1800 244 735

Helpline (02) 9874 9777

Focused drug screening leads to improved drugs to increase the rate of cellular recycling

Recycle Sign

Build-up of unwanted chemicals in cells is one way the HD mutation causes damage to neurons. A cellular recycling process called autophagy is crucial to getting rid of these harmful chemicals. Now researchers have found a way of identifying safe drugs that can increase the rate of garbage disposal in HD.

Autophagy

A large body of work indicates that a process in cells called autophagy is important in HD. Autophagy literally means self-eating, and it’s a process by which cells digest bits of themselves that are damaged, or that they no longer need. It ensures that the building blocks of the cell are efficiently recycled and can be used to support healthy growth.

In HD, scientists know that the mutant huntingtin protein builds up in cells. Eventually, this accumulation results in clumps, or aggregates, that can be seen microscopically in the brains of patients who have died of HD. These aggregates aren’t present in normal brains, and have been taken to suggest that there’s something wrong with the cellular recycling bin in HD.

There are molecules that cause the autophagy pathway to become more active, increasing the rate at which cellular parts are recycled. Some scientists have suggested that this might help HD. By cranking up the rate at which cells clean up proteins, we might help clear out the mutant huntingtin protein before it causes too much damage. The group of researchers led by David Rubinsztein, at the University of Cambridge, has been most active in this area and shown that molecules that increase autophagy improve the symptoms of HD animals such as mice.

But the compounds that do this are ‘dirty’ drugs, meaning that though they do what they’re supposed to do, they also have a number of other effects. In reality, all drugs are ‘dirty’, but drug development is all about making them as clean as we can to reduce side effects.

As an example, the drug most widely used by scientists to increase autophagy is called rapamycin, which powerfully suppresses the immune system. This wouldn’t be an acceptable side effect for an HD drug, because people might be taking these drugs for a long time. Side effects that are acceptable in a short-term cancer drug would not be OK for an HD treatment that’s going to be taken for life. Several groups of scientists, including David Rubinsztein’s and that of Junying Yuan at Harvard Medical School, have been working to develop autophagy drugs that have fewer side effects than rapamycin.

Drugs in brain cells

Another consideration when developing drugs is that the particular brain cells we’d like to rescue in HD – neurons – are very different from other types of cells. While blood and skin cells might live for a couple of days, neurons never divide. We have virtually the same neurons we were born with, and they’re irreplaceable. This means that neurons have very different challenges to face than regular cells. Much of the previous work on the authophagy pathway has been done in skin or cancer cells, which probably work very differently from neurons.

But neurons are expensive and difficult to grow in culture dishes, and not many groups have the expertise to do it well. This is where Steve Finkbeiner, at the University of California San Francisco, comes in. Finkbeiner’s team has been trying to figure out whether neurons handle autophagy differently from other cells.

Finkbeiner’s team used mouse neurons to let them rapidly test autophagy molecules in the right kind of cell. This process of testing lots of different molecules is called drug screening. Starting with a drug they suspected would increase autophagy (called ‘10-NCP’), they confirmed that they could measure when autophagy was increased in neurons.

Drug development

Starting with this molecule they knew was effective, Finkbeiner did some sophisticated drug development to search for new molecules that might have similar effects. By making educated guesses about which parts of the drug were causing the increased autophagy, and screening drugs with similar shapes, they were able to come up with a list of drugs that were effective in neurons.

Most interestingly, for this study they used a set of drugs that are already approved by the FDA for various indications. By using drugs that have already been approved, we can save a lot of drug development time. Research like this is called translational because it helps convert progress in laboratory research into treatments for patients.

The end result of this study is that we have a list of drugs that increase the autophagy pathway in neurons. These drugs may or may not be effective in treating HD in humans, but Finkbeiner and his team have shown that the drugs do what we want them to, they work in neurons and they’ve already been shown to be safe. This will make subsequent studies more informative when they do happen.

Share on facebook
Share on twitter
Share on pinterest
Share on email

Latest Research Articles

Updates from the EHDN Plenary Meeting 2020

Published date: 8 January, 2021

In September, the European Huntington’s Disease Network (EHDN) hosted a virtual webinar event which comprised presentations on some of the latest scientific research as well as clinical studies of Huntington’s disease (HD). Researchers, doctors, patients and other interested folks, tuned in for an afternoon of talks as well as question and answer sessions to learn ... Read more

Uncovering the dark side of DNA repair to design HD treatments

Published date: 22 December, 2020

A gene known as ‘MSH3’, which encodes a protein involved in fixing and maintaining our DNA, has become a hot topic in Huntington’s research since being implicated as a key driver of the disease by multiple genetic studies. In a recent publication, a team of scientists from the National University of Ireland, Galway, have provided ... Read more

Huntington Study Group (HSG) 2020 Annual Conference: HD in Focus – Day 2

Published date: 1 November, 2020

The second day of the HSG conference was another busy day of presentations from HD researchers and clinicians. The day kicked off with a talk from Vaccinex who gave us an overview of their work on the SIGNAL clinical trial. Unfortunately, pepinemab, the medicine tested in this trial, did not influence HD symptoms and the ... Read more

Huntington Study Group (HSG) 2020 Annual Conference: HD in Focus – Day 1

Published date: 30 October, 2020

The Huntington Study Group (HSG) is a clinical research network focused exclusively on HD. Yesterday the HSG annual conference began with a schedule jam-packed with virtual talks from researchers, clinicians and different companies who are all working towards finding new medicines for HD. The day encompassed many interesting presentations which covered a lot of the ... Read more

Treatment for neurological disorder could be repurposed for Huntington’s disease patients

Published date: 22 October, 2020

While developing a drug called branaplam for patients with SMA, the pharmaceutical company Novartis discovered that it could hold promise for people with HD. The FDA has granted a special status called Orphan Drug Designation to branaplam. An existing drug…for huntingtin lowering? The pharmaceutical company Novartis has announced that the U.S. Food and Drug Administration ... Read more

Sad news from the SIGNAL study: pepinemab does not influence HD symptoms

Published date: 23 September, 2020

The SIGNAL clinical trial was designed to test a drug called pepinemab in people with early Huntington’s disease. The key results of that trial were recently announced, and unfortunately, pepinemab did not slow or improve HD symptoms as hoped. What was the SIGNAL trial, and who participated? The SIGNAL trial was launched in 2015 by ... Read more