Researchers have suggested that gene therapy may be one of the options to treat Rett Syndrome, the most disabling of the autism spectrum disorders.
Gail Mandel, Ph.D., a Howard Hughes Investigator at Oregon Health and Sciences University, led study is the first to show reversal of symptoms in fully symptomatic mice using techniques of gene therapy that have potential for clinical application.
Rett Syndrome is an X-linked neurological disorder primarily affecting girls; in the US, about 1 in 10,000 children a year are born with Rett.
In most cases symptoms begin to manifest between 6 and 18 months of age, as developmental milestones are missed or lost. The regression that follows is characterized by loss of speech, mobility, and functional hand use, which is often replaced by Rett's signature gesture: hand-wringing, sometimes so intense that it is a constant during every waking hour.
Other symptoms include seizures, tremors, orthopedic and digestive problems, disordered breathing and other autonomic impairments, sensory issues and anxiety. Most children live into adulthood and require round-the-clock care.
The cause of Rett Syndrome's terrible constellation of symptoms lies in mutations of an X-linked gene called MECP2 (methyl CpG-binding protein). MECP2 is a master gene that regulates the activity of many other genes, switching them on or off.
Mandel said that gene therapy is well suited for this disorder, as MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug.
She said that therefore the best chance of having a major impact on the disorder is to correct the underlying defect in as many cells throughout the body as possible and gene therapy allows them to do that.
Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist.
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.
Because the virus has limited cargo space, it cannot carry the entire MECP2 gene. Co-author Brian Kaspar of Nationwide Children's Hospital collaborated with the Mandel lab to package only the gene's most critical segments. After being injected into the Rett mice, the virus made its way to cells throughout the body and brain, distributing the modified gene, which then started to produce the MeCP2 protein.
As in human females with Rett Syndrome, only approximately 50 percent of the mouse cells have a healthy copy of MECP2. After the gene therapy treatment 65 percent 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.
New research has been published in the Journal of Neuroscience. (ANI)