Category Archives: PSP

Nypta – treating PSP, so obtains orphan drug status

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Dr. Yvette Bordelon mentioned this experimental medication, Nypta, in her webinar on Thursday. There will be a phase II trial on the safety and tolerability of Nypta in the US and Europe, starting “before the end of the year” (according to the press release) and in early 2010 (according to Dr. Bordelon).

This financial news article is about the Spanish biotech company’s share price rising given its acquisition of orphan drug status from the FDA and the European Commission. Sorry, that’s all I could find on this drug so far.

http://www.reuters.com/article/rbssIndu … 1320091103

Zeltia’s Nypta gets orphan drug status, shares gain
Tue Nov 3, 2009 3:30am EST

* Being developed to treat progressive supranuclear palsy
* Shares up 2.2 pct

MADRID, Nov 3 (Reuters) – Spanish biotechnology firm Zeltia’s (ZEL.MC) Nypta drug to treat a degenerative brain disease has received orphan drug status from the European Commission and the U.S. Food and Drug Administration.

Nypta is being developed by Zeltia’s Noscira unit to treat progressive supranuclear palsy (PSP), a rare disease that gradually destroys nerve cells in the brain that control eye movements, breathing and muscle coordination.

Phase II clinical trials on the drug are due to begin before the end of the year, Zeltia said in a statement on Tuesday.

Orphan drug designation is reserved for new therapies that are being developed to treat rare medical conditions, and in the United States the label grants the drug developers seven years of market exclusivity.

Shares in Zeltia rose 2.2 percent to 4.44 euros by 0820 GMT, bucking the negative market trend in Spain to extend an 8 percent gain on Monday after its Yondelis drug received European approval to treat ovarian cancer.

Expert update on PSP/CBD genetics study

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Thursday’s CurePSP webinar with Dr. Yvette Bordelon included an update by Dr. Schellenberg of UPenn on the PSP and CBD Genetics Program. It was great to get this update from the expert. I thought it warranted its own (shorter) webinar.

What follows are my notes on Dr. Schellenberg’s presentation, a short comment made by Dr. Bordelon on the study’s findings, and some of my own comments.

Further down is the email I sent out to the local support group on 10/1 with a short update on the genetics study and some general background about the study. Just as Paul Freeman (CurePSP board member) told us in September at a local support group meeting, four new genetic mutations associated with PSP have been discovered through this brain research.

Robin

Presenter – Gerard Schellenberg, PhD
Univ of Pennsylvania School of Medicine

Topic – Charles D. Peebler Jr. PSP and CBD Genetics Program

What does it take to get PSP or CBD (at least in terms of the genetic components)?
* The bad form of one gene is very rarely the cause of PSP or CBD. What this means is that if you have a family member with PSP or CBD, your chances of developing the disease is pretty remote. In contrast: there are diseases, such as Huntington’s Disease and some forms of ALS, where a single gene is involved, and if you inherit the bad form of that gene you will get the disease. This type of genetics — “single gene inheritance” — tracks very strongly in families.
* Most cases are caused by the bad form of 5 to 10 genes. For each bad copy inherited, risk is increased. If you develop the good form of each of these genes, your chance of developing PSP or CBD is very low.
* We think there also might be some environmental insult involved. We don’t really have a good handle on what the environmental input is.

Goal: identify ALL the genes that contribute to PSP/CBD. They aren’t focusing on one gene, as this is rare. Put another way: they are focused NOT on the genes that cause PSP and CBD but rather on the genes that contribute to the risk of PSP and CBD.

This genetics study requires:
* DNA from a large number of autopsy-confirmed cases of PSP and CBD
* DNA from a large number of cases of those who do not have PSP or CBD. This is compared to the DNA from those who do have PSP or CBD.
* Genetic technology to study all regions of all chromosomes (across the genome or genetic material)
* A statistical analysis team

This is an international effort:
Germany (Dr. Muller, Dr. Hoglinger)
US: Mayo Jax (Dr. Dennis Dickson)
UK: Queen’s Square (Dr. Andrew Lees – one of the international experts on PSP and CBD, Dr. Rohan Silva)

Brains collected by the German team:
Munich – 8 CBD, 21 PSP
Wurzburg – 2 PSP
Barcelona – 3 CBD, 17 PSP
Netherlands Brain Bank – 23 PSP
London Brain Bank – 2 CBD, 8 PSP
Saskatchewan, Canada – 37 PSP
Wilrijk, Belgium – 2 PSP
Australian Brain Bank – 1 CBD, 9 PSP
Pamplona, Spain – 1 PSP
Subtotal – 14 CBD, 125 PSP

Other brains contributed:
Mayo Clinic Brain Bank – 78 CBD, 599 PSP

Other brains contributed:
Queen’s Square Brain Bank (London) – 144 PSP

Brains collected by Dr. Schellenberg from US-based institutions:
Emory Univ – 13 CBD, 6 PSP
McLean Brain Bank – 8 CBD, 64 PSP
Indiana – 12 CBD, 31 PSP
Los Angeles VA/UCLA – 1 CBD, 14 PSP
Massachusetts General – 34 PSP
NY Brain Bank – 6 CBD, 22 PSP
Rancho Los Amigos Medical Center – 3 PSP
Sun Health Research Institute – 38 PSP
Univ of Michigan – 23 PSP
UPenn CDNR – 30 CBD, 51 PSP
Univ of Washington – 4 PSP
Univ of Southern California – 2 PSP
UCSD – 10 PSP
Univ of Texas Southwestern – 6 CBD, 14 PSP
Johns Hopkins – 27 PSP
Subtotal – 75 CBD, 343 PSP

Total brains (or samples) contributed over the last two years:
CBD: 168
PSP: 1212
total autopsy-documented cases: 1380

In addition to the 1380 PSP/CBD samples, they have DNA from 3000 controls. These controls are healthy children who have come into the Children’s Hospital of Philadelphia for routine check-ups.

The genetic technology being used tests 660,000 sites across the human genome (all the inherited material or all of the inherited DNA). We can pretty much test everywhere in the human genome for change related to PSP and CBD.

What we learned through this study, after the statistical analysis: we learned about four new genes that are involved in one’s risk of developing PSP or CBD. We didn’t previously know about genes on chromosomes on 1, 3, 11 and 12. We knew about the tau genetic mutation on chromosome 17. This knowledge about four new genes is the exciting pay-off from two years of very hard work. Each of these genes tells us something about the mechanism or the pathway for how PSP or CBD develops.

Next:
* explore how each of these genes plugs into the disease. This knowledge is critical to understanding what causes it and what causes it to progress to the point where symptoms start to appear.
* explore how genetics and the environment interact

A lot of pharmaceutical discovery is based in part on genes found through these methods. This has been particularly true in Alzheimer’s Disease. Genetics findings are really driving a lot of the pharmaceutical discovery efforts by the big companies.

Next specific steps in this study:
* analyze tau in more detail. How does the bad form of tau contribute to risk? Is it simply making more tau protein or something more complicated?
* replication studies to verify these are not statistical artifacts. We are collecting 1000 more PSP cases to look at these four genes and tau. [Robin’s question: are they collecting more CBD brains as well?] * identify additional genes with the additional samples

Summary:
* The genetic experiment worked! And it worked spectacularly!
* 4 new genes previously not implicated in PSP or CBD
* potential for identifying new genes (which gives us insight into the disease process)
* potential for new leads for therapeutics to treat or prevent PSP or CBD

Thank you:
* families that contributed DNA. These contributions are absolutely essential.
* CurePSP that took a risk and put up a large amount of money for this study
* donors to CurePSP to make this research possible, particularly the Charles Peebler Jr. family

Comment by Dr. Yvette Bordelon on Dr. Schellenberg’s presentation:

This is spectacular! These are very exciting results for PSP and CBD.

These genome-wide screens have been attempted in other disorders, and haven’t been nearly as successful. In PD several attempts have been made, none of which have shown clear correlations.

Robin’s notes:

In a recent letter to a brain donor’s family, Mayo Jax confirmed the PSP diagnosis and indicated that it had 730 PSP brains in its brain bank. Dr. Schellenberg reported above that 599 PSP brains were included in the original group. Presumably the additional 131 brains collected thus far at Mayo Jax will be part of the goal of collecting 1000 more brains.

If your loved one has donated tissue to an institution not listed above (such as UCSF or the Univ of NM, to name two that I know have PSP or CBD brains), please contact the neuropathologist to find out if samples can be provided to Dr. Schellenberg to reach the goal of 1000 more brains.

I’m proud to report that I’ve played a role in having 15 path-confirmed PSP or CBD brains donated to institutions listed above as study participants. Most of these donations have been to Mayo Jax. (I’ve played a role in many more brains being donated to Mayo Jax for other disorders, and to other institutions not yet participating in the PSP/CBD study.

Date: Thu, 01 Oct 2009 20:58:13 -0700
To: local PSP/CBD support group
From: Robin
Subject: Small update on PSP/CBD genetics study

As many of you know, CurePSP (the new name for the Society for PSP) began the multi-year Genetics Consortium a couple of years ago. This description is from the 2008 CurePSP annual report:

“The CurePSP Genetics Program is a multi-year venture sponsored and supported by CurePSP (The Society for Progressive Supranuclear Palsy). Our goal is to search the entire genome for genes related to PSP and CBD and to identify previously unsuspected abnormal biochemical pathways against which scientists may be able to target therapeutic interventions. All activities will be carried out by the CurePSP Genetics Consortium, composed of neurologists, geneticists, and other scientists from the United States, the United Kingdom, and Germany working in collaboration with neuroscientists throughout the world.”

You can find a good layperson-oriented description of the genetics program starting on page 51 of the CurePSP 2008 annual report available online here:
http://www.psp.org/doc_library/12313603 … 202008.pdf

Last year, about this time, it was reported that the goal was to have 1000 PSP brains included in the study but they ended up with 1300 PSP brains. I’m unclear as to how many CBD brains were examined but I’m assuming it’s several hundred.

Certainly all of the PSP and CBD brains donated to Mayo Jax were included in the study, as the brain bank there has several hundred PSP brains and around 100 CBD brains, and Mayo Jax is part of the research consortium (though it’s not the lead institution). …

If your loved one has donated brain tissue to a brain bank other than Mayo Jax, perhaps you can inquire if the tissue was sent to the Genetics Consortium for study. …

This is a genome study or a DNA study. The goal is to find out what genes or genetic mutations are implicated in PSP and CBD. Some gene chip technology that became available in 2007 (out of the Human Genome Project) has made the study possible, along with the brain donations and some serious funding.

Recently, Ed Plowman described the study in this way: “Each brain tissue sample had a computer chip assigned to it. The project is attempting to analyze what all PSP brains might have in common genetically that is different from non-PSP brains. As I understand it, hundreds of thousands of bits of data from each tissue sample are cataloged and the findings compared with all the other samples. It may be quite some time before the analysis is complete and findings released.”

So….now we are *finally* to the “small update” part of this email. Paul Freeman, the CurePSP Board’s Treasurer attended our most recent support group meeting, and sat with the PSP/CBD group. He indicated that four genetic mutations have been discovered as being culprits in PSP. (He didn’t say if these genes were also implicated in CBD.) He said that the researchers are going through the data again to confirm these findings, and then a paper will be written. This gets us a step closer to being able to do genetics testing and to find therapeutic interventions. It does seem like important progress along the way.

Robin

No strong environmental risk factors for PSP

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This French study looked at 79 cases with a clinical diagnosis of PSP, and 79 controls who were relatives. They analyzed “demographic characteristics, occupation history, diet habits, anti-inflammatory drugs use, alcohol consumption, smoking habits, gardening and leisure activities, and exposure to pesticides.” They found no “strong environmental risk factors for PSP.”

According to the article, “only four case-control studies on risk factors of PSP” have been published. Dr. Golbe talked about these in his webinar on PSP and CBD several months ago.

The authors argue that: “These data also suggest that PSP and PD have no major risk factor in common. Similar conclusions can be drawn from studies about multiple system atrophy.”

You may note that the French used the “Golbe criteria” to diagnose PSP. I’d have to look this up again but I assume it’s those over 40, with a history of falls, cognitive issues, and supranuclear gaze palsy. (The citation is: Golbe LI. Progressive supranuclear palsy. In: Tolosa E, ed. Parkinson’s disease and movement disorders. 2nd edn. Baltimore: Williams & Wilkins, 1993:145­61.)

Robin

Journal of Neurology, Neurosurgery, and Psychiatry. 2009 Nov;80(11):1271-4.

Risk factors for progressive supranuclear palsy: a case-control study in France.

Vidal JS, Vidailhet M, Derkinderen P, de Gaillarbois TD, Tzourio C, Alpérovitch A.
INSERM Unit 708, Hôpital de La Salpêtrière, Paris, France.

BACKGROUND: The risk factors of progressive supranuclear palsy (PSP), a rare but severe Parkinsonian syndrome, are poorly known.

OBJECTIVE: To study the risk factors of PSP in a case control study among French patients.

METHOD: The study was conducted between April 2000 and December 2003. Cases were in- or outpatients of five large hospitals and fulfilled the Golbe criteria. Controls were relatives of patients from the same hospitals, free of Parkinsonian syndrome and dementia, and matched to cases for age, gender and living area. Data on demographic characteristics, occupation history, diet habits, anti-inflammatory drugs use, alcohol consumption, smoking habits, gardening and leisure activities, and exposure to pesticides were collected through a face-to-face questionnaire. A conditional logistic regression was used to analyse matched data and estimate OR.

RESULTS: 79 cases and 79 controls were included. Only a few comparisons were significant. Cases reached a lower education attainment than controls (odds ratio (OR) = 2.6 (1.3 to 5.3), p = 0.01). Analysis of diet habits did not show any major difference although cases ate meat or poultry more frequently. Conversely, controls ate fruits more frequently than did cases. No association was found between PSP and occupation, use of pesticides, gardening, alcohol consumption, smoking habits and anti-inflammatory agent use.

CONCLUSION: In this case-control study, we did not find any strong environmental risk factors for PSP.

PubMed ID#: 19864660 (see pubmed.gov for abstract only, available for free)

Concomitant PSP and MSA (4 Cases)

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This recently-published article is about one case of concomitant PSP and MSA in the Queen Square Brain Bank in the UK. (That’s one out of 120 cases of path-confirmed PSP.) And the article mentions that there are three other (independent) cases. One of these three is a Mayo Jax case; it was one case out of 290 path-confirmed PSP cases. So, that answers the question as to whether this is even possible!

Here are the highlights:

* “The apparent rarity of cases of coexistent PSP and MSA initially suggests they might be due to mere coincidence, rather than the result of any biological overlap.”

* “Grading of PSP tau pathology provided a score of 6, consistent with moderately severe tau pathology typical of Richardson’s syndrome [29].” [Robin’s note: this indicates that the RS form of PSP has more severe tau pathology than the other common form, PSP-P.]

* “Nevertheless, taking into consideration the rarity of MSA and PSP, in addition to the small number of cases that come to autopsy, the findings of 4 cases reported to-date is higher than expected.”

* “Whether these cases represent a pre-clinical stage of MSA, or simply a biological coincidence is yet unknown. The occurrence of pre-symptomatic MSA should be confirmed in prospective studies in which detailed neurological evaluation has been performed in the final months of life.”

* “Clinically our patient fulfilled the NINDS-SPSP operational criteria for the diagnosis of probable PSP and the only feature that might have suggested MSA was the urinary incontinence which started 20 years before death and resolved. The lack of overt cerebellar features of MSA is consistent with mild olivo-ponto-cerebellar pathology, whereas the prevailing parkinsonian syndrome is in line with more severe striato-nigral-degeneration, or the baseline PSP pathology.”

* “The rarity of pathologically proven cases of combined PSP and MSA does not provide sufficient evidence to confirm a common pathogenic mechanism for both diseases, but our findings suggest that systematic screening for PSP and MSA changes in atypical parkinsonian patients and control brain bank donors is warranted.”

The abstract follows.

Robin

Neuroscience Letters. 2009 Oct 14. [Epub ahead of print]

Concomitant progressive supranuclear palsy and multiple system atrophy: More than a simple twist of fate?

Silveira-Moriyama L, González AM, O’Sullivan S, Williams DR, Massey L, Parkkinen L, Ahmed Z, de Silva R, Chacón JR, Revesz T, Lees AJ, Holton JL.
Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are both rare neurodegenerative diseases.

In the Queen Square Brain Bank, from 2001 to 2008, we received 120 cases of pathologically confirmed PSP and 36 of MSA, and one had concomitant PSP and MSA pathology.

The clinical symptoms in this case were compatible with PSP and did not predict the dual pathology.

The growing number of collective case reports, including the one reported here, might suggest an increased prevalence of concomitant PSP and MSA than what would be expected by chance.

PubMed ID#: 19835934

Concommitant PSP and MSA (4 cases worldwide)

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This recently-published paper addresses the question of whether PSP and MSA can co-exist.  The answer is “yes” but it’s quite rare.

There is one case of concomitant PSP and MSA in the Queen Square Brain Bank in the UK.  (That’s one out of 120 cases of path-confirmed PSP.)  And the article mentions that there are three other (independent) cases.  One of these three is a Mayo Jax case; it was one case out of 290 path-confirmed PSP cases.  So, that answers the question as to whether this is even possible!

Here are the most interesting excerpts:

“The apparent rarity of cases of coexistent PSP and MSA initially suggests they might be due to mere coincidence, rather than the result of any biological overlap.”

“Grading of PSP tau pathology provided a score of 6, consistent with moderately severe tau pathology typical of Richardson’s syndrome [29].”  [Robin’s note:  this indicates that the RS form of PSP has more severe tau pathology than the other common form, PSP-P.]

“Nevertheless, taking into consideration the rarity of MSA and PSP, in addition to the small number of cases that come to autopsy, the findings of 4 cases reported to-date is higher than expected.”

“Whether these cases represent a pre-clinical stage of MSA, or simply a biological coincidence is yet unknown. The occurrence of pre-symptomatic MSA should be confirmed in prospective studies in which detailed neurological evaluation has been performed in the final months of life.”

“Clinically our patient fulfilled the NINDS-SPSP operational criteria for the diagnosis of probable PSP and the only feature that might have suggested MSA was the urinary incontinence which started 20 years before death and resolved. The lack of overt cerebellar features of MSA is consistent with mild olivo-ponto-cerebellar pathology, whereas the prevailing parkinsonian syndrome is in line with more severe striato-nigral-degeneration, or the baseline PSP pathology.”

“The rarity of pathologically proven cases of combined PSP and MSA does not provide sufficient evidence to confirm a common pathogenic mechanism for both diseases, but our findings suggest that systematic screening for PSP and MSA changes in atypical parkinsonian patients and control brain bank donors is warranted.”

Check out the abstract or full paper for more.  The abstract follows.

Robin

————————————

Neuroscience Letters. 2009 Oct 14. [Epub ahead of print]

Concomitant progressive supranuclear palsy and multiple system atrophy: More than a simple twist of fate?

Silveira-Moriyama L, González AM, O’Sullivan S, Williams DR, Massey L, Parkkinen L, Ahmed Z, de Silva R, Chacón JR, Revesz T, Lees AJ, Holton JL.

Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are both rare neurodegenerative diseases.

 

In the Queen Square Brain Bank, from 2001 to 2008, we received 120 cases of pathologically confirmed PSP and 36 of MSA, and one had concomitant PSP and MSA pathology.

The clinical symptoms in this case were compatible with PSP and did not predict the dual pathology.

The growing number of collective case reports, including the one reported here, might suggest an increased prevalence of concomitant PSP and MSA than what would be expected by chance.

PubMed ID#: 19835934