They say that cats have nine lives. If that’s true then the idea of ‘Gene Therapy’ must be part feline. Despite several hurdles over the years, gene therapy once again captured the spotlight; this time by demonstrating that replacing mutated MECP2 can reverse the symptoms of Rett Syndrome in mice. The new research led by Gail Mandel, a Howard Hughes Investigator at Oregon Health and Sciences University, is the first to suggests this approach may eventually be a feasible clinical option to treat Rett Syndrome, the most disabling of the autism spectrum disorders.
In 2007, co-author Adrian Bird published proof-of-concept that Rett is curable, by reversing symptoms in adult mice, which energized research into the best ways to bring those results into the clinic. The cause of Rett Syndrome’s symptoms lies in mutations of an X-linked gene called MECP2 (methyl CpG-binding protein), a master gene that regulates the activity of many other genes. The concept behind gene therapy is simple: deliver a healthy MECP2 gene to compensate for mutated ones.
“Gene therapy is well suited for this disorder,” Dr. Mandel explains. “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.”
Critical components of the MECP2 gene were delivered into cells aboard a virus, adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier, which provides the benefit of allowing the virus and its cargo to be administered intravenously. Here are some of the results:
- In Rett Syndrome mice (and humans, too), only approximately 50% of the cells have a healthy copy of MECP2. After the gene therapy treatment that rose to 65%.
- Treated mice showed profound improvements in motor function, tremors, seizures and hind limb clasping.
- Smaller body size of neurons seen in mutant cells was restored to normal.
- Biochemical experiments proved that MECP2 was present in the nuclei of cells and was functioning properly, binding to DNA.
“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.
Dr. Mandel cautioned that key steps remain before clinical trials can begin. “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. Collaborators Hélène Cheval and Adrian Bird see this as a promising follow up to the 2007 work showing symptom reversal in Rett mice. “That study used genetic tricks that could not be directly applicable to humans, but the AAV9 vector used here could in principle deliver a gene therapeutically. This is an important step forward, but there is a way to go yet.”
Read more about MECP2 gene therapy in action at The Journal of Neuroscience, August 2013