Many novel therapies are currently being clinically tested in Parkinson’s, and this week we heard the results of one clinical trial which provided some very interesting news.
Intra-Cellular Therapies has been testing their drug, ITI-214 – which is a potent and selective phosphodiesterase 1 (PDE1) inhibitor. Inhibitors of PDE1 prevent the breakdown of protein called cyclic nucleotides (cAMP, cGMP).
The results of the Intra-Cellular Therapies clinical trial suggest that in people with Parkinson’s, the drug not only improves symptoms, but also reduces dyskinesias.
In today’s post we will discuss what PDE1 is, how PDE1 inhibitors work, and what the results of the clinical trial suggest.
Every year in October, the American Neurology Association (ANA) gather in one of the major US cities to share research regarding neurological condtions, like Parkinson’s. And while I did not attend the ANA meeting this year, I was keen to hear the results of one particular clinical study.
It was a trial conducted by a company called Intra-Cellular Therapies.
What is special about ITI-214?
ITI-214 is a Phosphodiesterase inhibitor.
What is a phosphodiesterase inhibitor?
Here at the SoPD we are politically neutral.
That said, we will report on events that directly impact the world of Parkinson’s disease research (without adding any personal opinions). This week a vote took place that may have implications for the Parkinson’s disease research community over the coming year.
Here we will discuss what has happened and what it means for the Parkinson’s research community.
Researchers voting. Source: Science
On the 3rd February, the organising committee of the Commission G2 Massive Stars, part of the International Astronomical Union (IAU) announced that it would not hold any scientific meetings in the United States of America as long as a temporary ban on the entry of any persons from Libya, Sudan, Somalia, Syria, Iran, Iraq, and Yemen, is in place.
This vote was in response to the January 27th signing of Executive Order 13769, which limits the number of refugees arriving in the USA to just 50,000 and suspended the US Refugee Admissions Program (USRAP) for 120 days (after which the program will be resumed with new conditions for individual countries). The order also imposes a temporary travel ban on the 7 countries listed above for 90 days, after which an updated list will be made. Notably the suspension for Syrian refugees is indefinite, but the order allows for exceptions to be made on a case-by-case basis. (Source: Wikipedia).
With just 12,450 individual members (from 74 countries, including Iran), the IAU’s decision is purely a small symbolic gesture. And while their vote has nothing to do with Parkinson’s disease, we note that other scientific research organisations (and many individual scientists) are making/contemplating similar measures/gestures – not simply calls to boycott US-based conferences but also particular scientific journals (for more on this click here).
Of particular importance to the Parkinson’s community is the Society for Neuroscience (SfN) meeting to be held in Washington DC in November of this year (luckily the annual Parkinson’s disease and Movement disorder conference will be held in Vancouver this year). Each year, 30-40,000 scientists and advocates from around the world gather at these SfN meetings to share/discuss novel findings and form new collaborations. A great deal of Parkinson’s research is discussed at these meetings and the associated satellite meetings that take place the week before or after.
The president of the SfN has already issued a press release regarding the executive order (Click here to read that), but many researchers are already pulling out of invited presentations. For example, Adrian Owen, a well-known neuroscientist from Western University (Ontario) publicly announced on twitter that he was refusing an invitation to present a lecture at the meeting in Washington DC:
At the time of publishing this post, a federal appeals court had denied a Justice Department’s request to lift the restraining order and allow the immigration ban to continue. The 9th U.S. Circuit Court of Appeals in San Francisco has asked for the Justice Department to file a counter-response by 3pm Monday (Click here to see that statement), which means that the restraining order remains in place for the next 24 hours at least.
Whether the restraining order is lifted and Executive Order 13769 is brought back into effect is a matter for the courts to decide. The outcome, however, is already having an impact as many scientists symbolically refuse to attend conferences in the US (it will be interesting to see what attendance is this year at the SFN meeting).
We are not going to speculate on the possible consequences of Executive Order 13769, except to say that 2017 may not be a bonanza for US based research conferences. We will be watching events as they unfold and will discuss them here if they relate to the Parkinson’s community.
The banner for today’s post was sourced from ABC News
It is very closely associated with Parkinson’s disease, given that people with genetic mutations in the alpha synuclein gene are more vulnerable to the condition, AND the protein is a key component in the disease-related circular aggregations (called ‘Lewy bodies’) in the brain. Recently researchers have identified proteins that may be involved with the transfer of Alpha Synuclein between cells – the method by which the disease is believed to be spreading. By blocking or removing these proteins, the researchers have been able to block the transfer of alpha synuclein.
In this post, we will review the research and discuss what this could mean for Parkinson’s disease.
Science conference. Source: JPL
At the recent annual Society for Neuroscience conference in sunny San Diego, Dr Ravindran Kumaran, a neuroscientist in the laboratory of Professor Mark Cookson (at the National Institute on Aging in Bethesda, Maryland) stood up and presented data about an interesting protein that few people in the audience had ever heard of.
Title: High-content siRNA screen identifies cellular modifiers of pre-formed alpha-synuclein fibril uptake
Authors: Kumarani R, Fernandez D, Werner-Allen JW, Buehler E, Bax A, Lai-Nag M, Cookson MR.
Source: Click here to see the full abstract
Dr Kumaran and his colleagues had systematically removed the function of each gene – one by one – in cell cultures of human cancer cells, and then measured the efficiency of the cells to absorb (or ‘take up’) the Parkinson’s related protein, alpha synuclein. An absolutely laborious task (remember there are over 20,000+ genes), but when they turned off a gene called TM9SF2, something amazing happened:
The cells absorbed 75% less of the free floating alpha synuclein than normal health cells.
This caused a bit of excitement in the Parkinson’s research community. Here was a potential method of blocking the spreading of alpha synuclein.
The funny thing is: few people had ever heard of TM9SF2, and yet Dr Kumaran then showed that TM9SF2 is in the top 3% of all proteins present in the brain. In fact, the highest concentrations of TM9SF2 are in the substantia nigra and other brain regions that are most affected by Parkinson’s disease.
So you can hopefully understand why some people in the Parkinson’s research community thought that this was a wee bit exciting.
Plus, this data presentation came on the back of another study that was published in September which presented another protein (called Lag3) that exhibited a similar ability to reduce the absorption of alpha synuclein:
Title: Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.
Authors: Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM.
Journal: Science. 2016 Sep 30;353(6307).
In this study, the researchers conducted a screen of 352 proteins that sit on the membrane of cells. They were measuring the level of alpha synuclein binding. They identified three interesting candidates for further investigation, include lymphocyte-activation gene 3 (LAG3), neurexin 1β, and amyloid β precursor-like protein 1 (APLP1).
When the researchers compared the three, they found that by removing LAG3 less alpha synuclein was taken into the cell (by endocytosis) than the other two proteins. In addition, when they increased the amount of LAG3 that a cell produces, they observed a similar increase in the amount of alpha synuclein absorbed by cells.
Next the researchers investigated the transmission of alpha synuclein between brain cells in both normal cells and cells that had no LAG3, and they found not only that LAG3 is required for the transmission, but the absence of LAG3 reduces the damage caused by the transmission.
Finally the researchers used small proteins (antibodies) to bind to and block LAG3, and they observed less transmission and damage caused by alpha synuclein. In their conclusions, the authors pointed out that LAG3 is not the only protein involved with the transmission of alpha synclein – there will be others – but it represents a potential future target for therapeutic intervention in Parkinson’s disease.
So what does this mean?
If the theory of alpha synuclein – that this protein is passed between cells, causing the spread of the disease – is correct, then any agent that can block that transmission should slow down or halt Parkinson’s disease. We have previously talked about vacines and antibodies against alpha synuclein being tested in the clinic (Click here, here and here for more on this), but blocking TM9SF2 and LAG3 represent a new method of preventing the transmission of alpha synuclein. This is very exciting. The more angles of attack that we have for designing a treatment the better our options.
Schematic of how LAG3 may be working. Source: Science
We will be watching the field very closely and will keep you posted as new information comes to hand.
The banner for today’s post is sourced from Keepcalm-o-matic