December 23, 2003
SickKids researchers develop vector for potential cystic fibrosis gene therapy
TORONTO - A research team at The Hospital for Sick Children (SickKids) led by Dr. Jim Hu has developed a new gene therapy method that might be used for treating infections related to cystic fibrosis (CF). This research is reported in the December 23 issue of the scientific journal Proceedings of the National Academy of Sciences (PNAS).
“Previous efforts to use gene therapy for treating cystic fibrosis have been disappointing because of a combination of inflammation of lung tissue, toxicity and low-level gene expression,” said Dr. Jim Hu, a senior scientist in the SickKids Lung Biology Research Program, and an associate professor of Paediatrics, and Laboratory Medicine and Pathobiology at the University of Toronto. “Patients with CF are vulnerable to bacterial infections that don’t usually affect the general public. In a mouse model of CF, we demonstrated that our gene therapy vector can help fight a type of lung infection associated with cystic fibrosis.”
In gene therapy studies, a normal gene is used to replace a disease-causing gene. In CF the defective gene, discovered in 1989 at The Hospital for Sick Children, is known as CFTR. A vehicle called a vector is then used to deliver the correct CFTR gene, together with pieces of DNA to control its expression, to the patient. Both virus-based and non-virus-based vectors have been used in gene therapy studies. Because of the infectious nature of a virus, it is generally more efficient. However, viral vectors can present several problems to patients, including toxicity and inflammation. Also, there is a risk of cancer for some types of viral vectors that insert themselves into the patient’s DNA.
The CFTR vector developed by Dr. Hu’s group is based on viral technology invented at McMaster University combined with DNA control regions invented by Dr. Hu’s group. The DNA control regions ensure that the replacement CFTR gene is only active where it is needed in the patient. The CFTR gene, together with the DNA control regions, were packaged into a viral vector. The virus then delivers the replacement CFTR gene to the patient’s cells. This vector virus has been “gutted", meaning it doesn’t carry any of its own viral genes, so it causes less inflammation than earlier types of viral vectors. This type of viral vector also doesn’t insert itself into the patient’s DNA, alleviating the risk of cancer.
“We discovered that by modifying the DNA control regions, the CFTR gene was only affecting the intended cells, and operating only as it had been intended to operate,” said Dr. David Koehler, the study’s lead author, currently a research associate in Dr. Hu’s lab and previously a holder of a Canadian Cystic Fibrosis Foundation Postdoctoral Fellowship.
Testing of the specialized vector began in cultured cells and then progressed to a mouse model of CF. In a majority of cases, the mice treated first with the CFTR vector were able to successfully fight off a CF-related lung infection. While the results were very positive, they were done in small groups of six to eight mice and over a course of one month. Next stages of this research involve further testing in larger animal models over a longer period of time.
“Although this is a significant step forward in CF lung gene therapy research, it will take time and effort to see whether we can bring clinical benefits to patients,” Dr. Hu added. “If this technology can benefit CF patients, it may be modified for the treatment of other airway diseases as well.”
Cystic fibrosis is a fatal inherited disease. It affects multiple organ systems, including the lungs and the digestive system. Thick mucus in the lungs makes clearing bacteria difficult and leads to repeated cases of infection and inflammation, which damage lung tissues causing severe breathing problems. According to the Canadian Cystic Fibrosis Foundation, it is estimated that one in every 2,500 children born in Canada has CF.
Other members of the research team included Dr. Umadevi Sajjan, Dr. Yu-Hua Chow, Bernard Martin, Dr. Keith Tanswell. Dr. Colin McKerlie, and Dr. Janet Forstner, all from The Hospital for Sick Children, and Dr. Geraldine Kent from the University of Western Ontario.
This research was supported by the Canadian Cystic Fibrosis Foundation, the Canadian Institutes of Health Research, the US National Institutes of Health, and The Hospital for Sick Children. Dr. Hu holds a Canadian Cystic Fibrosis Foundation Scholarship.
The Hospital for Sick Children, affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.
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