Cystic Fibrosis Foundation Evidence-Based Guideline for the Management of CRMS/CFSPID.

A multidisciplinary committee developed evidence-based guidelines for the management of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID). A total of 24 patient, intervention, comparison, and outcome questions were generated based on surveys sent to people with CRMS/CFSPID and clinicians caring for these individuals, previous recommendations, and expert committee input. Four a priori working groups (genetic testing, monitoring, treatment, and psychosocial/communication issues) were used to provide structure to the committee. A systematic review of the evidence was conducted, and found numerous case series and cohort studies, but no randomized clinical trials. A total of 30 recommendations were graded using the US Preventive Services Task Force methodology. Recommendations that received ≥80% consensus among the entire committee were approved. The resulting recommendations were of moderate to low certainty for the majority of the statements because of the low quality of the evidence. Highlights of the recommendations include thorough evaluation with genetic sequencing, deletion/duplication analysis if <2 disease-causing variants were noted in newborn screening; repeat sweat testing until at least age 8 but limiting further laboratory testing, including microbiology, radiology, and pulmonary function testing; minimal use of medications, which when suggested, should lead to shared decision-making with families; and providing communication with emphasis on social determinants of health and shared decision-making to minimize barriers which may affect processing and understanding of this complex designation. Future research will be needed regarding medication use, antibiotic therapy, and the use of chest imaging for monitoring the development of lung disease.

Comprehensive Assessment of CFTR Modulators' Therapeutic Efficiency for N1303K Variant.

p.Asn1303Lys (N1303K) is a common missense variant of the CFTR gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of CFTR modulators on the restoration of N1303K-CFTR function using intestinal organoids derived from four CF patients expressing the N1303K variant. The forskolin-induced swelling assay in organoids offered valuable insights about the beneficial effects of VX-770 + VX-661 + VX-445 (Elexacaftor + Tezacaftor + Ivacaftor, ETI) on N1303K-CFTR function restoration and about discouraging the prescription of VX-770 + VX-809 (Ivacaftor + Lumacaftor) or VX-770 + VX-661 (Ivacaftor + Tezacaftor) therapy for N1303K/class I patients. Then, a comprehensive assessment was conducted on an example of one patient with the N1303K/class I genotype to examine the ETI effect on the restoration of N1303K-CFTR function using in vitro the patient's intestinal organoids, ex vivo the intestinal current measurements (ICM) method and assessment of the clinical status before and after targeted therapy. All obtained results are consistent with each other and have proven the effectiveness of ETI for the N1303K variant. ETI produced a significant positive effect on forskolin-induced swelling in N1303K/class I organoids indicating functional improvement of the CFTR protein; ICM demonstrated that ETI therapy restored CFTR function in the intestinal epithelium after three months of treatment, and the patient improved his clinical status and lung function, increased his body mass index (BMI) and reduced the lung pathogenic flora diversity, surprisingly without improving the sweat test results.

Cystic fibrosis year in review 2022.

Remarkable medical advancements have been made for people with cystic fibrosis (CF) in recent years, with an abundance of research continuing to be conducted worldwide. With concern for limitations in access to highly effective CFTR modulators, as well as the recent Coronavirus Disease-19 pandemic, there has been a consistent effort to understand and improve CF screening, disease burden, diagnosis, and management. Our aim in this review is to present articles from 2022 with an emphasis on clinically relevant studies. We hope this will serve as a broad overview of the research published in the past year.

Cost-effectiveness analysis of genetic tools to predict treatment response in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies show variable efficacy for patients with CF. Patient-derived predictive tools may identify individuals likely to respond to CFTRs, but are not in routine use. We aimed to determine the cost-utility of predictive tool-guided treatment with CFTRs as add-on to standard of care (SoC) for individuals with CF. METHODS: This economic evaluation compared two strategies using an individual level simulation: (i) Treat All, where all patients received CFTRs plus SoC and (ii) Test→Treat, where patients who tested positive on predictive tools received CFTRs plus SoC and those who tested negative received SoC only. We simulated 50,000 individuals over their lifetime, and estimated costs (2020 CAD) per quality-adjusted life year (QALY) from the healthcare payer's perspective, discounted at 1.5% annually. The model was populated using Canadian CF registry data and published literature. Probabilistic and deterministic sensitivity were conducted. RESULTS: The Treat All and Test→Treat and strategies yielded 22.41 and 21.36 QALYs, and cost $4.21 M and $3.15 M respectively. Results of probabilistic sensitivity analysis showed that Test→Treat was highly cost-effective compared to Treat All in 100% of simulations at cost-effectiveness thresholds as high as $500,000 per QALY. Test→Treat may save between $931 K to $1.1 M per QALY lost, depending on sensitivity and specificity of predictive tools. CONCLUSION: The use of predictive tools could optimize the health benefits of CFTR modulators while reducing costs. Our findings support the use of pre-treatment predictive testing and may help inform coverage and reimbursement policies for individuals with CF.

Effects of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis - a comprehensive assessment using lung clearance index, spirometry, and functional and structural lung MRI.

BACKGROUND: With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities. METHODS: 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDIV, DDIQ), and Eichinger score. Statistical analyses were performed using paired t-tests and multilevel regression models with bootstrapping. RESULTS: We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI2.5 (TO) -0.84 (-1.62 to -0.06); ΔFEV1 (z-score) 1.05 (0.56 to 1.55); ΔVDP (% of impairment) -6.00 (-8.44 to -3.55); ΔQDP (% of impairment) -3.90 (-5.90 to -1.90); ΔDDIV -1.38 (-2.22 to -0.53); ΔDDIQ -0.31 (-0.73 to 0.12); ΔEichinger score -3.89 (-5.05 to -2.72). CONCLUSIONS: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

CFTR gene variants, air pollution, and childhood asthma in a California Medicaid population.

Carriers of the cystic fibrosis transmembrane conductance regulator (CFTR) gene ("carriers") have been found to have an increased risk of persistent asthma. However, it is unclear at what level of CFTR function this risk exists and whether it is modified by asthmogens, such as air pollution. We conducted a retrospective cohort study of children born in California between July 2007 and December 2013, linking CFTR genotype data from the California newborn screening program to Medicaid claims records through March 17, 2020 to identify asthma cases, and to air pollution data from CalEnviroScreen 3.0 to identify levels of particulate matter with diameter 2.5 microns or smaller (PM2.5 ). Log-binomial regression models for asthma risk were fitted, adjusting for race/ethnicity and sex. Compared to population controls, carriers had higher risk of asthma (adjusted risk ratio (aRR) = 1.29, 95% confidence interval (CI): 0.98, 1.69; p < 0.1). Other non-CF-causing variants on the second allele did not appear to further increase risk. Genotypes with the greatest asthma risk were F508del with an intron 10 T7 or (TG)11T5 in trans (aRR=1.52, 95% CI: 1.10, 2.12). This association was higher among children living in areas at or above (aRR = 1.80) versus below (aRR = 1.37) the current national air quality standard for PM2.5 , though this difference was not statistically significant (pinteraction > 0.2). These results suggest carriers with CFTR functional levels between 25% and 45% of wildtype are at increased risk of asthma. Knowledge of CFTR genotype in asthmatics may be important to open new CFTR-related treatment options for these patients.

Analyzing the use and impact of elexacaftor/tezacaftor/ivacaftor on total cost of care and other health care resource utilization in a commercially insured population.

BACKGROUND: Cystic fibrosis (CF) is a rare, life-threatening disease that results in severe respiratory, digestive, and metabolic problems. Elexacaftor/tezacaftor/ivacaftor is an oral drug that was approved by the US Food and Drug Administration (FDA) on October 21, 2019, after demonstrating clinical improvements compared with previous CF transmembrane conductance regulator modulators. Use of CF transmembrane conductance regulator modulators has improved CF care, but their high costs exceed commonly used cost-effectiveness thresholds. The Institute for Clinical and Economic Review issued an access and affordability alert warning that these high costs could threaten sustainable access to high-value care. There exists little real-world evidence on the uptake of elexacaftor/tezacaftor/ivacaftor and the impact on total cost of care and other health care resource utilization. This exploratory study analyzed the uptake and total cost-of-care impact of elexacaftor/tezacaftor/ivacaftor using pharmacy and medical claims data in a commercially insured patient population. OBJECTIVE: To analyze the uptake of elexacaftor/tezacaftor/ivacaftor by members who qualified for treatment and to evaluate the differences in total cost of care and health care resource utilization in members who started treatment with elexacaftor/tezacaftor/ivacaftor. METHODS: Uptake and per-member per-month information was obtained from Prime Therapeutics databases using cystic fibrosis transmembrane conductance regulator (CFTR) modulator claims. The total cost-of-care and resource utilization analysis used pharmacy and medical claims from Prime Therapeutics and Blue Cross NC across approximately 1.34 million commercially insured members over 20 months. Members with CF were identified by 2 or more International Classification of Diseases, Tenth Revision codes (E84.xx) in any field at least 30 days apart or by a CFTR modulator claim. Only continuously enrolled members with CF with an elexacaftor/tezacaftor/ivacaftor pharmacy claim were included. The date of the first claim served as the index date. RESULTS: At 12 months after FDA approval, 77 (68%) Blue Cross NC members with CF were using elexacaftor/tezacaftor/ivacaftor. Of these, 33 had switched from a different CFTR modulator and 44 were naive to CFTR modulator therapy. Pharmacy and medical claims for 51 continuously enrolled members that initiated elexacaftor/tezacaftor/ivacaftor were analyzed. The average total cost of care increased by 52% (P < 0.00001). Hospitalizations decreased from an average of 7.7 (± 7.2) to 3.9 (± 5.5) (P < 0.00001). The sum and average number of Pseudomonas aeruginosa infections were numerically lower, but the results did not meet statistical significance. Use of other supportive medications was numerically lower, but no statistically significant differences were observed. CONCLUSIONS: The uptake of elexacaftor/tezacaftor/ivacaftor was rapid, and the total cost of care increased despite reductions in hospitalizations and nonpharmacy costs. Differences in use of other CF-related medications appeared to be minimally affected. DISCLOSURES: Dr Smith and Dr Borchardt have no financial conflicts of interest to report. Both authors are employed at BCBSNC at the time of writing. The project had no outside funding or sponsorship. The majority of the work and data analysis was completed as part of the requirements of the PGY1 Managed Care Pharmacy Residency program at BCBSNC during the 2020-2021 cycle year. This research does not meet the definition of human subject research as defined by the US Department of Health and Human Services at 45 C.F.R. § 46.102(f). According to definitions in section (e)(1), our research did not require either (i) information or biospecimens through intervention or interaction with any individuals or (ii) obtained, used, studied, analyzed, or generated private information or identifiable biospecimens. Therefore, institutional review board approval or a valid exemption is not required.

Current prices versus minimum costs of production for CFTR modulators.

BACKGROUND: While the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of the world's richest countries. Despite this, there is currently limited evidence regarding global access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment. METHODS: Minimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries. RESULTS: Costs of production for elexacaftor/tezacaftor/ivacaftor are estimated at $5,676 [$4,628-6,723] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for elexacaftor/tezacaftor/ivacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients worldwide would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion. CONCLUSIONS: Elexacaftor/tezacaftor/ivacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy, thereby exacerbating existing inequalities in CF care. Urgent action is needed to increase the availability of triple combination treatment worldwide. One strategy based on previous success is originator-issued voluntary licenses.

Genetic assessment using whole-exome sequencing for a young hypertriglyceridemic patient with repeated acute pancreatitis.

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.

Disease burden in people with cystic fibrosis heterozygous for F508del and a minimal function mutation.

BACKGROUND: People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. METHODS: People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. RESULTS: 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. CONCLUSIONS: People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

CFTR modulators: transformative therapies for cystic fibrosis.

DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties, and other forms of consideration provided to CFF. Some of these agreements are subject to confidentiality restrictions and, thus, CFF cannot comment on them.

The effectiveness and value of novel treatments for cystic fibrosis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.

Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.

Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.

Clinical and genetic characterization of patients with cystic fibrosis and functional assessment of the chloride channel with the pathogenic variant c.831G>A (p.Trp277*), described for the first time.

The clinical pictures of the disease of two Russian patients with cystic fibrosis with a rare nonsense variant c.831G>A (p.Trp277*) are described. The first case is a patient with the genotype comprising variant c.54-5940_273+10250del21kb (CFTRdele2,3), and the genotype of the second case included variant c.1521_1523delCTT (F508del). Patient 1, whose genotype had two class I genetic variants, revealed severe violations of CFTR synthesis based on the intestinal current measurements (ICM) and results obtained in the intestinal organoids. In both cases of patients with genetic variant c.831G>A, a severe course of cystic fibrosis was observed.

Cost-effectiveness of the CFTR gene-sequencing test for asymptomatic carriers in the Colombian population / [Costo-efectividad de la prueba de secuenciación del gen CFTR para portadores asintomáticos en la población colombiana].

Introduction: Cystic fibrosis is an autosomal recessive genetic disease classified as a highcost orphan disease. Objective: To determine the cost-effectiveness ratio of the diagnostic test for the CFTR gene-sequencing in asymptomatic family carriers in the first, second, and third degree of consanguinity. Materials and methods: We conducted a systematic search evaluating operative characteristics of the diagnostic test and decision-tree models in cost-effectiveness studies. A decision-tree model was elaborated taking prevention of future conceptions as a unit of analysis. We obtained the costs of the disease from the high-cost report of the Ministerio de Salud y Protección Social. The costs of the test were referenced by national laboratories. We carried out a deterministic and probabilistic sensitivity analysis with a third-payer perspective and a one-year horizon. Results: An ICER of USD$ 5051.10 was obtained as the incremental cost for obtaining 10.89% more probability of avoiding the birth of a child with cystic fibrosis per screened couple. For family members in second and third degrees, the ICER was USD$ 19,380.94 and USD$ 55,913.53, respectively, evidenced when applying the GDP per capita. This technology was cost-effective in 39%, 61.18%, and 74.36% for 1, 2, and 3 GDP per capita in first degree of consanguinity relatives. Conclusions: The genetic test for the detection of CFTR gene carriers was cost-effective depending on the threshold of availability to pay and the assumptions and limitations established in the model.

Introducción. La fibrosis quística es una enfermedad genética de carácter autosómico recesivo clasificada como enfermedad huérfana de alto costo. Objetivo. Determinar la razón de costo-efectividad de la prueba diagnóstica de secuenciación del gen CFTR para los portadores asintomáticos familiares en primer, segundo y tercer grados de consanguinidad. Materiales y métodos. Se hizo una búsqueda sistemática sobre la evaluación de las características operativas de la prueba diagnóstica y los modelos de árbol de decisiones en estudios de costo-efectividad. Se elaboró un modelo de árbol de decisiones tomando como unidad de análisis la prevención de futuras concepciones. Los costos de la enfermedad se obtuvieron del reporte de alto costo del Ministerio de Salud de Colombia. Los costos de la prueba se obtuvieron de laboratorios nacionales. Se hizo un análisis de sensibilidad, determinístico y probabilístico, con la perspectiva del tercer pagador y horizonte a un año. Resultados. Se obtuvo una razón incremental de costo-efectividad (RICE) de USD$5.051,10 por obtener 10,89 % más de probabilidades de evitar el nacimiento de un niño enfermo con fibrosis quística por pareja. Para los familiares de segundo y tercer grados, se encontró una RICE de USD$ 19.380,94 y USD$ 55.913,53, respectivamente, al aplicar el PIB per cápita. Esta tecnología fue costo-efectiva en 39 %, 61,18 % y 74,36 % para 1, 2 y 3 PIB per cápita en familiares de primer grado de consanguinidad. Conclusiones. La prueba genética de detección de portadores del gen CFTR resultó costo-efectiva dependiendo del umbral de la disponibilidad de pagar, y de los supuestos y limitaciones establecidas en el modelo.

Global assessment of the integrated stress response in CF patient-derived airway and intestinal tissues.

BACKGROUND: Chronic inflammation is a hallmark among patients with cystic fibrosis (CF). We explored whether mutation-induced (F508del) misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR), and/or secondary colonization with opportunistic pathogens, activate tissue remodeling and innate immune response drivers. METHODS: Using RNA-seq to interrogate global gene expression profiles, we analyzed stress response signaling cascades in primary human bronchial epithelia (HBE) and intestinal organoids. RESULTS: Primary HBE acquired from CF patients with advanced disease and prolonged exposure to pathogenic microorganisms display a clear molecular signature of activated tissue remodeling pathways, unfolded protein response (UPR), and chronic inflammation. Furthermore, CFTR misfolding induces inflammatory signaling cascades in F508del patient-derived organoids from both the distal small intestine and colon. CONCLUSION: Despite the small patient cohort size, this proof-of-principle study supports the use of RNA-seq as a means to both identify CF-specific signaling profiles in various tissues and evaluate disease heterogeneity. Our global transcriptomic data is a useful resource for the CF research community for analyzing other gene expression sets influencing CF disease signature but also transcriptionally contributing to CF heterogeneity.

The CFTR variant profile of Hispanic patients with cystic fibrosis: Impact on access to effective screening, diagnosis, and personalized medicine.

Hispanic patients comprise an appreciable and increasing proportion of patients with cystic fibrosis (CF) in the United States (US). Hispanic patients with CF are known to have increased morbidity and mortality compared to non-Hispanic white patients with CF, and ongoing investigations are underway to identify contributing factors amenable to intervention in order to address the disparate health outcomes. One contributing factor is the different CF transmembrane conductance regulator (CFTR) variant profile observed in Hispanic patients with CF. The most common CFTR variant, p.Phe508del (legacy name F508del), is proportionally underrepresented in Hispanic patients with CF. This difference has implications for prenatal screening, newborn screening (NBS), and CFTR variant-specific therapeutic options. In particular, the recent approval of a highly effective CFTR modulator for patients carrying at least one copy of F508del, elexacaftor/tezacaftor/ivacaftor triple combination therapy, underscores the potential for unequal access to personalized treatment for Hispanic patients with CF. We report the CFTR variant profiles of Hispanic patients with CF and non-CF Hispanic infants with a false-positive New York State CF NBS at a single center in New York City over a 5-year study period, as an opportunity to address the racial and ethnic disparities that currently exist in CF screening, diagnosis, and treatment. In addition to the previously documented disparate prevalence of the CFTR variant F508del in Hispanic patients, we observed two CFTR variants, p.His609Arg (legacy name H609R) and p.Thr1036Asn (legacy name T1036N), frequently identified in our Hispanic patients of Ecuadorian and Mexican ancestry, respectively, that are not well-described in the US population. The presence of population-specific and individually rare CFTR variants in Hispanic patients with CF further accentuates the disparity in health outcomes, as these CFTR variants are often absent from prenatal and NBS CFTR variant panels, potentially delaying diagnosis, and without an approved CFTR variant-specific therapy.