|Year : 2012 | Volume
| Issue : 1 | Page : 42-43
The need for human embryonic stem cell models of cystic fibrosis
David Cram, Michael F Azari, Steven Petratos
Monash Immunology and Stem Cell Laboratories, Monash University, Clayton Victoria 3800, Australia
|Date of Web Publication||13-Apr-2012|
Monash Immunology and Stem Cell Laboratories, Monash University, Clayton Victoria 3800
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Cram D, Azari MF, Petratos S. The need for human embryonic stem cell models of cystic fibrosis. Saudi J Health Sci 2012;1:42-3
Worldwide, Cystic fibrosis (CF) is one of the most common genetic diseases. In Caucasian populations, approximately one in 25 individuals are asymptomatic carriers and approximately one in 2,500 births produce a child with CF. CF is a multisystem disease that affects a number of organs, primarily the lung and upper respiratory tract but also the gastrointestinal tract, pancreas, liver, sweat glands and the genitourinary tract in males. Individuals affected with CF carry two Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations- one inherited from each biological parent. To date, over 1,000 sequence variants have been identified within the CFTR gene, which are detailed in the Cystic fibrosis genetic analysis consortium (CFGAC) database (http://www.genet.sickkids.on.ca/cftr). Of these mutations, approximately 85% have been associated with clinical CF, whilst the remaining 15% are classified as polymorphisms. The most prevalent CF mutation is delta F508 that accounts for approximately 70% of all CF chromosomes worldwide. Delta F508 corresponds to a 3 base pair deletion within exon 10 of the CFTR gene, which results in the loss of a phenylalanine residue at position 508 in the CFTR protein and its subsequent failure to mature into a fully glycosylated functional membrane protein.
As there is no cure for CF, treatment is primarily directed towards symptomatic management with the aim to alleviate the severity of symptoms. Treatment regimes have been successful in prevention or slowing of airway damage, reducing mucus build up, controlling infection and inflammation, delaying the progression of hepatic disease and optimizing nutrition. In limited cases, lung transplantation for severe life threatening CF has been successful. Such treatments have generally been effective in improving the quality of life for CF patients and increasing their lifespan. Gene replacement therapy has been the subject of intense research as an approach for the treatment of CF lung disease. The most extensively tested strategies in pre-clinical and clinical trials have involved the delivery of the CFTR gene to the lungs using either recombinant viruses or plasmid vectors. However, gene therapy by topical delivery to the airway of CF patients has proven disappointing to date, primarily due to inefficient expression of the CFTR gene, induced inflammatory responses and barriers such as mucous preventing the transfection of sufficient cells.
An alternative strategy of gene transfer is stem cell therapy. Patients may benefit from stem cell therapy, since lung inflammation and infection may promote stem cell engraftment and differentiation. Research is still in its infancy and is largely confined to mouse models of CF. For the humans; there are many questions to be answered. For example, which cell types should be targeted, how should stem cells be delivered - intravenously or locally to the site of injury, do sodium and chloride defects need to be corrected, how often and how many applications would be required and most importantly, what are the possible long term effects of administrating genetically modified stem cells. Further, an understanding of the factors that drive stem cells to lung cell lineages will be critical and such work is proceeding at the Monash Immunology and Stem Cell Laboratories at Monash University.
Currently, there are no useful human models of CF. Human embryonic CF stem cell lines will be useful models to assist scientists and clinicians in the quest towards finding a cure, since they can be directed to differentiate into lung cell types affected by the disease process. Several in vitro fertilization (IVF) laboratories that offer preimplantation genetic diagnosis have already begun to derive disease-specific stem cell lines from affected embryos, including CF lines. However, research access is either subject to commercial arrangements with private companies (i.e. Stemride International, refer to http://www.stemride.com) and/or restrictive material transfer agreements. Recent changes in legislation involving the regulation of embryo and stem cell research in several countries, including Australia, now permits the establishment of stem cell lines from embryos that would otherwise be discarded, subject to consent from IVF patients.
Most scientists and doctors agree that it would be advantageous, if human embryonic stem cells with clinically significant CF genotypes were available to the wider research community. Although, there are a small number of individuals who oppose all embryonic stem cell research, strict guidelines will ensure that such research is performed in an ethical way and that results will be of value for developing new treatments for diseases such as CF. The availability of CF stem cell lines with defined genotypes will provide useful in vitro models for research:
- Standardization of cell lines with respect to CF genotype and genetic background will allow meaningful comparisons of research findings between CF researchers and laboratories.
- Means to optimize viral - mediated gene therapy of lung derived cells and define better strategies for human trials.
- A source of lung cells for screening large drug banks to identify compounds that override the effect of the mutation and/or improve the functionality of the defective CF protein.
- A source of relevant cell types to gain further insights into the pathological processes affected by CF at the molecular level.
- An in vitro model to study the pathogenesis of Pseudomonas lung infections and develop strategies to prevent such infections.
In conclusion, the generation of a bank of CF human embryonic stem cell lines with defined genotypes (including homozygous delta F508) will accelerate basic research towards understanding the precise mechanisms of disease pathogenesis and ultimately lead to the development of more effective therapies for treating patients with this serious life threatening genetic disease.