Scientists have developed new drugs that may halt the brain-destroying impact of a genetic mutation behind some forms of Lou Gehrig's Disease and dementia.
Johns Hopkins scientists used neurons they created from stem cells known as induced pluripotent stem cells (iPS cells).
These were derived from the skin of people with Lou Gehrig's Disease, also known as amyotrophic lateral sclerosis (ALS), who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.
"Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials," said Jeffrey D Rothstein, a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the study.
"But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It's individualised brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology," he said.
Scientists in 2011 discovered that more than 40 per cent of patients with an inherited form of ALS and at least 10 per cent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene.
In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times.
Rothstein used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the "repeats" were causing the brain cell death characteristic of ALS.
In experiments, researchers found that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted.
The C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.
To counter this effect, the researchers developed a number of chemical compounds targeting the problem.
The compounds behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.
Rothstein said Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing in human ALS patients with the C9ORF72 mutation in the next several years.
The findings were published in the journal Neuron.
