A gene therapy research team at Cedars-Sinai Medical Center have developed a method of signaling therapeutic genes to turn "off" or "on," a mechanism that could enable scientists to fine-tune genetic- and stem cell-based therapies so that they are safer, controllable and effective.
As reported in a study published in the January issue of the Journal of Virology, the development of a delivery system that can effectively regulate therapeutic gene expression has important implications for efforts to advance gene and stem cell therapy strategies that may ultimately be used to treat life-threatening neurodegenerative diseases in the clinical setting.
The study, which involved laboratory rats, focused on the area of the brain that has already been the target for research into genetic therapies for Parkinson's disease.
"Since some diseases treated with gene therapy will require constant therapeutic expression while others may have periods of remission and therefore only require treatment during 'active' disease states, a system that can more closely monitor the 'how much' and 'when' the therapeutic gene is produced is a critically important tool in the development of gene therapy treatments that could help people suffering from Parkinson's and other diseases," said Maria Castro, Ph.D., co-director of the Board of Governors' Gene Therapeutic Research Institute at Cedars-Sinai and lead author of the study.
"Until now, researchers working to develop successful gene therapy for diseases such as Parkinson's have hit roadblocks such as toxic side-effects from over-expression of the therapeutic gene, and adverse events caused by immune system reactions to the viral delivery systems currently used to deliver the therapeutic genes," said Pedro Lowenstein, M.D., Ph.D., co-director of the Institute and co-author of the study.
"Now, we've engineered a genetic switch in a novel gene transfer vector that will overcome those barriers and set the stage to allow the next phase of research to occur."
In this study, researchers created a genetic switch system that is turned on in the presence of the antibiotic tetracycline. Therefore, if this method is tested eventually in humans, patients would need to be given this antibiotic before they begin gene therapy treatment.
The switch system also produces a protein called silencer, which completely shuts down gene expression in the "off" state, thereby preventing leakage of the therapeutic gene when it is no longer needed.
According to Castro, this vector system is much less likely to create an undesirable immune response in the host and would still be functional in the presence of an infection to wild type adenovirus (a non-engineered virus that causes conjunctivitis and upper respiratory tract infections) as is present in a high percentage of patients undergoing clinical trails.
These are the main hurdles that needed to be overcome before gene therapy can be considered a safe and efficacious clinical strategy.
According to Drs. Castro and Lowenstein, the next step in the development of this signaling system is to activate the developed genetic switch to actively express compounds that are known to be effective at reversing the symptoms and rescuing the damaged neurons in Parkinson's disease patients.