This federal Project Grant award of $2,519,726.00, provided by the National Heart Lung and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research), aims to analyze the pharmacokinetics, pharmacogenetics, and clinical utility of the triple combination therapy (TC) elexacaftor/tezacaftor/ivacaftor for cystic fibrosis (CF) patients. The study, titled "ENSURING ACCESS TO OPTIMAL THERAPY IN CF: ENACT STUDY," will: Analyze the population pharmacokinetics of the TC compounds in...
The federal Project Grant award R01HD117940, totaling $696,246.00, was provided by the National Institute of Child Health and Human Development (NICHD) under the Child Health and Human Development Extramural Research program (CFDA 93.865). The grant will fund a 5-year study titled "Evaluating Maternal and Neonatal Pharmacokinetics of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators - The ELECTRA Pregnancy Study". The study aims to 1) determine the...
This federal Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under the Cardiovascular Diseases Research program (CFDA 93.837) provides $730,494 to Emory University to conduct research on the mechanisms linking the cystic fibrosis transmembrane conductance regulator (CFTR) protein to dysregulated barrier function, insulin receptor function, and glucose transport in the cystic fibrosis (CF) lung. The research aims to identify the underlying mechanisms for the...
This $437,156 Project Grant award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) supports research to investigate the mechanisms underlying the development of diabetes in individuals with cystic fibrosis (CF). The key objectives of the research project are to: 1) Determine whether cystic fibrosis transmembrane conductance regulator (CFTR)-defective pancreatic ductal...
This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under the Cardiovascular Diseases Research Program (CFDA 93.837) provides $629,319 to Emory University for a project titled "Tuning Translation Efficiency to Overcome Refractory Defects in CFTR." The project aims to investigate how modulating ribosomal protein expression can rescue the synthesis and assembly of cystic fibrosis transmembrane conductance regulator (CFTR) variants with premature...
This $2,368,153 Project Grant awarded by the National Heart, Lung, and Blood Institute (NHLBI) under the Cardiovascular Diseases Research program (CFDA 93.837) will support research to evaluate the safety and efficacy of using recombinant adeno-associated viral (AAV) vectors to deliver a truncated version of the cystic fibrosis transmembrane conductance regulator (CFTR) gene as a gene therapy for cystic fibrosis. The key objectives are to: 1) assess single-dose administration of the...
This $168,330 Project Grant awarded by the National Institute of Diabetes and Digestive and Kidney Diseases (CFDA 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research) supports research to elucidate the fate specification of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) high expresser (CHE) cells in the intestine. The project aims to define the transcriptional network driving CHE cell fate specification (Aim 1) and the role of Notch signaling in CHE cell fate...
The National Heart, Lung, and Blood Institute (NHLBI), under the Cardiovascular Diseases Research program (CFDA 93.837), awarded a $783,000 Project Grant to the University of Toronto to develop a novel, non-viral base editing platform for treating cystic fibrosis (CF) caused by nonsense mutations. The project aims to refine adenine base editors (ABEs), formulate lipid nanoparticles (LNPs) for targeted pulmonary delivery, and validate the therapeutic efficacy and safety in a mouse model of CF. By...
This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI), under the Cardiovascular Diseases Research program (CFDA 93.837), provides $827,753 to The Children's Hospital Corporation (Boston Children's Hospital) to develop new computational methods for systems genetic analysis of the rare polygenic disorder idiopathic pulmonary fibrosis (IPF). The research aims to identify novel IPF genes and pathways by: (1) extending a pleiotropy-informed association test to leverage...
This Project Grant award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) provides $613,558 to Genetobe Inc. to develop novel, selective sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor compounds as an adjunctive therapy for cystic fibrosis (CF) associated metabolic disorders. The research aims to mitigate CF-related liver disease and CF-related diabetes,...
PULMONARY AND PANCREATIC RESPONSE TO CYSTIC FIBROSIS MODULATOR THERAPY IN YOUNG CHILDREN - PROJECT SUMMARY HIGHLY EFFECTIVE MODULATOR THERAPY (HEMT) WHICH DRAMATICALLY IMPROVES PULMONARY FUNCTION HAS BEEN DEVELOPED FOR PEOPLE WITH CYSTIC FIBROSIS (CF). IN 2019, THE HEMT ELEXACAFTOR, TEZACAFTOR, IVACAFTOR (ETI) BECAME AVAILABLE FOR THE 90% OF CF TEENS AND ADULTS WITH AT LEAST ONE F508DEL MUTATION. USE OF ETI IS NOW WIDESPREAD IN THE US AND IS STANDARD OF CARE. WITH CHRONIC USE OF ETI, SOME PEOPLE WITH CF (PWCF) HAVE RESOLUTION OF PULMONARY SYMPTOMS AND SUCCESSFULLY WEAN BURDENSOME DAILY PULMONARY TREATMENTS. UNFORTUNATELY, THE PULMONARY RESPONSE IS VARIABLE AND THERE ARE SOME PWCF WHO HAVE NO, OR ONLY MILD, PULMONARY IMPROVEMENT WITH ETI. FURTHERMORE, THERE IS NO EVIDENCE OF IMPROVEMENT IN EITHER EXOCRINE OR ENDOCRINE PANCREATIC FUNCTION IN CF TEENS AND ADULTS WITH ETI. THIS LACK OF A PANCREATIC RESPONSE MOST LIKELY IS RELATED TO THE FACT THAT IN CF THE PANCREAS IS LARGELY REPLACED BY LIPOFIBROTIC TISSUE BY THE TEENAGE YEARS, LEAVING LITTLE TO NO PANCREATIC TISSUE FOR ETI- MEDIATED RESTORATION OF FUNCTION. HOWEVER, RECENT DATA SHOW THAT YOUNGER CF CHILDREN MAY HAVE A SIGNIFICANT PANCREATIC RESPONSE TO ETI. IN APRIL 2023, THE FDA APPROVED ETI FOR CF CHILDREN AGED 2 TO 5 YEARS. OUR OVERALL HYPOTHESIS IS THAT IN THIS YOUNG AGE GROUP, CHRONIC ETI WILL PREVENT PROGRESSION OF AIRWAY DISEASE TO BRONCHIECTASIS, PREVENT FURTHER DESTRUCTION OF PANCREATIC EXOCRINE TISSUE, POSSIBLY PERMIT REPAIR/REGENERATION OF EXOCRINE FUNCTION, AND PREVENT CF RELATED DIABETES (CFRD), THE MOST SERIOUS COMPLICATION OF PANCREATIC DISEASE. IN THIS PROJECT, WE PROPOSE TO STUDY A COHORT OF 30 CF CHILDREN AGED 2- TO 5-YEARS OLD BEFORE AND FOUR YEARS AFTER STARTING ETI FOR CLINICAL INDICATIONS. WE AIM TO: 1. DETERMINE THE IMPACT OF ETI-MEDIATED CFTR RESTORATION ON PROGRESSION OF AIRWAY DISEASE IN THESE YOUNG CF CHILDREN; 2. DETERMINE THE IMPACT OF ETI-MEDIATED CFTR RESTORATION ON PANCREATIC EXOCRINE AND ENDOCRINE FUNCTION IN THIS COHORT; AND 3. ELUCIDATE COMPUTATIONAL PHENOTYPES OF THERAPEUTIC RESPONSIVENESS IN THE LUNGS AND THE PANCREAS AND THEIR TRAJECTORIES USING MACHINE LEARNING. THIS PROJECT IS IMPORTANT AS IT HAS THE POTENTIAL TO USHER IN THE NEXT GENERATION OF THERAPEUTICS FOR CF WHICH WILL BE THE INITIATION OF HEMT IN INFANCY TO PREVENT THE MANY LATER MANIFESTATIONS OF CF INCLUDING BRONCHIECTASIS, PANCREATIC EXOCRINE INSUFFICIENCY, AND CFRD.