Scientists in Oregon have developed a new gene therapy for Rett Syndrome, the most disabling of the autism spectrum disorders. Field-tested in mice, it is the first therapy to reverse the course of the disorder in a fully symptomatic model, which represents an important step towards clinical application.
Nearly one in 10,000 kids are born each year with Rett syndrome. Neurological and behavioral features, like loss of speech, immobility, and seizures, typically appear after six months of age. The most frequent cause is the mutation of an X chromosome gene called MECP2, which explains why girls are primarily affected by the condition.
“Gene therapy is well suited for this disorder,” explained lead author Dr. Gail Mandel, a Howard Hughes investigator at Oregon Health and Sciences University. “Because MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug. 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. Gene therapy allows us to do that.”
In 2007, co-author and British geneticist Adrian Bird discovered that fixing these MECP2 mutations could relieve Rett symptoms in mice, but the genetic trick that he used in his investigation could not be applied to humans.
In the current study, healthy genes were delivered to mutant mice with a microbe called an adeno-associated virus. This virus, which is not harmful to people, has corrected genetic errors in over 100 clinical trials of human disease.
The researchers used a special verision of adeno-associated virus – designated “AAV9” – that has the unique property of being able to penetrate the nervous system’s protective coating called the blood brain barrier. Failing to cross the blood brain barrier is the major impediment for most drugs that flop during the early and late stages of clinical development.
Delivering the corrective genetic material with AAV9 to ailing mice improved motor function, tremors, and seizure. This was witnessed despite the fact that only a few cells received the remedy.
“We learned a critical and encouraging point with these experiments – that we don’t have to correct every cell in order to reverse symptoms. Going from 50% to 65% of the cells having a functioning gene resulted in significant improvements,” said co-author Saurabh Garg. Abnormal respiration was one symptom that was not fixed by the gene therapy, which the authors attributed to lower delivery in the brainstem.
The researchers will work towards enhancing the therapy’s distribution, by slightly tweaking the carrier virus, before they attempt clinical trials in humans.
“Gene therapy has had a tumultuous road in the past few decades but is undergoing a renaissance due to recent technological advances. Europe and Asia have gene therapy treatments already in the clinic and it’s likely that the US will follow suit,” said Monica Coenraads, Executive Director of the Rett Syndrome Research Trust and mother of a teenaged daughter with the disorder. “I congratulate the Mandel and Bird labs on today’s publication, which is the third to be generated from the MECP2 Consortium in a short period of time.”