Latest Research News and Announcements (updated August 2011)
Please note: The following overview of recent research into the Niemann-Pick diseases is provided for your information only. By providing this information, the NPDG (UK) does not advocate or endorse the findings. The information provided is in no way intended to replace professional medical care and should not be used as a basis for diagnosis or choice of treatment. All users are strongly advised to seek the advice of their local healthcare team before acting on any information provided herein, as no responsibility can be accepted by the NPDG (UK). If you have any questions about the information provided please contact the Niemann-Pick Disease Group, email niemann-pick@zetnet.co.uk or telephone 0191 415 0693
To read the Niemann-Pick Disease Group (UK) Research Strategy, please click here.
Facilitating progress towards therapeutic interventions for all of the Niemann-Pick diseases is at the heart of everything we do in the NPDG (UK) and has been for the past 20 years.
At present we are monitoring internationally all current developments in these diseases through our network of contacts in the scientific and medical world. Together with all the other patient support groups worldwide, who meet three monthly by teleconference, and with the advice of the National Niemann-Pick Disease Foundation’s international scientific and medical advisory board, we are kept in touch with what is happening.
This means that we are also actively pursuing any opportunities that may occur for further trials in the UK, should a viable compound become available. This would build on the fact that we are already the only country outside of the USA to have hosted a clinical trial (Zavesca) for NPC. Our extensive clinical experience built up through the existence of a clinical centre and a clinical nurse specialist makes the UK very well placed to be a part of any future trials and was one of the reasons why we were chosen as the second centre for the Zavesca trial.
There is a lot happening just now on the research front, which is great news. Whilst we do believe that this news represents real and significant progress and provides hope, it is important that we do everything possible to ensure that the information we provide is accurate and the work and resources we put in are effectively used to maximise progress.
The NPDG (UK) Board is made up of people who have family members or friends directly affected by this group of diseases. We do understand the urgency and the fact that progress is never fast enough - but it is accelerating! We believe that if people work together then then this acceleration will be even faster.
Following a presentation made to the NPDG (UK) Board of Trustees by Professor Fran Platt, University of Oxford, it was agreed that the NPDG (UK) would provide funding for the following project, which will contribute to the collection of data for the proposed NIH clinical trial of Cyclodextrin for NP-C, planned to start in 2012:
ABSTRACT
We have been evaluating expansion of the lysosomal compartment in response to lipid storage as a potential biomarker for NPC using a probe called Lysotracker. During the course of these studies we have monitored blood cells (B cells) from patients who began intravenous cyclodextrin (CD) therapy on a compassionate use basis. We observed a dramatic increase in Lysotracker following CD therapy in these patients (but not in non-CD treated NPC patients) that was B cell specific. To gain insights into the mechanisms underlying this observation we will conduct a 6-month study to investigate the biochemical basis for this change and determine whether it adversely affects B cell function. These studies will shed light on the mechanisms of action of CD and help inform the most appropriate route of CD administration.
The NPDG (UK) continues to support and encourage requests to support research projects that will facilitate progress towards therapeutic interventions. The above project is funded in addition to support provided earlier this year to Cardiff University, enabling the completion of research work into the belief that stimulation of acid sphingomyelinase activity could clear the remaining sphingomyelin and cholesterol storage in NP-C cells.
The following information relating to recent announcements in NP-C research appears on the National Niemann-Pick Disease Foundation (NNPDF) website and can be read in full by visiting www.nnpdf.org
The information was compiled by the NNPDF Central Office staff with the assistance of the members of their esteemed Scientific Advisory Board
Paper Published on Study of Histone Deacetylase Inhibitor for Use in NPCUniversity of Notre Dame Press Release Claims Breakthrough
A paper regarding a study into Niemann-Pick Disease Type C (NPC) was published in a recent issue of Proceedings of the National Academy of Sciences (PNAS). The paper, coauthored by Olaf Wiest and Paul Helquist of the University of Notre Dame and Frederick Maxfield of Cornell University, says the use of a histone deacetylase inhibitor corrects the damage done by the genetic disorder NPC and allowed once-diseased cells to function normally.
Follow this link to read the paper's abstract at PNAS: http://www.pnas.org/content/early/2011/03/15/1014890108.
Follow this link to read the Notre Dame press release dated March 21, 2011: http://www.eurekalert.org/pub_releases/2011-03/uond-bin032111.php
What does this mean for those affected by NP-C?
To help us all to understand this information, the National Niemann-Pick Disease Foundation (NNPDF (USA)) consulted three respected experts in Niemann-Pick Disease Type C: Dr. Dan Ory of Washington University, Dr. Marc Patterson of Mayo Clinic, and Dr. Forbes "Denny" Porter of the National Institutes of Health.
Daniel Ory, M.D., Washington University School of Medicine, and Chair of the NNPDF’s Scientific Advisory Board (SAB), sent the following response to their inquiry:
“The results are promising, but represent an early step in the process of identifying effective compounds for NPC. More cell studies are needed to understand the mechanism [and] mouse studies should be pursued….there is a long history of compounds that are effective in reducing cholesterol in cultured cells but do not have benefits in animal models, so we should be cautious in extrapolating such results to humans.”
Marc C. Patterson, M.D., Chair of the Division of Child and Adolescent Neurology at Mayo Clinic, also a member of the NNPDF’s SAB, further cautioned against making premature assumptions:
“The work was done in cultured fibroblasts, so one should be very cautious about extrapolating these data to animals or humans. Moreover, the work was done in cells expressing one or two I1061T NPC1 mutations, and may not be relevant to other mutations; it was not effective in an NPC2 mutant cell line. Of note, the late Dick Pagano showed dramatic reversal of trafficking abnormalities and filipin staining in NPC fibroblasts in which rab 7 and 9 were overexpressed, but much more modest results in transgenic mice with NPC1 mutations and rab overexpression.
Mouse studies could certainly be justified, but it would be premature to assume that this approach will be applicable in humans with NPC.”
Another of the NNPDF's SAB members, Forbes “Denny” Porter, M.D., Ph.D., of the National Institute of Child Health and Human Development at the National Institutes of Health (NIH), stated, “It is always good news to have a potential new approach to treating NPC. Cells are the starting point, but to translate this to a potential therapy more work needs to be done.”
Histone deacetylase inhibitors (referred to as HDAC inhibitors) are a class of compounds that interfere with the function of histone deactylase. HDAC inhibitors have a history of use in psychiatry and neurology as mood stabilizers and anti-epileptics.
One HDAC inhibitor, valproic acid, was considered as a possible treatment for NPC, but results have not been overly promising.
Yiannis Ioannou, Ph.D., Department of Genetics and Genomic Sciences at Mount Sinai School of Medicine, also a member of the NNPDF’s SAB, made the following statement regarding his recent study of valproic acid and NPC:
“We have just concluded our mouse studies on valproic acid and have evaluated its effect on cells from a number of NPC patients and on the NPC mouse. Unfortunately, the results are not great.
* For NPC patient cell lines we have treated six different lines with valproate. Some cells responded positively; i.e., the cholesterol storage was cleared but some lines were completely resistant to the treatment. Upon analysis of our data it became clear that if the patient has a relatively mild mutation then they would respond to valproate, whereas if the mutation is more severe, then the cells don’t respond.
* With respect to the mouse study, we have treated about 25 mice with daily dosing of valproate. We can extend the life of these mice by about 10%. The mice live about 122 days on average vs. 108 days for the untreated mice.
At this point we don’t think that valproic acid would be beneficial for NPC patients.”
Some years ago, valproic acid was given to a few NPC patients, including Stacey Vorpahl (1985-2004), the daughter of Gary and Barbara Vorpahl of Fort Atkinson, Wisconsin, USA for the treatment of seizures. Barb, Vice Chair of the NNPDF Board of Directors, recently posted to the NNPDF listserv group about her family’s experience with valproic acid (as Depakote):
“We did have Stacey on valproic acid (Depakote) for seizures when she first started having seizures. This was at age seven. Once she started Depakote we saw a rapid decline. One of the side effects is muscle weakness. It can also actually cause seizures at higher doses. She was on Depakote for about a year. She quit talking, needed a wheelchair, could no longer sit up or roll over by herself. We didn’t think she would survive to age 8 at her rate of deterioration. We thought the decline was from NPC but after comparing notes with other parents and seeing strange seizures that their children were also experiencing when doses were increased, we decided to gradually wean her off of Depakote and try another seizure medication. It was like bringing her back from the dead. We saw her strength start coming back, alertness level [sic], her talking never resumed but she did have strength to walk with assistance. I know others have had success with valproic acid but for Stacey it was a very negative experience. I was very surprised when I saw research coming out on valproic acid. It may work in mice but it certainly did not help our daughter even controlling seizures.”
NIH to Develop Clinical Trial Utilizing Cyclodextrin
The National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), is developing a clinical trial utilizing cyclodextrin for Niemann-Pick Type C patients.
The clinical trial is in the planning phase and many criteria must be met and numerous approvals granted before the trial can take place. Dr. Forbes "Denny" Porter, a Senior Investigator at the NIH, and Dr. Daniel Ory, NNPDF Scientific Advisory Board Chair, are working collaboratively to bring this trial to our NPC patient community.
On May 2 2011 the NNPDF hosted a conference call with key constituents and researchers, for all interested parties in the NPC community to learn more about the work being done at the NIH. This conference call included information pertaining to the development of plans for a cyclodextrin trial.
For those who were not able to participate, or for those who participated and would like to review the information presented, a link is now available on the NNPDF website enabling access to the
Webinar and Audio programs:
http://www.nnpdf.org/CyclodextrinClinicalTrialNIH.html
The NNPDF are also working on creating a written summary of the call which will be made available shortly. In the meantime, if you have a question for the presenters regarding the information on the recording, please submit it to the NNPDF Central Office nnpdf@nnpdf.org
Genzyme-Sanofi Announcement February 17th 2011
The NPDG (UK) has received the following update from Annamarie Dillon, Patient Group Relations, Genzyme Europe
Sanofi-aventis have entered into an agreement under which Sanofi-aventis will acquire Genzyme. Sanofi-aventis is a global, diversified healthcare company, headquartered in Paris, France and a leader in diabetes, oncology, innovative medicines, vaccines, consumer health care products and animal health. With this transaction, Genzyme will move into a new phase of our development, continuing our patient-focused mission and developing treatments that change the lives of people with rare diseases.
Sanofi-aventis and Genzyme have a shared vision for our future together and believe we will emerge even better prepared to serve you. The plan is for Genzyme to become a division of Sanofi-aventis and global centre of excellence for rare diseases. We will continue to serve the rare genetic disease community as we have done for the past 30 years, and I believe that Sanofi-aventis will bring important new perspectives and new resources to this work.
Until the transaction closes, which is expected early in the second quarter of this year, both companies remain independent. Every aspect of how we work and our commitment to you remain the same.
I understand that this has been a very challenging time for the patient community. In partnership with you, Genzyme’s mission has always begun and ended with the patient. Sanofi-aventis is making a significant investment in Genzyme because they value what we do, and our mission will remain unchanged.
As we work through the details, we will share our progress with you. Our future is dependent upon the support and involvement of patients and the treatment community, and we are eager to hear your thoughts and feedback as well.
Thank you for your continued support of Genzyme, and we look forward to updating you soon on our progress and path forward.
Annamarie Dillon
Manager, Patient Group Relations
Genzyme Europe
To view a copy of the Press Release from Genzyme and Sanofi-aventis click here.