Extracellular interplay of amyloid fibrils and neural cells DOI Creative Commons
Vladimir P. Zhdanov

Biosystems, Journal Year: 2023, Volume and Issue: 231, P. 104971 - 104971

Published: July 8, 2023

Some neurological disorders such e.g. as Alzheimer disease are accompanied by the appearance of amyloid fibrils inside and outside cells. Herein, I present a generic coarse-grained kinetic mean-field model describing at extracellular level interplay It includes formation degradation fibrils, activation healthy cells with respect to fabrication death activated The corresponding analysis indicates that development can occur in two qualitatively different regimes. first one is controlled primarily intrinsic factors resulting slow increase fibril production second implies faster self-promoted growth population analogy explosion. This prediction reported hypothesis interest for conceptual understanding disorders.

Language: Английский

Unlocking the Mysteries of Rare Disease Drug Development: A Beginner's Guide for Clinical Pharmacologists DOI Creative Commons
Mariam A. Ahmed, Bilal Abuasal, Jeffrey S. Barrett

et al.

Clinical and Translational Science, Journal Year: 2025, Volume and Issue: 18(4)

Published: April 1, 2025

ABSTRACT Clinical pharmacologists face unique challenges when developing drugs for rare diseases. These conditions are characterized by small patient populations, diverse disease progression patterns, and a limited understanding of underlying pathophysiology. This tutorial serves as comprehensive guide, offering practical insights strategies to navigate its complexities. In this tutorial, we outline global regulatory incentives resources available support research, describe some considerations designing clinical development plan diseases, highlight the role biomarkers, real‐world data, modeling simulations challenges. By leveraging these tools pathways, can significantly contribute advancing therapeutic options

Language: Английский

Citations

0
Advancing precision medicine therapeutics for Parkinson’s utilizing a shared quantitative systems pharmacology model and framework DOI Creative Commons
Christopher Denaro, Diane Stephenson, Martijn L.T.M. Müller

et al.

Frontiers in Systems Biology, Journal Year: 2024, Volume and Issue: 4

Published: March 8, 2024

A rich pipeline of therapeutic candidates is advancing for Parkinson’s disease, many which are targeting the underlying pathophysiology disease. Emerging evidence grounded in novel genetics and biomarker discoveries illuminating true promise precision medicine-based strategies PD. There has been a growing effort to investigate disease-modifying therapies by designing clinical trials genetic forms PD - providing clearer link pathophysiology. Leading candidate genes based on human findings that under active investigation an array basic translational models include SNCA, LRRK2, GBA. Broad investigations across mechanistic show these signal through common molecular pathways, namely, autosomal lysosomal inflammation mitochondrial function. Therapeutic date genetically defined targets have not yet achieved approvals; however, much be learned from such pioneering trials. Fundamental principles drug development proof pharmacology target tissue critical confidence precision-based therapies. clear need downstream biomarkers leading demonstrate mechanism. The current regulatory landscape poised primed support modeling effective advancement candidates. convergence complex data available, framework model informed (MIDD), new biological integrated staging frameworks when combined collectively setting stage approaches accelerate progress. This perspective review highlights potential quantitative systems (QSP) contributing field hastening pace progress collaborative urgently needed treatments.

Language: Английский

Citations

3
Systems biology platform for efficient development and translation of multitargeted therapeutics DOI Creative Commons
Karim Azer,

Irina A. Leaf

Frontiers in Systems Biology, Journal Year: 2023, Volume and Issue: 3

Published: Sept. 18, 2023

Failure to achieve efficacy is among the top, if not most common reason for clinical trial failures. While there may be many underlying contributors these failures, selecting right mechanistic hypothesis, dose, or patient population are main culprits. Systems biology an inter-disciplinary field at intersection of and mathematics that has growing potential increase probability success in trials, delivering a data-driven matching mechanism patient, dose. Moreover, as part successful selection targets therapeutic area, systems prime approach development combination therapies combating complex diseases, where single have failed sufficient clinic. approaches become increasingly powerful with progress molecular computational methods represent novel innovative tool tackle mechanisms human disease biology, linking it phenotypes optimizing multiple steps drug discovery development. With increasing ability probing cellular organ level omics technologies, here stay positioned one key pillars development, predicting advancing best can combined together optimal pharmacological effect Here we describe platform stepwise starts characterization pathways contributing Mechanism Disease (MOD) followed by identification, design, optimization, translation into clinic able reverse disease-related pathological through Mechanisms Action (MOA).

Language: Английский

Citations

1
Extracellular interplay of amyloid fibrils and neural cells DOI Creative Commons
Vladimir P. Zhdanov

Biosystems, Journal Year: 2023, Volume and Issue: 231, P. 104971 - 104971

Published: July 8, 2023

Some neurological disorders such e.g. as Alzheimer disease are accompanied by the appearance of amyloid fibrils inside and outside cells. Herein, I present a generic coarse-grained kinetic mean-field model describing at extracellular level interplay It includes formation degradation fibrils, activation healthy cells with respect to fabrication death activated The corresponding analysis indicates that development can occur in two qualitatively different regimes. first one is controlled primarily intrinsic factors resulting slow increase fibril production second implies faster self-promoted growth population analogy explosion. This prediction reported hypothesis interest for conceptual understanding disorders.

Language: Английский

Citations

0