For the first time, researchers have successfully constructed a strategy targeting a specific genetic mutation that causes amyotrophic lateral sclerosis and a type of dementia. And the exciting news is that their findings show it may be possible to treat a large number of patients who have these two diseases.

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Both ALS and FTD involve degeneration of neurons in the brain.

Amyotrophic lateral sclerosis (ALS) – also known as Lou Gehrig’s disease – has been in the news and social media as of late. The widespread “ice bucket challenge” – in which nominated people dump ice water on themselves in a video to raise money for the disease – has included celebrities such as Martha Stewart, Matt Lauer and Lance Bass.

ALS is a progressive neurodegenerative disease that impacts nerve cells in both the brain and spinal cord. With this disease, an individual progressively loses voluntary muscle action and may eventually become completely paralyzed.

Frontotemporal dementia (FTD) is similar, in that it is also a neurodegenerative disease through which neurons in the frontal lobes of the brain are destroyed.

Both diseases involve a mutation in a gene called C90RF72, and it involves a repeat expansion – a longer-than-usual repetitive genetic sequence. The resulting effect is that abnormal RNA strands are formed and toxic “c9RAN proteins” are produced.

The researchers, from the Florida campuses of The Scripps Research Institute (TSRI) and the Mayo Clinic, have developed small-molecule drug candidates and were able to show how they interfere with the abnormal protein involved in causing both diseases.

Lead author Prof. Matthew Disney, of TSRI, says:

”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. Our findings show for the first time that targeting this mutation with a small-molecule drug candidate can inhibit toxic protein translation.”

He adds that their findings establish “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.”

Results of their study are published in the journal Neuron.

In a prime example of collaboration, the researchers from TSRI first designed three small-molecule drug candidates that decreased RNA translation or creation of the toxic proteins in a cell culture. Then, the Mayo team created the cell models derived from patients in which they could test the compounds and the biomarker to observe the compound’s activity.

Fast facts about ALS
  • Early symptoms include muscle weakness involving the arms, legs, speech, swallowing or breathing
  • Around 5,600 people in the US are diagnosed with ALS each year
  • About 20% of people diagnosed with ALS live 5 years or more, and up to 10% will survive more than 10 years, though average life expectancy of an ALS patient is 2-5 years from diagnosis.

The two teams then worked in tandem to show that the main agent was targeting the toxic RNA by binding to and blocking its ability to mingle with other important proteins.

The team found that two of the three compounds dramatically decreased levels of the toxic protein, eventually discovering that the highest dosage reduced the toxic protein by almost 50%.

Additionally, they found that the toxic c9RAN proteins can be measured in the spinal fluid of patients with ALS. Further research will reveal whether or not the same holds true for patients with FTD.

“A decrease in the levels of toxic proteins in cerebrospinal fluid in response to treatment would demonstrate the drug is working,” explains co-lead author Prof. Leonard Petrucelli of the Mayo Clinic.

He adds that although further studies need to be conducted, “this finding suggests that these proteins may provide a direct means to measure a patient’s response to experimental drugs that target abnormal RNA.”

Speaking with Medical News Today, Prof. Disney said he and his team are “collaboratively conducting follow-up studies to further develop the compound to enhance potency, selectivity and bioactivity.” He added that they are also doing animal studies for pre-clinical development.

“A lot of work needs to be done. But the initial results appear promising,” he told us.

Medical News Today recently reported on a study that suggested eating foods high in omega-3 fatty acids could reduce the risk of developing ALS.