By Debbie Strickland
Special to BioWorld Today
WASHINGTON - Ariad Pharmaceuticals Inc. is working on a method of small-molecule regulation of insulin gene therapy that has successfully treated hyperglycemia in mice, project manager Victor Rivera told those attending the plenary session of the American Society of Gene Therapy meeting.
The technology, introduced for the first time at the conference, could be applicable to a variety of genes whose secreted proteins require frequent dosing, the most tantalizing being insulin.
The technique combines one gene for insulin and one for a mutant version of FKBP12 that bind to form an aggregate too large to escape the endoplasmic reticulum (ER). The aggregates become lodged in the ER - ballooning it noticeably with protein.
A synthetic analogue of a small-molecule ligand called FK506 breaks apart FKBP12, unlocking it from the insulin. Both FKBP12 and the insulin are then released and secreted from the cell - in quantities several hundred times what is secreted in the absence of the ligand.
"The idea is to trick the cell into using endoplasmic reticulum for storage," Rivera said.
The preclinical insulin study used mice whose insulin-making beta cells had been destroyed, rendering them highly glycemic. They were then dosed with the gene therapy - housed in human HT1080 cells, a cell line frequently employed in research.
The mice started out with diabetic levels of glucose, 600 mg/dL. There was little or no secretion of insulin in the first 20 minutes after dosing, but in the next 30 minutes high levels were obtained as the ER discharged the accumulated insulin. Glucose levels were cut by 90 percent over the course of two hours, reaching normal levels.
The same effects were achieved with thrice daily dosing, at 7 a.m., noon and 5 p.m., in a regimen designed to mimic human mealtime schedules.
If all continues to go well, the goal, as the program moves forward into adeno-associated viral vectors and eventually to larger animal models, would be to develop an oral drug that would activate the gene therapy as needed - ideally in the form of a pill taken in conjunction with meals.
"Treating diabetes is something you really couldn't talk about doing with gene therapy before," Rivera said.
As for possible adverse effects, Rivera said there is no evidence the buildup of the insulin-FKBP12 aggregate is getting in the way of the ER's protein-making function. Nor is there any sign of harm caused by release of the FKBP12 protein.
In addition to insulin, the method has been tested using human growth hormone and alkaline phosphatase.
The project is unpartnered, though the Cambridge, Mass., company has collaborated on it with Memorial Sloan-Kettering Cancer Center and the University of Geneva.
Ariad's shares (NASDAQ:ARIA) closed Friday at $1.406, up 9.38 cents.