The Latest Research
Latest Research Highlights from the NNPDF Research
Committee
and our Scientific Advisory Board Chair, Dr. Dan Ory,
MD
Research Update from the February 2009 NNPDF Board Meeting
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| Janet Ward Pease Research Committee Chair Aunt of Adam and Amanda |
Adam Ward, NPC |
Amanda Ward, NPC |
Contact Janet Ward Pease via e-mail: NNPDF Research
Committee Chair
Research Committee Chair's Report -- December 2009
The research funded by the NNPDF is made possible in great part due to
the
efforts of our NPD families and their extended support
network via local
community-sponsored events. The NNPDF is truly grateful
for this support.
Research Grants funded by the NNPDF
Fellowships funded by the NNPDF
Clinical Research and Services funded by the NNPDF
Hearing on Rare and Neglected Pediatric Diseases
On Wednesday, July 21, the US Senate Committee on Health, Education, Labor, and Pensions held a hearing entitled, "Treating Rare and Neglected Pediatric Diseases: Promoting the Development of New Treatments and Cures."
A panel at the hearing featured Dr. Jesse Goodman, chief scientist at the FDA, and Dr. Alan Guttmacher, the new director of the National Institute of Child Health and Human Development of the National Institutes of Health. A second panel included representatives from various non-governmental organizations.
Participants advocated for a range of solutions, including increased federal funding for clinical registries, more stringent guidelines for patient registries, and establishing a federal policy in regards to orphan drugs and rare diseases; all of which would have an ultimate goal of encouraging researchers to develop drugs for those rare diseases that currently have none.
For more information and a video, visit: http://help.senate.gov/hearings/hearing/?id=d132692d-5056-9502-5da9-23c77808a20f
[Sept 1, 2010 mem]
Promising Therapies for Niemann-Pick Type C Disease
National Institute of Neurological Disorders and Stroke Meeting
June 2010
We have had quite a bit of discussion on our listserv pertaining to the recent research and treatment options for Niemann-Pick Type C (NPC) Disease.
To provide some background and insight for these continuing discussions, we have compiled a summary of the presentation abstracts from the "Promising Therapies for Niemann-Pick Type C Disease" meeting sponsored by the National Institute of Neurological Disorders and Stroke (a division of the US National Institute of Health) in Rockville, Maryland, June 3-4.
[July 9, 2010 mem]
Niemann-Pick Type C Pathogenesis and Treatment: From Statins to Sugars
Moneek Madra and Stephen L. Sturley
A paper titled Niemann-Pick type C pathogenesis and treatment: from statins to sugars was recently published. The paper is by Moneek Madra, Department of Pediatrics, and Stephen L. Sturley, Institute of Human Nutrition, both of Columbia University Medical Center in New York, New York. Click here for the pdf.
[June 9, 2010 mem]
FDA grants “Orphan Drug Designation” to Cyclodextrin for treatment of
Niemann-Pick Disease Type C
Due to the efforts of Hugh and Chris Hempel, Dr. Caroline Hastings and Ron Browne, an application to the Food and Drug Administration requesting “Orphan Drug Status” for Cyclodextrin has been approved.
What exactly does that mean for our NPD community? It is important to emphasize that an Orphan designation does not make any assessment at all on how the drug works in clinical trials, whether it is safe or effective in patients, nor whether it will ever be commercially available – the Orphan designation’s main purpose is to make the development of the drug more financially viable for the developer.
Please visit our cyclodextrin page for a bit of background and glossary terms that will help you to understand this latest development.
[May 25, 2010 mem]Are Stem Cells or Gene Replacement Viable Therapies for NPC?
April 13, 2010: In response to recent questions from NPC families, the NNPDF asked Dr. Dan Ory, Chair of the Foundation's Scientific Advisory Board, about the possibility of using either stem cells or gene replacement as therapies for Niemann-Pick Disease Type C.
Here is Dr. Ory's response:
I know of no evidence that gene replacement therapy is effective for NPC disease. There may be work going on in this area, but there is nothing promising on the horizon.
[ Re. the suggestion ]... that stem cell therapy is efficacious in the NPC1 mouse model... I am not aware of this. In fact, in my own lab I replicated the experiments done by labs claiming to show benefit from stem cell transplantation, only to find that the protocols actually worsened symptoms and shortened the life span of the mice. Any claim that with our current technology that stem cell transplantation is beneficial should be met with extreme skepticism.
[Apr 15, 2010 mem]
Report from WORLD Meeting
Cate Walsh Vockley, NNPDF Coordinator of Education, Referral and Advocacy, recently returned from the 2010 WORLD (We're Organizing Research for Lysosomal Diseases) meeting.
Click here to read Cate's summary of the meeting's sessions.
[Mar 17, 2010 mem]
NIH and FDA Announce Collaborative Initiative
Partnership to Speed New Treatments to Patients
The U.S. Food and Drug Administration and the National Institutes of Health have announced an initiative intended to accelerate the timeline between scientific breakthrough and the availability of innovative medical therapies to patients.
From the NIH's press release:
The initiative involves two interrelated scientific disciplines: translational science, the shaping of basic scientific discoveries into treatments; and regulatory science, the development and use of new tools, standards and approaches to more efficiently develop products and to more effectively evaluate product safety, efficacy and quality. Both disciplines are needed to turn biomedical discoveries into products that benefit people.
As part of the effort, the agencies will establish a Joint NIH-FDA Leadership Council to spearhead collaborative work on important public health issues. The Joint Leadership Council will work together to help ensure that regulatory considerations form an integral component of biomedical research planning, and that the latest science is integrated into the regulatory review process.
Click here to read the entire press release.
[Mar 5, 2010 mem]
United States FDA Advisory Committee Backs Use of Zavesca for NPC
Significant Step Toward Possible FDA Approval
An advisory committee comprised of medical and clinical experts will recommend to the U.S. FDA that Zavesca (miglustat) be approved for use in Niemann-Pick Disease Type C (NPC) patients. The advisory committee reviewed data and heard statements and testimony from scientists, doctors and NPC families in a daylong review January 12.
If the FDA approves the use of Zavesca for NPC, it will be an historic step, as this would be the first authorized treatment for the symptoms of NPC in the United States.
Please visit our Newsline page for more details. Also, read the Reuter's article about the panel's review and recommendation here.
[Jan 13, 2009 mem]
More Details on Cyclodextrin from Dr. Dietschy's Lab
Work continues in Dr. John Dietschy's lab at UT Southwestern (Texas), aimed at understanding the way cyclodextrin works in NPC cells and the effect of its administration at various stages of disease in the NPC1 mouse. A recent paper shows reversal of cholesterol storage and decreased inflammation in a variety of tissues 48 hours after administration of cyclodextrin. However, lifespan of the NPC1 mouse is extended only following very early administration of the compound. Research continues.
For more details, visit: http://www.jlr.org/cgi/rapidpdf/jlr.M000257v1
[Dec 21, 2009 mem]
Adenovirus RID-
activates an autonomous cholesterol regulatory mechanism
that rescues defects linked to Niemann-Pick disease type C
An adenovirus membrane protein called RID-α (RID-alpha) may provide a route to bypass the lipid-sorting defects in cells of patients who have NPC by providing an alternate pathway for cholesterol trafficking.
Learn more at:
Abstract http://jcb.rupress.org/cgi/content/abstract/187/4/537
Podcast http://jcb.rupress.org/cgi/content/full/jcb.200903039/DC2
[Dec 21, 2009 mem]
Stem Cell Derived Neurons for Research Relevant to
Alzheimer's and Niemann-Pick Type C Diseases
Work being done in the lab of award-winning scientist Dr. Lawrence Goldstein at the University of California, San Diego, looks at the relationship between Niemann-Pick disease, type C and Alzheimer disease. Failure of proper transport of proteins, lipids and other materials may play a significant role in the cell breakdown and death in these 2 diseases. To learn more, click the following link: http://www.sciencedaily.com/releases/2009/12/091209134627.htm
[Dec 21, 2009 mem]
Edinburgh Neuroscience Christmas Lecture 2009
While the following link will take you to a fairly technical overview , for those who are interested in the potential for stem cell therapies, it is a fascinating lecture. Two University of Edinburgh, Scotland, professors provide a review of the current status of developments in stem cell research and future applications to clinical medicine. Their focus is on neurological disorders such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig disease) and Parkinson disease. Their initial work focuses on study of genes that are active in regenerating brain tissue, something that does happen, but which becomes less efficient with age. They look at targeting expression of these genes through use of medications in order to carry out brain repair. They also look at use of stem cells, both embryonic stem cells and those created from adult cell lines. Note that this is an overview and some issues, such as the difficulties encountered with aging of "embryonic" stem cells produced from adult cells, are not discussed.
http://www.edinburghneuroscience.ed.ac.uk/ChristmasLecture/2009/Index.html
[Dec 21, 2009 mem]
New Postdoctoral Research Fellowships
The NNPDF is very pleased that contracts have been finalized for the first two Peter G. Pentchev Research Fellowships. Visit our Current and Recent Research Grants page for links to read the lay summaries of fellows Dr. Ian Williams and Dr. Fabrizio Vacca.
[Dec 18, 2009 mem]
U.S. Food and Drug Administration Grants Priority Review for Zavesca
Committee Discussion Scheduled for January 12, 2010
A press release issued by Actelion Ltd, makers of Zavesca (miglustat), announced that a supplemental new drug application for an extension of indication for Zavesca for the treatment of progressive neurological manifestations in NPC has been accepted by the U.S. Food and Drug Administration (FDA).
Further, the FDA has granted Zavesca a priority review designation, given to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. It also means that the FDA will aim to complete the review within six months. Read the full press release here.
On January 12, 2010, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee will discuss new drug application (NDA) 21–348, ZAVESCA (miglustat), 100 milligram (mg) capsules, by Actelion Pharmaceuticals, Ltd., proposed for the treatment of progressive neurological manifestations (symptoms related to the nervous system) in patients with Niemann-Pick Disease (type C). Read more, including how you can submit a written statement or make an oral presentation to the committee, here: http://www.fda.gov/AdvisoryCommittees/Calendar/ucm191156.htm
[Dec 1, 2009 mem]
New Paper on Cyclodextrin
"Cyclodextrin overcomes deficient lysosome-to-endoplasmic
reticulum transport
of cholesterol in Niemann-Pick type C cells."
Research from the lab of Drs. Michael Brown and Joseph Goldstein was recently published online (in advance of print publication) in a highly regarded
scientific journal, The Proceedings of the National Academy of Science. The abstract, or summary, of the work is available at:
http://www.ncbi.nlm.nih.gov/pubmed/19884502?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1
The paper provides details about the processing of cholesterol in NPC1-deficient cells if it can be released from the lysosomes, and about how
cyclodextrin assists in moving cholesterol out of the lysosome and into the
cell cytoplasm, where they hypothesize that it will be less damaging to cell function.
The authors note that additional study is needed to understand
whether there are specific conditions under which the cyclodextrin works to
move cholesterol, and the specific way it works, which is not yet
understood.
The full paper should be available in about six months. We
look forward to reading more about this work in the future.
Please contact me if you have any questions..
Cate Walsh Vockley, MS, CGC
Coordinator of Education, Referral and Advocacy
National Niemann-Pick Disease Foundation
Senior Genetic Counselor
412-692-7349
catherine.walshvockley@chp.edu
[Nov 16, 2009 mem]
Psychosocial Aspects of Niemann-Pick Disease, Type B
Dr. Wendy Packman, et al.
A new research article titled, "Psychosocial Aspects of Patients with Niemann-Pick Disease, Type B," was published recently in the online American Journal of Medical Genetics. The article is by Dr. Wendy Packman and colleagues.
For more information, including the abstract, please click here.
[Nov 16, 2009 mem]
New Paper from Dr. Wraith and Jackie Imrie
"New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat"
A new paper by Dr. James E. "Ed" Wraith and Jackie Imrie, regarding Miglustat (Zavesca) and NPC, was published recently. Please visit Dovepress to read the abstract and the complete document.
[Nov 10, 2009 mem]
Study Conclusively Ties Rare Disease Gene to Parkinson's Disease
Dr. Ellen Sidransky’s Research Regarding Gaucher and Parkinson Disease
"An international team led by a National Institutes of Health researcher has found that carriers of a rare, genetic condition called Gaucher disease face a risk of developing Parkinson’s disease more than five times greater than the general public. The findings were published ... in the New England Journal of Medicine.
In previous studies, several genes have been linked to Parkinson's disease. However, researchers say their work conclusively shows that mutations in the gene responsible for Gaucher disease are among the most significant risk factors found to date for Parkinson's disease. The discovery was made by investigators from the National Human Genome Research Institute (NHGRI) and the National Institute on Aging (NIA), both parts of the National Institutes of Health, in collaboration with scientists from 16 research centers across four continents.
'This analysis illustrates how studying a rare but important disorder, like Gaucher disease, can provide powerful clues about more common disorders, such as Parkinson's disease," said NHGRI Scientific Director Eric Green, M.D., Ph.D. "Understanding the genetic basis of rare conditions can thus provide insights into normal cellular and biological processes, which in turn may lead to improved diagnostic and therapeutic strategies.' "
Read the full article here: http://www.nih.gov/news/health/oct2009/nhgri-21.htm
Dr Sidransky is also interested in investigating the possible association between NPC and three specific neurodegenerative disorders - Parkinson disease, ALS (Lou Gehrig disease), and early-onset Alzheimer disease (diagnosed before the age of 65). The aim would be to see if a relative of an NPC patient who has any of these other neurodegenerative diseases also carries an NPC mutation. See also “Neurodegenerative Disease in Family Members of Patients with Niemann-Pick Disease, Type C” .
[Oct 30, 2009 mem]
Enzyme Replacement Therapy Clinical Trial (Type B)
Phase 1 Concluded
Results from Phase 1 of the Enzyme Replacement Therapy Clinical Trial (Type B) will be presented at the American Society of Human Genetics Meeting in October. Read the message from Dr. Margaret McGovern regarding the conclusion of Phase 1, and view the poster she and her team presented at the International Congress for Inborn Errors of Metabolism.
[Sept 14, 2009 mem]
Zavesca Officially Launched in United Kingdom
On July 21, 2009, Actelion Ltd. announced the launch of Zavesca® (miglustat) in the UK and Republic of Ireland; the first and only licensed treatment available for people with Niemann-Pick type C (NP-C) disease.
Ed Wraith, M.D., Royal Manchester Children's Hospital, commented: "For the first time we have an approved therapy for NP-C. The data on the effects of treatment with Zavesca® obtained in a clinical trial and in a retrospective cohort study consistently showed a favorable clinical response. As a treating physician I am acutely aware of the importance of reducing progression of neurological symptoms."
Zavesca®, which was granted orphan drug status allowing for a faster approval process, is now approved in all EU countries for the treatment of patients with NP-C and is available in all the EU countries according to the local reimbursement process. Regulatory proceedings to extend the use of Zavesca® in patients with NP-C are ongoing in other countries worldwide.
Click here to read the complete press release.
[Aug 19, 2009 mem]
NPC Clinical Trial Opportunity
Message from Dr. Forbes "Denny" Porter, National Institutes of Health
The NNPDF has received an update from Dr. Denny Porter at the National Institutes of Health regarding an upcoming NPC Clinical Trial opportunity. Please click here to read Dr. Porter's message.
We encourage anyone with questions about the study to contact Nicole Yanjanin at Dr. Porter’s office: 1-301-594-1765; nyanjanin@mail.nih.gov.
Dr. Porter plans to present more details related to this trial at our upcoming NNPDF Family Support and Medical Conference in Seattle, Washington, July 30 - Aug. 2. Please contact the NNPDF Central Office if you need assistance registering or finalizing your travel plans for the NNPDF Family Conference.
[July 9, 2009 mem]
Updates on OrphaNews
Newsletter of the Rare Diseases Task
Force
Visit OrphaNews Europe to read the following updates:
National and International Policy Developments: A Canadian province adopts rare disease drug evaluation programme.
Ethical, Legal and Social Issues: An international expert group reiterates the need to adhere to guidelines for stem cell clinical applications.
[July 13, 2009 mem]
Papers Published in Cell Metabolism Journal
Dr. Heiko Runz of the University Clinic - Heidelberg (Germany), has a paper titled "Identification of Cholesterol-Regulating Genes by Targeted RNAi Screening" published in the July 2009 issue of Cell Metabolism.
Read the announcement here: http://www.eurekalert.org/pub_releases/2009-07/embl-sic070609.php
The full text of the paper is available here: http://www.cell.com/cell-metabolism/fulltext/S1550-4131(09)00157-0
This research was funded in part by the Ara Parseghian Medical Research Foundation.
In the same issue of Cell Metabolism is an article by Drs. Munkacsi, Pentchev and Sturley:
Spreading the Wealth: Niemann-Pick Type C Proteins Bind and Transport Cholesterol
[July 13, 2009 mem]
NNPDF/Peter G. Pentchev
Research Fellowship
Request for Applications
In 2008 the NNPDF Board undertook an extensive review of its research funding strategy and produced a new Strategic Plan for Research.
As a result, we are pleased to announce that the NNPDF will fund Post Doctoral Research Fellowships in all areas of promise with regard to Niemann-Pick Disease.
The NNPDF Board is determined to ensure that research funds are well spent and to provide funding that is most likely to accelerate finding an effective therapy or cure for all types of Niemann-Pick Disease.
Please click here to learn more about NNPDF/Peter G. Pentchev Research Fellowships, or hover your mouse pointer/cursor over the Niemann-Pick Research tab in the bar above (in light blue box) to view a dropdown list of more Research pages.
[Feb 20, 2009 mem]
A Prospective, Cross-sectional Survey Study of the Natural History of Niemann-Pick Disease Type B
Read the Publication published July 14th, 2008
Chemical chaperone could open door to treatment of neurological disorder. (Posted February 6th, 2008.)
Read the press release from Washington University of St. Louis
Year-1 results show that miglustat improves or stabilizes several clinically relevant markers of Niemann-Pick Type C.
Read the press release from Actelion
Genzyme announces novel gene therapy approach for NPD Types A and B.
The National Niemann-Pick C1 Disease Database: Report of clinical features and health problems.
Graver WS, Francis GA, et al. 2007. Am J Med Genet A. 143A(11):1204-1211.
Miglustat (Zavesca) animal toxicology study data released
Injection of mouse and human neural stem cells into neonatal Niemann-Pick A model mice.
Sidman RL, Li J, Stewart GR, Clarke J, Yang W, Snyder EY, Shihabuddin LS. Brain Res. 2007 Apr 6;1140:195-204. Epub 2007 Jan 9. PMID: 17289003 [PubMed - in process]
Stem cell treatment of mouse model of NPD type A shows improvement in some areas.
Mihaylova V, Hantke J, Sinigerska I, Cherninkova S, Raicheva M, Bouwer S, Tincheva R, Khuyomdziev D, Bertranpetit J, Chandler D, Angelicheva D, Kremensky I, Seeman P, Tournev I, Kalaydjieva L. Brain. 2007 Mar 14; [Epub ahead of print]
Findings indicate that mutation analysis is of limited value in predicting brain damage in intermediate ASM deficient NPD (Type A/B variant), and the option of enzyme replacement therapy should be considered.
Kinematic analysis of motor dysfunction in Niemann-Pick type C.
Floyd AG, Yu QP, Piboolnurak P, Wraith E, Patterson MC, Pullman SL. Clin Neurophysiol. 2007 Feb 26; [Epub ahead of print]
The first descriptive analysis of upper limb motor physiology in Niemann-Pick Type C disease. These quantitative methods may help to evaluate efficacy, and side effects, of new treatments as they are developed.
The natural history of Niemann-Pick disease type C in the UK.
Imrie J, Dasgupta S, Besley GT, Harris C, Heptinstall L, Knight S, Vanier MT, Fensom AH, Ward C, Jacklin E, Whitehouse C, Wraith JE. J Inherit Metab Dis. 2007 Feb;30(1):51-9. Epub 2006 Dec 11. PMID: 17160617 [PubMed - indexed for MEDLINE]
The clinical presentation and follow-up of 94 patients with NPC is described, 58 of whom were still alive at the time this report was prepared. The age at diagnosis ranged from the prenatal period (with hydrops fetalis) up to 51 years.
Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations.
larner B, Klunemann HH, Lurding R, Aslanidis C, Rupprecht R. J Inherit
Metab Dis. 2007 Feb;30(1):60-7. Epub 2006 Dec 11.
PMID: 17160616 [PubMed - indexed for MEDLINE]
Evaluation of a test battery that could be used to assess cognitive deficits in different stages of NPD Type C. Observations found that visuospatial working memory was less affected by the neurodegenerative process than verbal working memory.
Beltroy EP, Liu B, Dietschy JM, Turley SD. J Lipid Res. 2007
Jan 14; [Epub ahead of print]
PMID: 17220530 [PubMed - as supplied by publisher]
Studies used npc1-mutant mice to investigate the association between liver dysfunction and unesterified cholesterol accumulation. Results suggest it is the late endosomal/lysosomal content of unesterified cholesterol that correlates with cell damage in NPC disease.
Characterization of liver disease and lipid metabolism in the Niemann-Pick C1 mouse.
Garver WS, Jelinek D, Oyarzo JN, Flynn J, Zuckerman M, Krishnan K, Chung BH, Heidenreich RA. J Cell Biochem. 2007 Jan 10; [Epub ahead of print] PMID: 17216601 [PubMed - as supplied by publisher]
Results from this study support the hypothesis that an accumulation of lipoprotein-derived cholesterol within late endosomes/lysosomes, in addition to altered intracellular cholesterol homeostasis, has a key role in the biochemical and cellular pathophysiology associated with NPC1 liver disease.
Lipid homeostasis and lipoprotein secretion in Niemann-Pick C1-deficient hepatocytes
Kulinski A, Vance JE. J Biol Chem. 2007 Jan 19;282(3):1627-37. Epub 2006 Nov 15. PMID: 17107950 [PubMed - indexed for MEDLINE]
Investigation of liver disease in NPC1-deficient mice. Observations indicate that the enhanced secretion of lipoproteins from NPC1-deficient hepatocytes is due, at least in part, to increased lipid synthesis.
Linder MD, Uronen RL, Holtta-Vuori M, van der Sluijs P, Peranen J, Ikonen
E. PMID: 17050734 [PubMed - indexed for MEDLINE]
Mol Biol Cell. 2007 Jan;18(1):47-56. Epub 2006 Oct 18.
Results show that the overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts. Rab8 is established as a key component of the regulatory machinery that leads to ABCA1-dependent removal of cholesterol from endocytic circuits.
Clues to neuro-degeneration in niemann-pick type C disease from global gene expression profiling.
Reddy JV, Ganley IG, Pfeffer SR. PLoS ONE. 2006 Dec 20;1:e19. PMID: 17183645 [PubMed - in process
NPC1 mutant cells display an inappropriate homeostatic response to accumulated intracellular cholesterol. In addition, a number of striking parallels were observed between NPC disease and Alzheimer's disease.