Just add a chromosome

06/16/04

GENETIC diseases might one day be treated by adding an entirely new chromosome to people's cells. A Canadian company has shown the approach could be a feasible method of gene therapy.

Conventional gene therapy relies on modified viruses to insert the desired bit of DNA into a cell's genome. But viruses can carry only short sequences of DNA. And if the DNA lands in the wrong place, as happened to two boys in a French gene therapy trial, it can trigger cancer. Adding an entirely separate chromosome, however, eliminates this risk. And rather than being limited to one or two small genes, vast chunks of DNA can be added if desired. "For certain diseases it could be very useful to have the ability to deliver multiple therapeutic genes," says Gil Van Bokkelen, chief executive of Athersys in Cleveland, Ohio, one of several teams worldwide trying to develop artificial chromosomes. Most, like Athersys, are trying to create artificial chromosomes from scratch.

Chromos Molecular Systems of Burnaby, British Columbia, has taken a different approach, creating its artificial chromosome by building it up from the key elements of a normal mouse chromosome. This artificial chromosome behaves like a normal one in mice: it is duplicated when cells divide and is passed from generation to generation (New Scientist, 8 July 2000, p 7). Now the company has shown how the chromosome could be used for gene therapy. The researchers started with two cell lines containing the artificial chromosome, and added the gene for the human blood hormone erythropoietin to the chromosome.

Cells with the artificial chromosome carrying the gene were selected and injected into mice. As expected, the animals showed significant increases in their red blood cell counts compared with others injected with cells carrying the artificial chromosome without the added gene. The results will appear in BioProcessing Journal. The hope is that the same approach can be used to treat inherited diseases such as haemophilia. The artificial chromosome carrying the correct version of a gene would be inserted into cells- possibly stem cells- taken from a patient, and the modified cells would then be injected back into the patient. This notion of combining gene therapy with cell delivery is already the focus of about a third of gene therapy trials, says Chromos executive Harry Ledebur. Chromos has engineered its artificial chromosome so that extra sequences can be added in specific locations. A single gene or even multiple genes up to 1.5 million DNA bases long can be added to the chromosome before it is inserted into cells.

One concern might be the fact that the artificial chromosome is derived from mice. Chromos says there is no evidence it contains any undesirable elements such as stray genes. But before Chromos or anyone else can move to human trials, says Huntington Willard of Duke University in Durham, North Carolina, they will have to run a series of rigorous studies to prove that their product is stable and consistently churns out the desired proteins. Recent studies suggest that some of the artificial chromosomes created by other groups might not be as stable as real chromosomes. "Time will tell whether [Chromos's work] stands scrutiny," he says. It will also be important to investigate the consequences of having an extra chromosome, says Bruce Bunnell of Tulane University in New Orleans, who is collaborating with Chromos. "The cell needs to maintain it. What is the long-term outcome of this?" he asks. While companies like Chromos are interested only in gene therapy, their work could have far-reaching consequences.

Some researchers regard artificial chromosomes as the most promising method for germ-line genetic engineering of humans (New Scientist, 3 October 1998, p 24). One day our children might have 47 chromosomes.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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