Expert opinion on drug discovery
-
Expert Opin Drug Discov · Aug 2020
Review Comparative StudyThe preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis.
Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, F508del, induces protein misprocessing and loss of CFTR function. The discovery through in vitro studies of the CFTR correctors (i.e. lumacaftor, tezacaftor) that partially rescue the misprocessing of F508del-CFTR with the potentiator ivacaftor is promising in giving an unprecedented clinical benefit in affected patients. ⋯ CF patient-derived tissue models are being explored to determine donor-specific response to current approved and future novel CFTR modulators for F508del and other rare mutations. The discovery and validation of biomarkers of CFTR modulation will complement these studies in the long term and in real-life world.
-
Expert Opin Drug Discov · Aug 2020
ReviewIn vivo near-infrared fluorescent optical imaging for CNS drug discovery.
In vivo imaging technologies have become integral and essential component of drug discovery, development, and clinical assessment for central nervous system (CNS) diseases. Near-infrared (NIR) fluorescence imaging in the range of 650-950 nm is widely used for pre-clinical in vivo imaging studies. The recent expansion of NIR imaging into the shortwave infrared (SWIR, 1000-1700 nm) window enabled improvements in tissue penetration and resolution required for anatomical, dynamic, and molecular neuroimaging with high potential for clinical translation. ⋯ Propelled through concomitant technological advancements in imaging instrumentation, algorithms and new SWIR emitters, SWIR imaging has addressed key barriers to optical imaging modalities used in pre-clinical studies addressing the CNS. Development of biocompatible SWIR emitters and adoption of SWIR into multi-modal imaging modalities promise to rapidly advance optical imaging into translational studies and clinical applications.
-
The highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are lethal zoonotic viruses that have emerged into human populations these past 15 years. These coronaviruses are associated with novel respiratory syndromes that spread from person-to-person via close contact, resulting in high morbidity and mortality caused by the progression to Acute Respiratory Distress Syndrome (ARDS). ⋯ Expert opinion: Treatment of SARS and MERS in outbreak settings has focused on therapeutics with general antiviral activity and good safety profiles rather than efficacy data provided by cellular, rodent, or nonhuman primate models of highly pathogenic coronavirus infection. Based on lessons learned from SARS and MERS outbreaks, lack of drugs capable of pan-coronavirus antiviral activity increases the vulnerability of public health systems to a highly pathogenic coronavirus pandemic.
-
Expert Opin Drug Discov · Oct 2018
ReviewChronic orofacial pain animal models - progress and challenges.
Chronic orofacial pain is one of the most common pain conditions experienced by adults. Animal models are often selected as the most useful scientific methodology to explore the pathophysiology of the disorders that cause this disabling pain to facilitate the development of new treatments. The creation of new models or the improvement of existing ones is essential for finding new ways to approach the complex neurobiology of this type of pain. ⋯ Choosing an animal model that most closely represents the human disease helps to increase the chances of finding effective new therapies and is key to the successful translation of preclinical research to clinical practice. Models using genetically modified animals seem promising but have not yet been fully developed for use in chronic orofacial pain research. Although animal models have provided significant advances in the pharmacological treatment of orofacial pain, several barriers still need to be overcome for better treatment options.
-
Expert Opin Drug Discov · Jun 2018
ReviewBundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics.
Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. ⋯ Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.