Local researchers are intrigued by the recent discovery of a technique through which genes can be tricked into storing large amounts of proteins such as insulin and later prompted by a pill to release their cache. The research marks another step toward genetic treatment of conditions such as diabetes.
But, the Augusta doctors caution, the technology is still early in the development, and it faces the same difficulty other gene therapies face: finding a reliable way to deliver the gene into the cell.
Researchers at the ARIAD Corp. reported in last week's edition of the journal Science that they have been able to genetically engineer a way for an essential protein such as insulin, which the body needs to regulate blood-sugar levels, to be stored inactive in cells. The protein is altered to include an element that causes the insulin cells to clump together in the cell's endoplasmic reticulum, which is normally a factory for creating enzymes. The protein cluster is too large for other elements of the cell to act upon, so it remains inactive. Then by administering a pill, which contains a molecule that will cut apart the cluster, called a ligand, the protein is released in a rapid burst. The amount released can be regulated by the amount of ligand given.
The researchers used engineered human insulin gene that was injected into mice bred to be diabetic. The mice successfully stored the insulin, which was then released in bursts when the mice were given the pill.
"This is clever," said Bill Dynan, professor and chief of the program of gene regulation at Medical College of Georgia. "It's a natural pathway that they have used a clever trick to keep this protein from being secreted, and then they use another clever trick to get it out."
The researchers must still find a way to insert a gene into the cell to make the engineered insulin, a point at which many early lab successes in gene therapy have broken down in clinical trials. Sometimes it has come with disastrous results, as in a study at the University of Pennsylvania in which patients undergoing gene therapy became severely sick or died.
MCG neurosurgeon and gene-therapy researcher James Fick used an approach similar to that of the ARIAD researchers in battling a deadly and incurable brain tumor called glioblastoma multiforme. The therapy sent in a cell altered to contain a gene from the herpes simplex virus that would then be spread through the tumor; by administering a powerful drug especially effective against herpes, the tumor cells would be killed. That trial was halted by the sponsor when the results didn't live up to expectations, but it remains a promising area of research, Dr. Fick said.
But the ARIAD researchers were able to turn their inserted gene into a ready-made protein engine that would merely need to be turned on, rather than go through the whole process of gene transcription, Dr. Dynan said.
"If you think of a pathway or pipeline of gene expression, they're really turning on the faucet or releasing the protein at the end of that pipeline," Dr. Dynan said.
"It's all about the delivery of genetically engineered cells, not the delivery of genes," Dr. Fick said.
The news is encouraging for those who treat diabetics, including medical endocrinologist Ian Herskowitz at University Hospital. And there is encouraging news from other types of gene therapy research, Dr. Herskowitz said.
"A lot of us feel that the next step in managing diabetes will involve molecular biology and using those techniques to convert some of the pancreatic cells into insulin-producing cells," or islet cells, Dr. Herskowitz said. "But any time you're altering the cell mechanism there is some risk."
And the safety and effectiveness must still be replicated in higher animals and then humans, Dr. Herskowitz said.
Insulin-dependent diabetics wanting to trade their needles in for a pill may yet get good news this year: Inhaled insulin is showing good results in clinical trials and could go up for approval by the Food and Drug Administration by the end of the year, Dr. Herskowitz said.