Using brain cells grown from skin to find new potential drugs

Researchers in Oxford are using pioneering stem cell techniques to understand the earliest problems that occur inside brain cells in Parkinson’s — and hunt down new drugs that can tackle them.

An experimental drug, tasquinimod, originally developed for prostate cancer has exciting potential for treating Parkinson’s according to research published today in Cell Stem Cell.

The findings suggest that tasquinimod works by interacting with a key protein inside brain cells called HDAC4 which controls the activity of genes that may play a vital part in the development of Parkinson’s.

What the researchers did

The team at the Oxford Parkinson’s Disease Centre used cutting-edge techniques to grow dopamine-producing brain cells, just like those found in the brain, from skin cell samples donated by people with of the most common genetic forms of Parkinson’s (caused by a mutation in the GBA gene) and from healthy people of similar age without the condition.

Brain cells grown from people with a GBA mutation gradually develop problems that we know occur in the brain — so now researchers can study cells in the lab in extraordinary detail to help us understand where and how the trouble starts, and give us clues as to where we may be able to intervene.

Ultimately the cells go on to develop problems in a range of key areas that are believed to play a part in the damage that occurs in the brain in people with Parkinson’s. These include:

• Problems manufacturing proteins — the endoplasmic reticulum (ER) is a complex structure inside cells that plays a crucial role in making proteins and folding them into the right shape. Studies have suggested that in Parkinson’s the ER becomes stressed and may be the source of the misfolded proteins that accumulate inside affected cells.
• Problems recycling waste — brain cells affected in Parkinson’s also seem to have problems with ‘autophagy’, a process that helps cells clear out unwanted material. And the same issue affects the dopamine-producing cells grown in this study.
• Increased alpha-synuclein release — finally and crucially, the cells grown in the lab also started releasing the protein alpha-synuclein. This protein has long been believed to be a key player in Parkinson’s, forming sticky bundles inside affected cells. Recent studies suggest that alpha-synuclein released from affected cells may be able to enter neighbouring healthy cells, causing problems to spread throughout the brain.

Targeting where the trouble starts

But by the time cells are struggling with all these problems it may well be too late to save them.

So in this study the team used RNA sequencing techniques to look for differences in gene activity between cells with the GBA mutation and those from healthy volunteers before any significant problems developed.

They spotted that the activity of a number of important genes became reduced — suggesting that they may lie at the heart of the crucial very early stages of problems inside the Parkinson’s cells.

And when they investigated further they realised these key genes were all controlled by one important regulatory protein called Histone deacetylase 4 or HDAC4.

In healthy brain cells, the HDAC4 protein floats around freely in the cytoplasm — the jelly-like fluid that fills our cells. But when cells become stressed, HDAC4 moves into the nucleus — the control centre of the cell where the DNA lives where it interacts with genes and affects their activity.

Professor Richard Wade-Martins who co-led the team at the Oxford Parkinson’s Disease Centre explains more:

“Our results pinpoint HDAC4 as a ‘master regulator’ of a whole host of genes whose activity becomes dampened in our patient brain cells. We think that the loss of activity in these genes may play a vital early role in exacerbating problems that lead to cell damage and death, so finding a way to correct their activity could be an important new avenue for developing new treatments for Parkinson’s.

“We tried using a number of different drugs in our brain cells in the lab that we knew interacted with HDAC4 and we were very excited that tasquinimod was able to move HDAC4 out of the nucleus and restore gene activity to normal.

“Most importantly, treatment with tasquinimod was able to completely prevent the problems with protein manufacture, recycling and alpha-synuclein that we saw in untreated cells, giving us hope that it could stop the development of the damage that occurs in real Parkinson’s cells inside the brain.”

Do these findings hold true for other forms of Parkinson’s?

It’s important to point out that this study was conducted using cells grown from people with a mutation in a gene called GBA which is a relatively rare form of Parkinson’s. To find out whether the results and the role of HDAC4 hold true the team have begun studying brain cells grown from people with the more common, non-genetic form of the condition.

Richard explains further:

“We’ve only studied brain cells from eight individuals so far so it’s early days but interestingly it seems that some people with ‘regular’ Parkinson’s do seem to have the same pattern of gene activity and HDAC4 in the nucleus as we see in our genetic brain cells — however others don’t. This may mean that targeting HDAC4 with tasquinimod or other drugs will work for some people with Parkinson’s and not for others.

“We still need to study this further in brain cells from more people to understand this better and we also plan to start looking at the effects of tasquinimod in mice with genetically-induced Parkinson’s. Our aim is to do this as rapidly as possible, and hopefully move towards testing tasquinimod in people with Parkinson’s.”

Could tasquinimod be a future treatment for Parkinson’s?

Tasquinimod was originally developed to block the growth of new blood vessels to the cancer to stop the cancer from growing. It has been tested in international phase 3 clinical trials in men with prostrate cancer.

Results from these trial suggested that tasquinimod was generally safe although can cause side effects including sickness, tiredness and decreased appetite. However, because treatment did not increase the length of time men lived it was not taken forward to become an approved drug for prostate cancer.

Tasquinimod is now being tested in other types of cancer but this is the first suggestion that it could also have potential for Parkinson’s.

Because tasquinimod has already been extensively tested in clinical trials for cancer we know a lot about it’s safety and that means the road to potentially testing it in people with Parkinson’s could be much shorter than with a brand new drug.

There are still important questions to answer to understand more about the potential of this drug for Parkinson’s, including:

• Does tasquinimod have potential for everyone with Parkinson’s or only those with a GBA mutation?
• Does the drug reach the brain in sufficient quantities to have beneficial effects on the dopamine-producing cells affected?
• What kind of dose might be needed? Is this within a safe and acceptable range?
• Does the drug interact with or affect regular Parkinson’s medications?

And if tasquinimod doesn’t have quite the right attributes to progress into trials for Parkinson’s, it could still provide the template for developing similar molecules that do tick all the boxes.