Stem Cells, PD Genetics, Nicotine, DBS, etc
I attended Dr. William Langston's short presentation at a local Parkinson's Disease (PD) support group meeting on Thursday 11/13. It was billed as an "update on PD research." He spoke for 20 minutes or so, mostly about stem cell transplants, a research grant proposal they've recently handed in, a bit about the role of genetics in PD, the helpful role of nicotine, a little about deep brain stimulation, and two sentences about methylene blue. Dr. Langston is a neurologist and is the head of The Parkinson's Institute in Sunnyvale. Here are the notes I took (hopefully these will make sense!):
There's good news and bad news about stem cell transplants (also called "neural transplants").
The bad news is that stem cell transplants have been hyped. There's been a huge push for stem cell research in the PD community.
The good news is that President Obama will likely overturn the ban on fetal cell transplants.
Some history: Reagan blocked fetal cell transplants. Clinton overturned this. George W Bush banned stem cell research; this has been a disaster for the research world in the US. We expect President Obama to overturn this ban.
Dr. Langston was originally very optimistic about stem cells. Now, he doesn't think stem cells will be a treatment or cure for PD in his lifetime.
Fetal cells are available through abortions. The idea was to provide that fetal cells work and then we could use stem cells.
In open trials with stem cells in PD patients, the patients got better. (In an open trial, both patient and MD knows who receives the real therapy and who receives a placebo.) In two blinded clinical trials, the outcome was poor in both: patients didn't get better. On top of this, patients had a bad side effect -- dyskinesia. Even when the amount of Sinemet was reduced or the medication was removed entirely, the dyskinesias continued! Brain cells had gone into over-drive.
The bad news is that we discovered that dopaminergic cells don't handle all of the problems in PD. Dopaminergic cells do NOT handle balance/gait, speech, and cognition. Many areas of the brain are affected in PD.
The bad news is that transplanted cells develop PD! There have been four cases thus far where PD patients received fetal cell transplants and have died. Three of these cases have been reported elsewhere; post-mortem brain tissue analysis revealed that the healthy young fetal cells developed Parkinson's Disease!
(A few months ago, I helped arrange for over three dozen cases of brain tissue to be sent from The Parkinson's Institute to Mayo Jax for analysis. I did this because seven or eight of our local support group members had loved ones with tissue that had been sitting around TPI for as long as two years!) One of these brains sent to Mayo Jax was the case of someone who had PD and had received a fetal cell transplant. In that case as well, the transplanted cells developed PD. Dr. Langston wants to publish an article about this.
Either in all four of these cases or in three of these cases (sorry, I was confused about this) the time interval between fetal cell transplant and death was at least ten years. (I think in one of the cases a woman was hit by a tree that landed on her house after Hurricane Oscar and died. She died four years after the transplant.)
A major focus of research at the Parkinson's Institute is drugs that can be used for neuroprotection. They are screening large numbers of small molecules to see if any are helpful in neuroprotection. The PI wants to find a drug that is already FDA-approved for some other disorder that is helpful in PD. The costs to develop a completely new drug are $1 billion and ten years. The PI has found some already-approved medications that seem to work in PD.
One big problem the PD research community has is that there's no animal model on which to test these drugs. One way to get around this lack of an animal model is to use stem cells.
A Japanese researcher recently discovered that skin cells can be changed to stem cells, after some genes are added. (These stem cells are called induced pluripotent cells.) This gets around the ethical issues of fetal cells. And it addresses the issue of immunological rejection (because a patient's skin cells are used to make stem cells that will be transplanted in that same patient). This researcher will likely win the Nobel Prize in a couple of years. (In SF, the researcher recently demonstrated using skin cells and turning them into heart cells.)
The PI had put in a grant proposal to CIRM (the CA stem cell research organization) to investigate taking skin cells back to stem cells and then forward to dopamine cells. This probably can't be used to treat PD any time soon. But....we can use these dopamine cells in a dish (or "PD in a dish") to test the already-approved medications to see if they work. We'll know in 3 or 4 days if the tested compound works. A compound works if the aggregation of the protein alpha-synuclein is blocked. (We think aggregation of this particular protein is the fundamental problem in PD.) After testing drugs on living dopamine cells, we can go to human trials.
Despite the Children's Hospital of Oakland research that was recently published, there is no good data on methylene blue as a helpful agent in PD treatment or neuroprotection. Dr. Langston is doubtful that it would be a successful compound in the "PD in a dish" tests.
GENETICS AND PD
There are five monogenetic forms of PD. These are all rare. One of these five is more common than the other four forms: LRRK-2. LRRK-2 (called "lark-two") accounts for 1.5% of all PD. LRRK-2 is very similar to "regular PD." Maybe a cure for LRRK-2 will be found, and this will help "regular PD." Sergey Brin (one of the Google founders) has the LRRK-2 gene; he will likely get PD some day. Hopefully he can use some of his money to fund LRRK-2 research. (Sergey Brin's blog about this is here: http://too.blogspot.com/
Over 50 studies show that cigarette smoking protects against PD. Smokers have a 50% reduction in their chance of getting PD. The more you spoke, the better off you are (in terms of reduced chances of getting PD). The likely compound involved in this is nicotine.
The best compound for blocking dyskinesias is nicotine. This was reported about six months ago by the PI. Amantadine is also helpful in blocking dyskinesias but this compound has not been investigated.
DBS (DEEP BRAIN STIMULATION)
About 10K people have gotten DBS. Most of Dr. Langston's patients are conservative and don't want this surgical treatment (where wires are placed in the brain and chest).
There is a group of patients who is helped by DBS. They are: healthy patients in whom levodopa (Sinemet) works but there are side effects to the medication. The best days for these patients after DBS is no better than the best days for these patients before DBS and on Sinemet.
There is some evidence of an increase in cognitive problems after ten years of having DBS.
Michael J. Fox had a thalamotomy to block tremors. (In a thalamotomy, the thalamus, which controls some involuntary movements, is destroyed.) Dr. Langston doesn't think that Michael J. Fox has had DBS.