New study points to statins as a possible treatment in Rett Syndrome
Rett Syndrome is the most physically disabling of the autism spectrum disorders. It strikes at random in early childhood, affecting little girls almost exclusively. Many girls live into adulthood, requiring total, 24-hour-a-day care. Symptoms include loss of speech and motor control, Parkinsonian tremor, disordered breathing and orthopedic abnormalities including scoliosis and fragile bones. There is no treatment beyond supportive, and often ineffective, measures such as feeding tubes, bracing, orthopedic and GI surgeries, and medications for anxiety and seizures. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.
Mutations in a gene called MECP2 (methyl-CpG-binding protein 2) were identified as the cause of Rett Syndrome in 1999.
The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.
The challenge of treating Rett Syndrome is what drove Dr. Monica Justice, PhD., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics, Director Mouse ES Cell Core Facility at the Baylor College of Medicine and senior author of this study, looked beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease.
Professor Adrian P. Bird, PhD, world’s leading expert in the gene MECP2, trustee of the Rett Syndrome Research Trust in February published the landmark paper in Science establishing the principle of reversibility of Rett symptoms in mice, providing the proof-of principle which suggests reversal may be possible in humans.
Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. The research team was looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.
Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, and then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome according to their genes but did not according to the good health of the mice.
Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescue mice did not develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer. However, the drugs did not improve breathing.
Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed.
“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” said Dr. Justice. An important note made was that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.
Cholesterol is of course best known for its negative effects on the cardiovascular system such as atherosclerosis, heart attack and stroke however, the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.
Next the researchers tested the statins fluvastatin and lovastatin on Rett mice. Just like the Sqle mutation, the symptoms had improved. The treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer.
Christie Buchovecky, research assistant, graduate student in the Justice lab and first author of study commented “When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins.”
Dr. Aleksandra Djukic, MD, PhD, Associate Professor of Clinical Neurology and Clinical Pediatrics, Director of the Center for Rett Syndrome which is the only Center for Rett syndrome in the Tri-State area, with additional RSRT funding undertook a detailed review of lipid data in girls with Rett Syndrome. Dr. Djukic discovered that a subset have elevated cholesterol levels which normalize as they age. This data does not currently appear in the published study but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.
Dr. Djukic cautions “Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins.” The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”
In closing Dr. Justice explains “The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome.” “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”
Monica Coenraads, Co-Founder, Trustee, Executive Director of RSRT, and mother of a teenaged daughter with Rett Syndrome, who was diagnosed at age two, commented “I have a special affinity for this project because it’s one that I’ve followed closely from the very beginning. The concept for the modifier screen came from an early morning brainstorming session at a science meeting I organized in 2006. After discussing the feasibility of the project with various investigators, I invited Dr. Justice to submit a proposal. It’s been a rewarding experience to follow the science from the kernel of an idea to the discovery of the first handful of modifiers, one of which, Sqle, is leading to a clinical trial. RSRT is committed to seeing the screen through to completion. Having a comprehensive list of modifiers will likely open more doors to novel treatments. I congratulate Dr. Justice and her colleagues on the publication and thank all of our donors who make this work possible.”
This study appears in Nature Genetics.
Clinical trials on Rett Syndrome can be found online at Clinical Trails.Gov.