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Cystic Fibrosis milestones at SickKids

Cystic Fibrosis research at SickKids has thrived thanks to the multi-disciplinary, collaborative approach that is characteristic within the SickKids Research Institute. State-of-the-art laboratory research in cystic fibrosis has been linked to outstanding clinical research and clinical care at SickKids for the past three decades. The synergy between laboratory, clinical research and clinical care places SickKids at the forefront for future CF therapy development and implementation in patients.

Implementation of high caloric diet leading to improved survival in CF (D. Crozier, M. Corey)

Creation and development of the CF Patient Database – covering the longest period of phenotypic data for CF patients in the world (Mary Corey).

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes the disease (Johanna Rommens, John Riordan and Lap-Chee Tsui)

Lap Chee Tsui and colleagues 1989
Lap-Chee Tsui, centre, with Francis Collins and John Riordan, on that special day in 1989

Cystic Fibrosis Genetic Analysis Consortium creates the Cystic Fibrosis Mutations Database (CFMD) as a resource for the international cystic fibrosis genetics research community. Created in 1989, the specific aim of the database is to provide CF researchers and other related professionals with up to date information about individual mutations in the CFTR gene and phenotypic data associated with CFTR genotypes. The database contains over 1600 mutations and the website has received approximately half a million visitors from around the world. (Julian Zielenski, Mary Corey and Lap-Chee Tsui)

Development of genotype: phenotype correlations enabling to future prognoses and predictions regarding disease severity in the multiple organs affected. Established in the early 1990s, this area of study was continues to the present day; (Peter Durie, Mary Corey and Lap Chee Tsui)

Discovery that the protein produced by the CFTR gene functions as a pore in the cell membrane which mediates chloride flux and accounts for normal fluid transport in airways, pancreatic ducts, gastrointestinal tract and the sweat ducts. (Christine Bear, Canhui Li, Mohabir Ramjeesingh and John Riordan)

Establishment of an internationally-renowned Toronto CF Lung Transplant Program together with the University Health Network,

Definition of the role of CF mutations in male infertility due to Congenital Bilateral Absence of the Vas Deferens (CBAVD) (Lap Chee Tsui, Peter Durie, Julian Zielenski, Michael Wilschanski) together with Keith Jarvi (UHN) and Elizabeth Tullis at St Michael’s Hospital.

SickKids scientists overcome gene therapy hurdle, enabling the therapeutic gene to work only in the desired location in the lung and uses only human genetic material to make the gene work. (Yu-Hua Chow and Jim Hu )

First structural evidence that the major mutation (F508del CFTR) leads to production of a protein with an abnormal conformation. (Gergely Lukacs, Norbert Kartner and Fred Zhang). Further evidence of the conformational defects in this protein was reported by the group (including Manu Sharma) in 2004.

Demonstration, in mice lacking cftr, of the potential of 'CFTR protein replacement' to partially restore proper function in the respiratory tract (Mohabir Ramjeesingh, Michael Wilschanski, Keith Tanswell, Ernest Cutz, Peter Durie and Christine Bear)

Discovery of secondary genetic modifiers which affect CF disease severity (Julian Zielenski , Richard Rozmahel, Mary Corey, Peter Durie and Lap Chee Tsui)

Structural studies of a CFTR protein defect caused by a mutation associated with milder forms of cystic fibrosis. (Charles Deber)

Evidence in a mouse model that CF-related infections can be ameliorated by delivery of the normal CF gene. (David Koehler, Uma Sajjan, Colin McKerlie, Janet Forstner and Jim Hu).

The CCFF and CIHR funded BREATHE CF research program is established at SickKids. (Christine Bear, Lori Burrows, Charles Deber, Peter Durie, Clifford Lingwood, Felix Ratjen, Daniela Rotin and Herman Yeger)

CF Discoveries in SickKids from 2004-2009 in addition to BREATHE
See BREATHE accomplishments

Study proves genetic variations influence severity of cystic fibrosis by showing for the first time that particular variants of the transforming growth factor beta 1 (TGF b 1) gene are largely responsible for how badly the illness affects patients' lungs. (including Julian Zielenski, Michael R. Knowles, Peter Durie, Lap Chee Tsui and Mitchell L. Drumm)

A novel structural model for the regulation of the CFTR protein using NMR spectroscopy. (Jennifer Baker and Julie Forman-Kay)

Identification of key genetic factors influencing the severity of lung disease in CF paediatric patients. Paediatric patients with CF who carry a gene variant that produces a low amount of MBL2 or mannose binding lectin 2, and who carry a high producing variant of the TGFB1gene or transforming growth factor beta 1 gene, have a greater risk of acquiring the bacterial infection that may accelerate the decline of their lung function. (Ruslan Dorfman, Mary Corey, Lap Chee Tsui, Peter Durie and Julian Zielenski)