Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may hold the key to finding a treatment for Rett Syndrome, a severe autistic disorder that affects young girls.
The Connecticut-based Rett Syndrome Research Trust (RSRT) has sponsored work to identify a number of targetable genes that act on the Rett gene, MECP2 (methyl-CpG-binding protein 2), in mice. Results of the
MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes. This was well known to be linked to Rett Syndome, which affects about one in 10,000 girls in Western countries, causing them to lose speech, mobility and use of their hands while still toddlers.
Many girls also suffer seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood but require round-the-clock care.
The study’s senior author Professor Monica Justice – from the departments of molecular and human genetics, and molecular physiology and biophysics at Houston’s Baylor College of Medicine – decided to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease.
This does seem possible: in 2007, Prof. Adrian Bird – Buchanan professor of genetics at the Wellcome Trust centre for cell biology at the University of Edinburgh – showed that Rett symptoms in mice were reversible regardless of the age of the animal.
Since then, exploring cholesterol metabolism has become an emerging area in neurological diseases, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But cholesterol had not been on the radar for Rett Syndrome – until now.
Prof. Monica Justice said:
“Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one.”
The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.
Prof. Monica Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring whose genes made them liable to develop the syndrome but who remained healthy.
The most drug-targetable gene they found was squalene epoxidase (Sqle), which is linked to the cholesterol biosynthetic pathway.
“Frankly, this discovery was a surprise,” Prof. Monica Justice said, noting that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.
The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. However, the drugs did not improve breathing.
First author Christie Buchovecky, a Baylor graduate student, said:
“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.”
With additional RSRT funding, pediatric neurologist and director of the Tri-State Rett Syndrome Center in New York, Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome.
She has found that some young Rett sufferers have elevated cholesterol levels that normalize as they grow older. These data are not included in the published study but will be part of a subsequent paper, based on clinical trial.
Prof. Monica Justice says a series of carefully designed and rigorously executed clinical trials are essential to determine if the mice results will also apply to girls with Rett Syndrome. These should also determine ways to identify which girls are most likely to respond to statins, which drugs to trial and what dosages are effective without being toxic.
Dr. Sasha Djukic also counsels caution.
“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,” Dr. Sasha Djukic adds. “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.”
Prof. Monica Justice says the biggest finding from the study is the discovery that the cholesterol pathway is so important to the pathology of Rett Syndrome.
“Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic,” Prof. Justice said.
“Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”