Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

Berkers, Gitte; Mourik, Peter van; Vonk, Annelotte M.; Kruisselbrink, Evelien; Dekkers, Johanna F.; Groot, K.M. de Winter-de; Arets, Hubertus G.M.; Wilt, Rozemarijn E.P. Marck-van der; Dijkema, Jasper S.; Vanderschuren, Maaike M.; Houwen, Roderick H. J.; Heijerman, H.G.M.; Graaf, E.A. van de; Elias, Sjoerd G.; Majoor, Christof J.; Koppelman, Gerard H.; Roukema, Jolt; Bakker, Marleen; Janssens, Hettie M.; Meer, Renske van der; Vries, Robert G.J.; Clevers, Hans; Jonge, Hugo R. de; Beekman, Jeffrey M.; Ent, Cornelis K. van der

doi:10.1016/j.celrep.2019.01.068

Cited by 222 publications

(190 citation statements)

References 37 publications

(51 reference statements)

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“…Despite the clinical heterogeneity in adults with CF and homozygous for F508del mutation, forskolin-induced swelling of intestinal organoids positively correlated with FEV 1 and BMI (de . Responses from intestinal organoids were also demonstrated to correlate with intestinal current measurements, reduction in sweat chloride concentration and improvement in lung function of patients after CFTR modulator therapies (Dekkers et al, 2016a;Berkers et al, 2019). In N-of-1 trial series, an increase in CFTR-dependent chloride transport in nasal epithelial cell cultures was only found in the three patients who also demonstrated a reduction in sweat chloride concentration after ivacaftor treatment (McGarry et al, 2017).…”

Section: Continuing the Development Of Transformative Therapeutics Tomentioning

confidence: 98%

“…Primary, reprogrammed and engineered human cell models have become important tools to identify novel pharmacotherapies. The effects of certain therapies may also be exploited at an individual level in ex vivo patient-derived specimens, such as primary bronchial/nasal epithelial cells, and intestinal/respiratory organoids (Fulcher and Randell, 2013;Dekkers et al, 2016a;Dekkers et al, 2016b;Pranke et al, 2017;Awatade et al, 2018;Brewington et al, 2018;Chen et al, 2018;Berkers et al, 2019;Merket et al, 2019). As these cell models recapitulate several features of the parental organ, they are useful to understand the impact of genetic factors on individual disease and predict clinical efficacy of therapies.…”

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

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CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Continuing the Development Of Transformative Therapeutics Tomentioning

confidence: 98%

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…This model design could lead to the optimization of patient treatments before application, reducing chance of treatment failure. Recently, rectal organoids derived from patients with cystic fibrosis were successfully used to predict patient response to treatment (62). This was particularly important as cystic fibrosis patients with rare genetic mutations are not examined in clinical trials.…”

Section: Throughputmentioning

confidence: 99%

Intestinal Organoids as a Tool for Inflammatory Bowel Disease Research

et al. 2020

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Inflammatory Bowel Diseases (IBD) are difficult to model as freshly acquired tissues are short-lived, provide data as a snapshot in time, and are not always accessible. Many patients with IBD are non-responders to first-line treatments, and responders are prone to developing resistance to treatment over time-resulting in reduced patient quality of life, increased time to remission, and potential relapse. IBD is heterogenous and we are yet to fully understand the mechanisms of disease; thus, our ability to diagnose and prescribe optimal treatment remains ineffective. Intestinal organoids are derived from patient tissues expanded in vitro. Organoids offer unique insight into individual patient disease and are a potential route to personalized treatments. However, organoid models do not contain functional microbial and immune cell components. In this review, we discuss immune cell subsets in the context of IBD, and the requirement of immune cell and microbial components in organoid models for IBD research.

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“…The potential of intestinal organoids as pre-clinical model and for personalized medicine has been demonstrated in studies showing that FIS-rates of infant-derived organoids harbouring all kinds of CFTR mutations correspond with clinical phenotypes at 1 year of age as well as in vivo sweat chloride concentration (SCC), enabling accurate estimation of in vivo residual CFTR function on the individual patient level [35] . In addition, in vitro CFTR modulator responses in organoids appeared to correlate significantly with the two most important therapeutic endpoints, change in FEV1 and SCC and displayed excellent accuracy for stratifying drug responders from non-drug responders [36] . Even within the F508del homozygous patient group, intestinal organoids showed varying residual function and drug responsiveness [ 35 , 36 ], comparable to what has been reported in vivo [37] , and thus prove highly useful to study individual factors that contribute to individual relations between CFTR genotype, CFTR expression and CFTR function.…”

Section: Body Of Textmentioning

confidence: 95%

Intestinal organoids for Cystic Fibrosis research

Poel

Lefferts

Beekman

2020

Journal of Cystic Fibrosis

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a b s t r a c tSignificant progress has been made in the development of CFTR modulator therapy; however, current CFTR modulator therapies are only available for a minority of the CF-patient population. Additionally, heterogeneity in in vivo modulator response has been reported among individuals carrying homozygous F508del-CFTR, adding to the desire for an optimal prediction of response-to-therapy on an individual level. In the last decade, a lot of progress has been made in the development of primary cell cultures into 3D patient-derived disease models. The advantage of these models is that the endogenous CFTR function is affected by the patient's mutation as well as other genetic or environmental factors. In this review we focus on intestinal organoids as in vitro model for CF, enabling for CF disease classification, drug development and treatment optimization in a personalized manner, taking into account rare CFTR mutations and clinical heterogeneity among individuals with CF.

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Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

Abstract: Highlights d Organoids of CF patients were used to quantitate individual drug response in vitro d Organoid responses correlate with two clinical response parameters ppFEV 1 and SCC d In vivo (non)responders were identified with a PPV of 100% and a NPV of 80%

Cited by 222 publications

References 37 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Intestinal Organoids as a Tool for Inflammatory Bowel Disease Research

Intestinal organoids for Cystic Fibrosis research

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