Precision medicine for rare diseases: The times they are A-Changin'

Amaral, Margarida D.

doi:10.1016/j.coph.2022.102201

Cited by 8 publications

(6 citation statements)

References 55 publications

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“…Preclinical experimentation could contribute to an increase in the functional characterization of CFTR variants and obtain information on their pharmacologic responses relative to currently approved or innovative compounds [ 18 – 21 ]. In this context, most in vitro systems for drug testing used so far are either inefficiently obtained (primary bronchial cells) or not based on patient cells (CFTR variant overexpression on commercial cell lines) [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…In this context, most in vitro systems for drug testing used so far are either inefficiently obtained (primary bronchial cells) or not based on patient cells (CFTR variant overexpression on commercial cell lines) [ 22 ]. Thus, more efficient and patient-specific in vitro approaches are required for the research of rare variants, considering the limited number of these patients and the paucity of their samples [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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L1077P CFTR pathogenic variant function rescue by Elexacaftor–Tezacaftor–Ivacaftor in cystic fibrosis patient-derived air–liquid interface (ALI) cultures and organoids: in vitro guided personalized therapy of non-F508del patients

Lo Cicero,

Castelli,

Blaconà

et al. 2023

Respir Res

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Cystic fibrosis (CF) is caused by defects of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR-modulating drugs may overcome specific defects, such as the case of Trikafta, which is a clinically approved triple combination of Elexacaftor, Tezacaftor and Ivacaftor (ETI) that exhibited a strong ability to rescue the function of the most frequent F508del pathogenic variant even in genotypes with the mutated allele in single copy. Nevertheless, most rare genotypes lacking the F508del allele are still not eligible for targeted therapies. Via the innovative approach of using nasal conditionally reprogrammed cell (CRC) cell-based models that mimic patient disease in vitro, which are obtainable from each patient due to the 100% efficiency of the cell culture establishment, we theratyped orphan CFTR mutation L1077P. Protein studies, Forskolin-induced organoid swelling, and Ussing chamber assays congruently proved the L1077P variant function rescue by ETI. Notably, this rescue takes place even in the context of a single-copy L1077P allele, which appears to enhance its expression. Thus, the possibility of single-allele treatment also arises for rare genotypes, with an allele-specific modulation as part of the mechanism. Of note, besides providing indication of drug efficacy with respect to specific CFTR pathogenic variants or genotypes, this approach allows the evaluation of the response of single-patient cells within their genetic background. In this view, our studies support in vitro guided personalized CF therapies also for rare patients who are nearly excluded from clinical trials.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

L1077P CFTR pathogenic variant function rescue by Elexacaftor–Tezacaftor–Ivacaftor in cystic fibrosis patient-derived air–liquid interface (ALI) cultures and organoids: in vitro guided personalized therapy of non-F508del patients

Lo Cicero,

Castelli,

Blaconà

et al. 2023

Respir Res

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“…Precision medicine is instrumental in diagnosing and managing rare genetic disorders such as cystic fibrosis, muscular dystrophy, and certain metabolic disorders [ 25 ].…”

Section: Precision Medicine and Public Healthmentioning

confidence: 99%

Advancing Precision Medicine in South Tyrol, Italy: A Public Health Development Proposal for a Bilingual, Autonomous Province

Wiedermann¹

2023

JPM

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This paper presents a comprehensive development plan for advancing precision medicine in the autonomous province of South Tyrol, Italy, a region characterized by its bilingual population and unique healthcare challenges. This study highlights the need to address the shortage of healthcare professionals proficient in language for person-centered medicine, the lag in healthcare sector digitalization, and the absence of a local medical university, all within the context of an initiated pharmacogenomics program and a population-based precision medicine study known as the “Cooperative Health Research in South Tyrol” (CHRIS) study. The key strategies for addressing these challenges and integrating CHRIS study findings into a broader precision medicine development plan are discussed, including workforce development and training, investment in digital infrastructure, enhanced data management and analytic capabilities, collaboration with external academic and research institutions, education and capacity building, securing funding and resources, and promoting a patient-centered approach. This study emphasizes the potential benefits of implementing such a comprehensive development plan, including improved early detection, personal ized treatment, and prevention of chronic diseases, ultimately leading to better healthcare outcomes and overall well-being in the South Tyrolean population.

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“…Selection of clinically appropriate and responsive end-points is of great importance for any clinical trial, but especially in rare diseases, where comparison and meta-analysis of trials are needed [13,14]. Outcomes should be clearly defined, as clear definitions are needed to replicate and compare trials [15].…”

Section: Introductionmentioning

confidence: 99%

A BEAT-PCD consensus statement: a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia

Kos,

Goutaki,

Kobbernagel

et al. 2023

Paediatric Respiratory Epidemiology

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Precision medicine for rare diseases: The times they are A-Changin'

Cited by 8 publications

References 55 publications

L1077P CFTR pathogenic variant function rescue by Elexacaftor–Tezacaftor–Ivacaftor in cystic fibrosis patient-derived air–liquid interface (ALI) cultures and organoids: in vitro guided personalized therapy of non-F508del patients

L1077P CFTR pathogenic variant function rescue by Elexacaftor–Tezacaftor–Ivacaftor in cystic fibrosis patient-derived air–liquid interface (ALI) cultures and organoids: in vitro guided personalized therapy of non-F508del patients

Advancing Precision Medicine in South Tyrol, Italy: A Public Health Development Proposal for a Bilingual, Autonomous Province

A BEAT-PCD consensus statement: a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia

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