A therapeutic strategy targeting a specific genetic mutation that causes a common form of amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease, as well a type of frontotemporal dementia (FTD) has been designed by an international team led by scientists from the Florida campuses of The Scripps Research Institute (TSRI) and the Mayo Clinic.
The scientists developed small-molecule drug candidates and showed they interfere with the synthesis of an abnormal protein that plays a key role in causing both diseases. The team also developed biomarkers that can test the efficacy of this and other therapies.
The study, led by Professor Matthew Disney of TSRI and Professor of Neuroscience Leonard Petrucelli of the Mayo Clinic, was published online ahead of print August 14, 2014 in the journal Neuron
"Our small molecules target a genetic defect that is by far the most major cause of familial ALS, and if you have this defect you are assured of getting ALS or FTD," Disney said. "Our findings show for the first time that targeting this mutation with a small-molecule drug candidate can inhibit toxic protein translationand establishes that it could be possible to treat a large number of these patients, but this is just the start of these studies and additional investigations need to be done."
Currently, ALS is usually fatal two to five years after diagnosis, and there is no effective treatment for FTD, a neurodegenerative disease that destroys neurons in the frontal lobes of the brain.
The mutation that can cause both diseases affects a gene known as C90RF72 and involves a repeat expansion, a longer than usual repetitive genetic sequence. This results in abnormal strands of RNA and the production of toxic "c9RAN proteins."
Disney and his Scripps Florida colleagues initially designed three small-molecule drug candidates that decreased RNA translation or production of these toxic proteins in cell culture. The Mayo team developed the patient-derived cell models in which to test the compounds and the biomarker to assess compound activity. Both teams then worked together to show that the lead agent's mode of action was targeting the toxic RNA, binding to and blocking the toxic RNA's ability to interact with other key proteins.
Two of the compounds significantly decreased levels of the toxic protein. Using a series of increasing dosages of the drug candidates, the scientists found that the highest dosage of one reduced the toxic protein by nearly 50 percent.
The scientists also discovered that c9RAN proteins produced by the abnormal RNA can be measured in the spinal fluid of ALS patients. They are now evaluating whether these proteins are also present in spinal fluid of patients diagnosed with FTD.
"A decrease in the levels of toxic proteins in cerebrospinal fluid in response to treatment would demonstrate the drug is working," Petrucelli said. "While additional studies must be done, this finding suggests that these proteins may provide a direct means to measure a patient's response to experimental drugs that target abnormal RNA."
Toxic proteins found in spinal fluid could also become an enrollment tool in human clinical trials, added Disney, who was enthusiastic about the collaboration with the Mayo Clinic and the larger team. "Our collective biological and chemical expertise made this research possible," he said. "This is just the beginning of what we can do together."