Scientists may have figured out a solution to treating ALS, which currently has no cure.,
Ice Bucket Challenge: Scientists may have figured out a solution to treating ALS, which currently has no cure.Getty Images

Scientists at Thomas Jefferson University have discovered that blocking certain types of proteins in the brain may help drugs that have so far failed to treat Amyotrophic lateral sclerosis (ALS) to be able to work.

ALS is a neurodegenerative disease that kills motor neurons and leads to paralysis and death between two to five years after the condition has been diagnosed. At present, there is no cure.

You might know ALS, also known as Lou Gehrig's Disease or motor neurone disease, from the popular Ice Bucket Challenge global charity fundraising drive that went viral earlier this year. Stephen Hawking has suffered from this disease for 51 years.

In the brain, there are certain proteins responsible for removing toxins and pumping them out to the lymph system.

Unfortunately, in ALS patients, these pumps work overtime and pump the ALS drugs out of the brain too, which is why a majority of ALS drugs fail to work despite promising early-stage research.

"Drug resistance via these types of cellular drug-pumps is not new. In fact, drug companies routinely check novel compounds for interactions with these transporter proteins, but they typically check in healthy animals or individuals," said co-senior author Dr Davide Trotti, an associate professor of neuroscience and co-director of the Weinberg Unit for ALS research at Jefferson.

Blocking pumps in mice infected with ALS

Currently there is only one drug in the world, called Riluzole, that is approved for treating ALS. Riluzole works by suppressing the activity of glutamate – a chemical messenger in the central nervous system.

Glutamate is released in nerve impulse transmissions, and too much of this compound causes brain and spinal cord nerve damage.

Unfortunately, Riluzole has been shown to lose its effectiveness in patients as the disease progresses, and it only prolongs the lives of ALS patients for between three to six months.

The researchers decided to analyse the brains of mice infected with ALS, instead of analysing healthy animals. They identified two specific pumps in the brain that interact with Riluzole, namely P-glycoprotein (P-gp) and breast-cancer resistant protein.

When they blocked these two types of proteins by treating the mice with an experimental compound called Elacridar together with Riluzole, the scientists found that the treatments extended the life span of the mice and alleviated some of the disease's symptoms, such as improving and preserving muscle strength.

"The fact that Elacridar is selective may explain why we didn't see obvious side effects: other transporter proteins in the brain were still active and removing toxins. We simply plugged the ones that allowed Riluzole to leak out," said co-senior author Dr Piera Pasinelli, an associate professor of neuroscience who works with Trotti to direct the Weinberg Unit for ALS Research.

Revisiting "failed" ALS drugs

The researchers' findings, published in the latest issue of the journal Annals of Clinical and Translational Neurology, mean that other ALS drugs which did not make it to market could be revisited.

The reason that many ALS drugs seem to fail, despite seeming to work initially, could be due to the fact that as the disease increasingly attacks and damages motor neurons, the brain creates more pumps to try to fight back and remove the damaged neurons, thus removing the ALS drugs with greater efficiency.

"The research paves a way for improving the efficacy of an already ALS approved drug, if the findings hold true in human clinical trials," said Pasinelli.

"But more importantly it also sheds light on a basic pathological mechanism at play in ALS patients that might explain why so many treatments have failed, and suggests a way to re-examine these therapies together with selective pump-inhibitor."