Girls are supposed to have fun. Well, they do, until Rett’s Syndrome attacks. Imagine a little girl humming a song while combing her Barbie’s hair. All of a sudden, a blank stare eclipses her face. Her body is as stiff and immobile as her doll, both lying parallel to each other on her bedroom floor. Seizures are an unwelcomed guest to the tea parties she hosts with her dolls. Her excessive, non-stop hand wringing has been set to a routine that’s timed better than a newborn’s sleeping schedule.
It breaks her parents’ hearts to see her suffer through the difficult symptoms of Rett’s syndrome. With about 1 in 10,000 children a year born with this condition, many parents are all too familiar with this scenario.
The girls who suffer from Rett’s have become the damsel in distress. The mutated genes, MECP2 (methyl CpG-binding protein) parade around like menacing warriors, “regulat[ing] the activity of many other genes, switching them on or off,” subjecting her to physiological changes.
But Dr. Gail Mandel, a Howard Hughes Investigator at Oregon Health and Sciences University has discovered a Trojan horse that may save the girls who have become Rett’s Helen of Troy.
In the article it states how gene therapy can make more progress than drug intervention, which cannot pinpoint a specific gene to have any effect on the syndrome:
Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist. Dr. Mandel used adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier. This allows the virus and its cargo to be administered intravenously, instead of employing more invasive direct brain delivery systems that require drilling burr holes into the skull.
After injecting a modified MECP2 gene into female mice, Dr. Mandel found the following results:
As in human females with Rett Syndrome, only approximately 50% of the mouse cells have a healthy copy of MECP2. After the gene therapy treatment 65% of cells now had a functioning MECP2 gene.
The treated mice showed profound improvements in motor function, tremors, seizures and hind limb clasping. At the cellular level the smaller body size of neurons seen in mutant cells was restored to normal. Biochemical experiments proved that the gene had found its way into the nuclei of cells and was functioning as expected, binding to DNA.
Although there were many advantages gained to this experiment, Dr. Mandel still has some major hurdles to cross. She has to determine a way to make improvements in abnormal respiration. She explains,
“Our study is an important first step in highlighting the potential for AAV9 to treating the neurological symptoms in Rett. We are now working on improving the packaging of MeCP2 in the virus to see if we can target a larger percentage of cells and therefore improve symptoms even further,” said Mandel.
Many parents including Monica Coenraads, Executive Director of the Rett Syndrome Research Trust, are optimistic about future clinical trials paving the way for the intervention to be available for use.
Our goal now is to prioritize the next key experiments and facilitate their execution as quickly as possible. Gene therapy, especially to the brain, is a tricky undertaking but I’m cautiously optimistic that with the right team we can lay out a plan for clinical development.
Girls will be awaiting this assistance, too, so they can worry themselves about whom Barbie will drive around in her Corvette instead of the next uncontrollable body movement.
*First pre-clinical gene therapy study to reverse Rett symptoms.” Medical News Today. August 22, 2013. http://www.medicalnewstoday.com/releases/265074.php