficial effect of SIL1 increase in surviving neurons in neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer disease. In the present study, we systematically addressed these controversial findings. Using cell biological, morphological and biochemical methods, we could demonstrate that that SIL1 is increased in various mammalian cells and neuronal tissues upon induction of cellular stress. Investigation of heterozygous SIL1/Sil1 mutant cells and tissues supported this finding. Moreover, SIL1 protein was found to be stabilized during ER stress. Increased SIL1 initiates ER stress in a concentration-dependent manner which is in accordance with the described adverse effect of increased SIL1. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 (no longer perturbing ER homeostasis) and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Results of our immunoprecipitation studies indicate that under cellular stress conditions SIL1 might act in a BiP-independent manner. Unbiased proteomic studies revealed that elevated SIL1 levels alter the expression of several proteins including crucial players in neurodegeneration, especially in Alzheimer disease. This finding is in accordance with our observation of increased SIL1-immunoreactivity in surviving neurons of Alzheimer disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.
2020-07-24 | PXD005218 | Pride
Project description:Introduction:Smartphones are ubiquitous in the digital society. Although this powerful device is useful because it supports and simplifies many tasks in everyday life, a growing number of researchers is concerned that smartphones might have detrimental effects on the human brain and related psychological processes. Evidence indicates that social media platforms such as WhatsApp and Facebook are essential drivers of smartphone usage. Thus, a critical, yet unexplored issue is how excessive use of those platforms is related to Smartphone Use Disorder (SUD). Furthermore, since the roles of life satisfaction and fear of missing out (FoMo) have been demonstrated to be of particular importance for Internet Use and Internet Communication Disorder, those constructs were examined in the context of SUD. Methods:In total, n = 2299 participants filled in questionnaires assessing SUD, WhatsApp and Facebook Use Disorder, FoMO, life satisfaction, and reported owning a WhatsApp and Facebook account. Results:The study revealed that SUD was linked to WhatsApp Use Disorder, and to a lesser extent, to Facebook Use Disorder. Associations between SUD and WhatsApp Use Disorder were most strongly pronounced in females. Additionally, FoMo predicted SUD, WhatsApp, Facebook Use Disorder, and (fully) mediated the relationship between life satisfaction and those variables. Conclusion:The findings of the present study suggest that WhatsApp use plays an important role to understand SUD. Regarding the mediating role of FoMO, the present work might help disentangle inconsistent results on the link between life satisfaction and (excessive) social networking sites use.
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Project description:BACKGROUND:Drug development for rare diseases is challenging because it is difficult to obtain relevant data from very few patients. It must be informative to grasp current status of clinical trials for drug development in rare diseases. OBJECTIVE:Clinical trials in rare diseases are to be outlined and compared among the US, EU and Japan. METHOD:ClinicalTrials.gov (NCT, National Clinical Trial), EU Clinical Trials Register (EUCTR) and the Japan Primary Registries Network (JPRN) were analyzed. Clinical trials involving information on rare diseases and drugs were extracted by text-mining, based on the diseases and drugs derived from Orphanet and DrugBank, respectively. RESULTS:In total, 28,526 clinical trials were extracted, which studied 1,535 rare diseases and 1,539 drugs. NCT had the largest number of trials, involving 1,252 diseases and 1,332 drugs. EUCTR and JPRN also had registry-specific diseases (250 and 22, respectively) and drugs (172 and 29, respectively) that should not be missed. Among the 1,535 rare diseases, most diseases were studied in only a limited number of trials; 70% of diseases were studied in fewer than 10 trials, and 28% were studied in only one. Additionally, most studied rare diseases were cancer-related ones. CONCLUSION:This study has revealed the characteristics of the clinical trials in rare diseases among the US, EU and Japan. The number of trials for rare diseases was limited especially for non-cancerrelated ones. This information could contribute to drug development such as drug-repositioning in rare diseases.
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Project description:A homologous series of pore-forming amphiphiles (PFAs), derived from cholic acid, lysine, and spermine, have been used as "thermal gates" for releasing sucrose from liposomes made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt) [DPPG]. Binding measurements have established that these PFAs are fully bound to these liposomes in their gel state and that their transfer to fluid phase membranes is negligible. Release experiments have shown that thermal gating is sensitive to both the size and the concentration of the PFA that are used. Increases in the extent of release of sucrose with increasing temperature that have been found in the gel/fluid coexistence region indicate the existence of heterogeneity among the liposomes.
| S-EPMC2765578 | biostudies-other