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 Mayo research (for PD, LBD, MSA): Blocking alpha-synuclein 
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Joined: Fri Aug 11, 2006 1:46 pm
Posts: 4811
Location: SF Bay Area (Northern CA)
Post Mayo research (for PD, LBD, MSA): Blocking alpha-synuclein
Here's a press release from Mayo Clinic about new therapy they are developing which may slow the progression of Parkinson's Disease (PD). DLB is specifically mentioned in the press release. "The new method involves the delivery of RNA interference compounds directly to selected areas of the brain via injection. The RNA interference compounds silence the gene that produces alpha-synuclein, according to the Mayo researchers." PD, MSA, and LBD are all synucleinopathies. This therapy has been tested in mice.

There's an 8-minute video interview with Demetrius Maraganore, MD (Mayo Rochester), and Matthew Farrer, PhD (Mayo Jax), two of the researchers available here: (near the bottom of the page) ... s-disease/
I recommend the online video (very understandable!). Dr. Maraganore talks about the neurosurgery and pump that will be required to introduce the RNA interference compounds.

On that Mayo News Blog web page, there's also an image of a mouse brain, showing the treated side and the untreated side. This image is also shown in the online video.

The press releases notes that this research was published this month in Molecular Neurodegeneration. You can find the full article available for free in provisional form here:
http://www.molecularneurodegeneration.c ... 6-3-19.pdf
I've copied the abstract from the journal article below. Both the full article and the abstract are very hard to understand (for me). Page 27 of the full article have the same mouse brain image as described above plus several more.

Mayo Clinic Develops Potential New Therapy to Stop the Progression of Parkinson's Disease
Monday, November 17, 2008

Mayo Clinic researchers have developed a method to reduce the production of alpha-synuclein in the brain. Alpha-synuclein is a protein that is believed to be central to the cause of Parkinson's disease. All patients with Parkinson's disease have abnormal accumulations of alpha-synuclein protein in the brain.

VIDEO ALERT: Additional audio and video resources, including excerpts from an interview with Dr. Maraganore describing the research, are available on the Mayo Clinic News Blog.

The new method involves the delivery of RNA interference compounds directly to selected areas of the brain via injection. The RNA interference compounds silence the gene that produces alpha-synuclein, according to the Mayo researchers. The study was published this month in Molecular Neurodegeneration.

Parkinson's disease is a progressive disorder that affects nerve cells in the part of the brain that controls muscle movement. Symptoms include tremor, slowed movement and rigid muscles. At least 1 million people in the U.S. are believed to have Parkinson's disease, and 2 percent of the population can expect to develop the disease during their lifetime.

"While our research has not yet been tested on humans, we expect that these findings will lead to an effective treatment for slowing or even halting the progression of Parkinson's disease," says Demetrius Maraganore, M.D., a Mayo Clinic neurologist.

Previous studies conducted by Dr. Maraganore and Matthew Farrer, Ph.D., a Mayo Clinic neuroscientist, found that variations in the alpha-synuclein gene result in increased protein production and are sufficient to cause Parkinson's disease in some families, or otherwise increase the risk for Parkinson's disease across populations worldwide.

Drs. Maraganore and Farrer invented a method to treat Parkinson's disease by reducing alpha-synuclein expression. Mayo Clinic patented and licensed their invention to Alnylam Pharmaceuticals, Inc. Alnylam is leading the effort to commercialize the Mayo invention using Alnylam RNA interference compounds.

"For this study, we developed a lead compound of small interfering RNAs," says Heather Melrose, Ph.D., a Mayo Clinic neuroscientist and a lead author of this study. "By infusing this into the brains of mice we were able to effectively reduce the production of alpha-synuclein in the brain. The therapy produced gene silencing that lasted up to three weeks after treatment, and the mice exhibited no ill effects. These are desirable characteristics of a drug therapy ultimately intended to treat disease in humans."

"Our next step with this research is to test the therapy in mice and primates with experimental forms of Parkinson's disease and prove that we are able to stop the disease progression in those animals," says Dr. Farrer. "We are hopeful, as preliminary studies suggest this is possible."

"It is important to note that there are significant hurdles to this therapy. The compound needs to be directly delivered to the brain through a neurosurgical procedure � it cannot be given by mouth or injection into a vein," says Dr. Maraganore. "We envision that the therapy would be delivered through Food and Drug Administration (FDA)-approved devices currently used for deep brain stimulation therapy. The deep brain stimulation would treat the existing symptoms of Parkinson's disease, while the administration of the RNA interference compounds might halt the progression of the disease."

Alpha-synuclein protein also accumulates abnormally in other brain degenerations, including multiple system atrophy (MSA) and dementia with Lewy bodies. Therefore, Mayo researchers expect that RNA interference therapy could be beneficial for patients with those conditions.

Other members of the Mayo Clinic research team included Jada Lewis, Ph.D.; Andrew Hope, Ph.D.; Cynthia Zehr, Ph.D.; Sarah Lincoln; Adam Braithwaite; Zhen He, Ph.D.; Sina Ogholikhan; Kelly Hinkle; Caroline Kent; Michael Heckman and Julia Crook, Ph.D. Contributors from Alnylam Pharmaceuticals, Inc. included David Bumcrot, Ph.D.; Ivanka Toudjarska; Klaus Charisse; Ravi Braich and Rajendra Pandey.

This study was funded in part by a grant from the Michael J. Fox Foundation. Mayo Clinic has an agreement with Alnylam whereby Mayo has granted Alnylam an exclusive license to certain patents and know-how. Mayo Clinic and inventors of this intellectual property may receive developmental milestone and/or royalty payments pursuant to this agreement.

Here's the abstract of the research paper:
Molecular Neurodegeneration. 2008 Nov 1;3(1):19. [Epub ahead of print]

In vivo silencing of alpha-synuclein using naked siRNA.

Lewis J, Melrose H, Bumcrot D, Hope A, Zehr C, Lincoln S, Braithwaite A, He Z, Ogholikhan S, Hinkle K, Kent C, Toudjarska I, Charisse K, Braich R, Pandey RK, Heckman M, Maraganore DM, Crook J, Farrer MJ.

BACKGROUND: Overexpression of alpha-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD.

RESULTS: We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion.

CONCLUSIONS: We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for alpha-synucleinopathies resulting from SNCA overexpression.

PubMed ID#: 18976489 (see for abstract only)

Tue Nov 18, 2008 7:08 pm

Joined: Wed Oct 08, 2008 10:30 pm
Posts: 976
Location: Henderson, Nv.
mm...Just a million questions :lol:

1. Relative to the study of the new brain injections. How far off is the possibility of testing/use in humans?

2. Is anyone working on a study of "stages of LBD" so we have an idea where we are in the progression of the disease. I know each patient is individual with symptoms, however, is there a possible way of detecting what is to come as the disease progresses or again is this individual specific?

What a great opportunity for you...and ultimately all of us! Good luck!

Dianne C.

Mon Mar 23, 2009 2:08 pm

Joined: Sat Oct 06, 2007 4:28 pm
Posts: 781
Location: LA
Post Post mortem brain donations
MM, We know research scientists value the brain donations of persons in studies. Are the donations of our average Joes, John and Jane Doe, held in the same high regard? Ask your guest to please address this subject. Is there more that we can do for brain research?


"See this lady she's 85 but she's nice", This is the way my husband, Mr B., introduced me in 2006 to the people only he knew. Death due to pneumonia. Lewy Body Dementia diagnosed post mortem at Mayo Clinic in Jacksonville Florida.

Mon Mar 23, 2009 4:02 pm

Joined: Fri Aug 11, 2006 1:46 pm
Posts: 4811
Location: SF Bay Area (Northern CA)

I will be interested in the good doctor's response to your question but I can tell you that Mayo Jax *welcomes* any brain donation -- even from presumably "normal" people. This is the only way they can know what "normal" aging looks like in the brain. Both my husband and I (presumably normal) are signed up to donate our brains to Mayo Jax. It gives me some comfort to think my brain will be in a freezer in the same facility as my father's!

Not all brain banks want normal brains. It just depends on what sort of research that they are doing.


Mon Mar 23, 2009 5:21 pm

Joined: Fri Aug 11, 2006 1:46 pm
Posts: 4811
Location: SF Bay Area (Northern CA)
MM -

It seems that Dr. Ahlskog is a clinician at Mayo Rochester.

He was a co-author of a Boeve paper on RBD; see:

And I just posted another recently published abstract for which he was a co-author. It's a well-done study on rapidly progressive dementias, which normally LBD is not.

Is the conference at which he's speaking -- which you've mentioned at -- on LBD only or on PD and LBD?


Mon Mar 23, 2009 5:33 pm
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