Extent of Rescue of F508del-CFTR Function by VX-809 and VX-770 in Human Nasal Epithelial Cells Correlates with SNP rs7512462 in SLC26A9 Gene in F508del/F508del Cystic Fibrosis Patients

Kmit, Arthur; Marson, Francesco; Pereira, Stéphanie Villa-Nova; Vinagre, Adriana Mendes; Leite, Gabriela Silva; Servidoni, Maria de Fátima; Ribeiro, José Dirceu; Ribeiro, Antônio Fernando; Bertuzzo, Carmen Sílvia; Amaral, M.D.

doi:10.2139/ssrn.3215598

Cited by 7 publications

(22 citation statements)

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“…Traditionally, HNECs have been cultured using the same methods as HBECs (20), with expansion in bronchial epithelial growth medium (BEGM). Conditionally reprogrammed cell (CRC) technology improves HNEC growth capacity (21–23). However, the CRC technique requires co-culture with irradiated or mitomycin-treated NIH3T3 feeder cells.…”

Section: Resultsmentioning

confidence: 99%

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Robust W1282X-CFTR rescue by a small molecule GSPT1 degrader

et al. 2021

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With the approval of elexacaftor/tezacaftor/ivacaftor (trade name Trikafta), the vast majority of people with cystic fibrosis (CF) are eligible for CF transmembrane conductance regulator (CFTR) modulator therapy. Remaining individuals have premature termination codons or rare CFTR variants with limited treatment options. Although clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, these cells can be expanded by overexpression of mouse Bmi-1 and human TERT (hTERT). We therefore used this approach to develop two non-CF and three CF (F508del/F508del, F508del/S492F, W1282X/W1282X) nasal cell lines and two W1282X/W1282X bronchial cell lines. Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The F508del/F508del and F508del/S492F cell lines robustly responded to Trikafta, which was mirrored in the parent primary cells and the cell donors' clinical response. CC-90009, a novel cereblon E3 ligase modulator targeting the GSPT1 protein, rescued ~20% of wildtype CFTR function in our panel of W1282X/W1282X cell lines and primary cells. Intriguingly, CC-90009 also diminished epithelial sodium channel function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirror primary cell responses to CFTR modulators and illustrate novel therapeutic approaches for the W1282X CFTR variant.

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Section: Resultsmentioning

confidence: 99%

“…Cells were maintained in Pneumacult ALI medium (STEMCELL Technologies, no. 05001) for[21][22][23][24][25][26][27][28][29][30][31][32]…”

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confidence: 99%

Robust W1282X-CFTR rescue by a small molecule GSPT1 degrader

et al. 2021

Preprint

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“…Thus, drugs that can decrease the degradation of ΔF508 CFTR protein, increase the export of ΔF508 CFTR protein to the plasma membrane, and improve its ion channel function, would contribute to restoring the epithelial cell function and alleviating the associated symptoms of cystic fibrosis. Such drugs and drug candidates include lumacaftor/ivacaftor (Deeks 2016;Gentzsch and Mall 2018;Kmit et al 1865), tezacaftor/ivacaftor (Sala and Jain 2018;Faure et al 2016;Donaldson et al 2018), fatty acid cysteamine (Vu et al 2017), or even rattlesnake phospholipase A2 (Faure et al 2016). How to evaluate efficacy and toxicity of these drugs with transcriptomic data?…”

Section: Drug Efficacy and Toxicity: Restorative Drugmentioning

confidence: 99%

Drug efficacy and toxicity prediction: an innovative application of transcriptomic data

Xia

2020

Cell Biol Toxicol

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Drug toxicity and efficacy are difficult to predict partly because they are both poorly defined, which I aim to remedy here from a transcriptomic perspective. There are two major categories of drugs: (1) restorative drugs aiming to restore an abnormal cell, tissue, or organ to normal function (e.g., restoring normal membrane function of epithelial cells in cystic fibrosis), and (2) disruptive drugs aiming to kill pathogens or malignant cells. These two types of drugs require different definition of efficacy and toxicity. I outlined rationales for defining transcriptomic efficacy and toxicity and illustrated numerically their application with two sets of transcriptomic data, one for restorative drugs (treating cystic fibrosis with lumacaftor/ivacaftor aiming to restore the cellular function of epithelial cells) and the other for disruptive drugs (treating acute myeloid leukemia with prexasertib). The conceptual framework presented will help and sensitize researchers to collect data required for determining drug toxicity.

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“…First, a new drug should be prescribed only for patients who will truly benefit from it, primarily on the basis of the individual response to CF drugs in nasal cell cultures (from patients with CFTR and modifier gene variants). 7 - 10 Second, all CFTR genotypes should be identified in order to determine whether precision medicine is feasible. Third, the government and the pharmaceutical industry should discuss costs, benefits, and a partnership for mutual benefit.…”

Section: To the Editormentioning

confidence: 99%

Cost of precision medicine at a referral center for cystic fibrosis

Marson

2020

J Bras Pneumol.

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Extent of Rescue of F508del-CFTR Function by VX-809 and VX-770 in Human Nasal Epithelial Cells Correlates with SNP rs7512462 in SLC26A9 Gene in F508del/F508del Cystic Fibrosis Patients

Cited by 7 publications

References 0 publications

Robust W1282X-CFTR rescue by a small molecule GSPT1 degrader

Robust W1282X-CFTR rescue by a small molecule GSPT1 degrader

Drug efficacy and toxicity prediction: an innovative application of transcriptomic data

Cost of precision medicine at a referral center for cystic fibrosis

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