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Potential treatment for inherited dementia

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A new drug has successfully treated Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in mice.

C9 ALS/FTD is one of the most common inherited forms of ALS, also known as Lou Gehrig’s disease, and frontotemporal dementia.

A collaboration led by scientists at Scripps Research in Florida has successfully treated the genetic disease in mice with a drug molecule engineered in the lab of chemist Matthew Disney, PhD.

The compound works by directing the cell’s own immune machinery to degrade and eliminate the disease-causing RNA.

Disney’s team designed a compound that targeted the RNA that causes the disease. The compound causes an interaction between the RNA and pathways that a cell uses to eliminate RNAs.

The compound eliminated 70 per cent of the toxic protein fragments from mice bread to have the disease, and removed most hallmarks of the disease from the patient-derived nerve cells.

Scripps graduate Jessica Bush, the paper’s first author, said a single injection in the mice showed benefit through the entire length six-week length of the study period.

She said: “I think that it’s so exciting that we can look at a disease like ALS, and by taking a different approach or new perspective, we can open the door to a whole new world of possibilities, and start down the road toward therapies.”

AALS causes progressive loss of motor neurons, the elongated nerve cells that connect muscles to the central nervous system. As motor neurons die, paralysis, muscle loss, swallowing and eventually, breathing difficulties develop, leading ultimately to death. Scientists are learning that ALS has multiple causes, some of them sporadic, and some inherited or familial.

Frontotemporal dementia similarly has both familial and sporadic causes. It involves progressive damage to neurons in the brain’s frontal and temporal lobes. Symptoms may include difficulty walking or odd behavioral and emotional states. Like ALS, there is no cure for frontotemporal dementia.

While people with FTD appear outwardly to have a completely different illness than people with ALS, those whose condition is caused by the C9 genetic repeat have the same disease. Manifestations differ according to cell types affected. The more times the sequence repeats, the earlier and more severe the disease symptoms.

Disney designed the compound by applying 15 years of his group’s research on finding druggable structures on RNA, a notoriously changeable and transient molecule, and building a library of compounds able to bind those druggable structures.

The successful compound works by binding tightly to the disease-causing RNA in multiple places, while also attracting an enzyme that eliminates RNAs. Nature apparently created the degrading enzyme to defend cells from viral infection and provide quality control for protein production.

However, Disney said moving the technology forward to where it can be tested in humans requires a large number of additional tests and refinements, a process that may take several years.

He said: “This is a disease that runs in families. Based on the number of repeats, doctors can assess whether a patient would be affected with the disease.

“So, you know before a patient has symptoms that they have a high likelihood of developing it, and yet there is no treatment. That makes it even more imperative to develop strategies to that could create a medicine.

“We co-opt a natural process to eliminate disease-causing RNA. A full analysis of the RNAs in the cells treated with the compound showed it was very specific and selective.

“These studies, we hope, will advance new ways of targeting the RNA that causes ALS as well as other diseases. There is a possibility here to eventually treat these patients before they develop symptoms, but it will be a long road before reaching the clinic.”

The team’s study is published Wednesday in the journal Science Translational Medicine.

Collaborators include Leonard Petrucelli, PhD, of the Mayo Clinic in Jacksonville, and Jeffrey Rothstein, MD, PhD, of Johns Hopkins University in Baltimore.

Photo credit: Jessica Bush, Disney Lab at Scripps Research

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