Miércoles 20 de Junio de 2007, Ip nº 195

Stem cell genes may provide medicine's dream ticket
Por Peter Aldhous Seattle

GENE therapy meets stem cells. That is the wave of the future, if the recent annual meeting of the American Society of Gene Therapy in Seattle is any guide. There was a palpable buzz around efforts to correct diseases by targeting therapeutic genes to stem cells already resident in the body.

Clinical trials are on the horizon for treatments for diabetes and a group of fatal neurodegenerative conditions called lysosomal storage diseases. Meanwhile, gene therapists are also using their skills to make "improved" stem cells for regenerative therapies (see "Stem cell enhancement"). "If you look at what is happening today and what is in the pipeline, I think genetic modification of stem cells is going to be a major theme," says Luigi Naldini of the San Raffaele Telethon Institute of Gene Therapy in Milan, Italy.

Stem cells have obvious appeal as targets for gene therapy, in which genes are inserted into an individual's cells in order to treat a disease. Once modified to carry a therapeutic gene, stem cells should continue to divide as normal, replenishing themselves and producing specialised daughter cells that will carry the same gene. By contrast, most other cells have a limited lifespan and capacity for division - one reason why gene therapists have so far struggled to achieve effective and lasting treatments.

Indeed, the most conspicuous success of gene therapy to date - the treatment of children with a severe inherited immune deficiency - was achieved by correcting genetic defects in blood-forming stem cells in their bone marrow. Now gene therapists are focusing on other types of stem cells and different diseases.

Among the most promising examples in Seattle was a therapy for type 1 diabetes based on modifying stem cells in the gut. People with type 1 diabetes are unable to regulate their blood sugar because their immune system destroys beta cells in the pancreas, which secrete insulin. The disease can be treated with insulin injections, but it is hard to mimic the body's precise regulation of insulin levels in response to glucose.

What's needed, says Anthony Cheung of enGene, a biotech company in Vancouver, Canada, is a type of cell that is sensitive to glucose and which can be engineered to produce insulin. K cells, which are found in the upper part of the small intestine, are good candidates as they produce a hormone called GIP in response to glucose in the gut. GIP sends a message to the pancreas that food is coming, priming the production of insulin. If K cells could be engineered to produce insulin themselves, they would cut out the middleman and deliver the hormone when it is needed.

The problem is that individual K cells live for only about a week before they are sloughed off into the gut. So enGene needed to deliver the gene for insulin to the stem cells that continually give rise to new K cells.

The company has now cracked this, using nanoparticles of a polysaccharide called chitosan, found in shrimp shells, to deliver the genes to the cells. The nanoparticles carry two loops of DNA called plasmids, one bearing the gene for human insulin, the other encoding an enzyme that can insert the insulin gene into a cell's genome. After a single dose of nanoparticles, animals produced human insulin for more than 130 days. "We're looking to move this into clinical trials by early 2009," says Cheung.

Because some stem cells are only accessible for modification during a narrow window of embryological development, a few groups are experimenting with in utero gene therapy to correct inherited diseases such as some forms of breast cancer. Jesse Vrecenak and her colleagues at the Children's Hospital of Philadelphia in Pennsylvania have modified the stem cells that form breast tissue by injecting lentiviruses that carry a marker gene into the amniotic fluid of pregnant mice. Eventually, this may enable carriers of the breast cancer genes BRCA1 and BRCA2 to bear children with healthy copies of the genes in their breast tissue.

Meanwhile, other researchers are working on ways to extract stem cells from the body, genetically modify them in the lab, and then return them to exert a therapeutic effect.

At the San Raffaele Telethon Institute, Alessandra Biffi and her colleagues are planning a clinical trial using modified bone marrow stem cells to treat metachromic leukodystrophy, or MLD. This is a lysosomal storage disease (LSD) in which toxins called sulphatides build up in the brain, and nerves lose their insulating layer of myelin. Children with severe forms of MLD go into a steep cognitive decline and lose motor control, usually dying before the age of 10.

The disease is caused by defects in the gene for an enzyme called ARSA. In experiments on mice, Biffi's team has shown that stem cells from the bone marrow can be modified to boost the production of ARSA and correct MLD. The stem cells give rise to immune cells called microglia, which migrate to the brain. "You can really generate a shuttle for your enzyme into the nervous system," Biffi says. Early next year, she will begin recruiting children with severe MLD into a clinical trial of the therapy.

Biffi's colleague Angela Gritti is also concentrating on LSDs, but she is adding genes for therapeutic enzymes to neural stem cells, which can give rise to new brain tissue. For some LSDs, Gritti believes they may need to modify both blood-forming and neural stem cells. "We also need a high degree of tissue repair," she says.

Neural stem cells also have some subtler therapeutic effects. Evan Snyder's team at the Burnham Institute for Medical Research in La Jolla, California, has delayed the onset of symptoms in a mouse model of an LSD called Sandhoff disease by injecting healthy human neural stem cells into the mice's brains. As well as providing the missing enzyme, the stem cells also had an anti-inflammatory effect, further protecting the brain.

While the idea of using stem cells to rebuild diseased tissues grabs most attention, Snyder predicts that their ability to deliver corrective genes and to protect other cells from damage will have a bigger impact in the future. "The low-hanging fruit are these molecular therapies," he says.

  13/06/2007. New Scientist Magazine.