University of Notre Dame Press Release Claims Breakthrough
A paper claiming a breakthrough in the fight against Niemann-Pick Disease Type C (NPC) appeared 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 an unspecified histone deacetylase inhibitor corrects the damage done by the genetic disorder NPC and allowed once-diseased cells to function normally. Follow this link to view an abstract of this paper at PNAS: http://www.pnas.org/content/early/2011/03/15/1014890108
To help understand the press release issued by Notre Dame on March 21, the NNPDF consulted three respected experts in Niemann-Pick Disease Type C: Dr. Dan Ory of Washington University, Dr. Marc Patterson of Mayo Clinic, and Dr. Denny Porter of the National Institutes of Health. Follow this link to view the Notre Dame press release dated March 21, 2011: http://www.eurekalert.org/pub_releases/2011-03/uond-bin032111.php
Daniel Ory, M.D., Washington University School of Medicine, and Chair of the NNPDF’s Scientific Advisory Board, responded to our 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.”
The paper by Wiest, Helquist and Maxfield does not name the specific histone deacetylase inhibitor. 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 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.
This summary was compiled by the NNPDF Central Office staff with thanks to the members of our esteemed Scientific Advisory Board. (March 31, 2011)
The National Niemann-Pick Disease Foundation (NNPDF) does not engage in the practice of medicine. It is not a medical authority nor does it claim to have medical knowledge. This site is an educational service of the National Niemann-Pick Disease Foundation and is not meant to provide diagnostic or treatment advice. Information contained or suggested on this Web site does not constitute medical advice. For all information related to care, medication or treatment, the NNPDF recommends consulting a physician to determine if information presented is applicable. Please review these additional cautions about medical information provided on the Internet.
April 9, 2011
Promising Trial
NIH to Develop Clinical Trial Utilizing Cyclodextrin
Informational Conference Call to be Scheduled
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. Porter, a Senior Investigator at the NIH, and Dr. Ory, NNPDF Scientific Advisory Board Chair, are working collaboratively to bring this trial to our NPC patient community.
In early May, the NNPDF will host 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 will include information pertaining to the development of plans for a cyclodextrin trial.
As a date and details for the conference call are confirmed, the NNPDF will update and inform our NPC family membership with the call-in information, agenda outlines and topics of discussion. We anticipate that after the presentation, the conference call format will allow participants to submit questions to the speakers/researchers.
Further updates on the clinical trial will be presented at the NNPDF Family Support and Medical Conference in Norfolk, Virginia, July 28th - 31st. Dr. Porter and Dr. Ory will answer questions pertaining to the clinical trial and will report up-to-date information about the trial at the conference.
For more information about Niemann-Pick Disease and the National Niemann-Pick Disease Foundation, visit http://www.nnpdf.org/.
Informational Conference Call to be Scheduled
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. Porter, a Senior Investigator at the NIH, and Dr. Ory, NNPDF Scientific Advisory Board Chair, are working collaboratively to bring this trial to our NPC patient community.
In early May, the NNPDF will host 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 will include information pertaining to the development of plans for a cyclodextrin trial.
As a date and details for the conference call are confirmed, the NNPDF will update and inform our NPC family membership with the call-in information, agenda outlines and topics of discussion. We anticipate that after the presentation, the conference call format will allow participants to submit questions to the speakers/researchers.
Further updates on the clinical trial will be presented at the NNPDF Family Support and Medical Conference in Norfolk, Virginia, July 28th - 31st. Dr. Porter and Dr. Ory will answer questions pertaining to the clinical trial and will report up-to-date information about the trial at the conference.
For more information about Niemann-Pick Disease and the National Niemann-Pick Disease Foundation, visit http://www.nnpdf.org/.
March 26, 2011
Ty's in Springfield making a splash!!
Sy's family reunion was this weekend in Springfield, Illinois! It is always a little hard on Tylor to travel and be out of his route but he had so much fun. He got to spend time with his cousin's and swim! He had a blast in the pool! He splashed me a lot...but don't worry I got him back. Here are some pictures from the weekend. I hope you enjoy them.
March 23, 2011
Breakthrough at Notre Dame
Artical from the Wall Street Journal
By Amy Dockser Marcus
Researchers at Weill Cornell Medical College and the University of Notre Dame said they used drugs being tested for cancer to correct a cholesterol-storage defect in a lethal, rare disease called Niemann-Pick Type C (NPC).
The researchers found that a compound called LBH589, part of a group of drugs called histone deacetylase (HDAC) inhibitors, corrected the defect in human NPC cells in a lab setting. The LBH589 compound is being studied in clinical trials to treat several forms of cancer, including brain cancer. The idea of repurposing drugs used in more common diseases to try to treat rare conditions is an increasingly popular approach to drug development.
The finding, published this week in the Proceedings of the National Academy of Science, is considered early stage since the experiments were done in tissue culture models of NPC, a genetic cholesterol-metabolism disorder that is ultimately fatal. Typically, promising compounds are then tested in an animal model before being tried in humans. Compounds that work in cells are not always effective in animals or humans.
Paul Helquist, one of the authors of the PNAS paper and a professor of chemistry and biochemistry at Notre Dame, says the researchers are hopeful that the class of inhibitors might be useful not only in NPC disease but in other neurodegenerative disorders where lipids inappropriately accumulate in cells. He said that they would like to test the compound in a cat model of NPC disease.
The paper comes at a time when the NIH is gearing up for a clinical trial involving another promising compound, cyclodextrin, that has been tested in animal models and is being given experimentally to a small number of children. Last week, NIH director Francis Collins discussed the NIH’s NPC efforts in a webinar sponsored by the FasterCures organization.
It isn’t easy to get clinical trials going in rare diseases like NPC, which affects only an estimated 500 people world-wide. The number of patients is so small that it is difficult to attract pharmaceutical company interest. As a result, unusual partnerships are sometimes needed between patient advocacy organizations and researchers to try to drive research and trials.
The PNAS paper represents one such partnership. The research was funded in part by the Ara Parseghian Medical Research Foundation. Parseghian, the former Notre Dame head football coach, had three grandchildren who died from NPC.
Last summer, the Notre Dame College of Science dean and his wife biked over 2000 miles from Tucson — where the Parseghian Foundation is based — to Notre Dame to raise awareness about NPC. The foundation set up an endowment at Notre Dame last year to support research into and an annual scientific conference about the disease.
Among the programs, Notre Dame offers an undergraduate course at its Center for Rare and Neglected Diseases to teach undergraduates how to collect and analyze data from NPC patients. Notre Dame also has a program open to researchers who want to synthesize potential drugs for use in experiments or trials in rare or neglected diseases, including NPC.
Photo: Associated Press
By Amy Dockser Marcus
Researchers at Weill Cornell Medical College and the University of Notre Dame said they used drugs being tested for cancer to correct a cholesterol-storage defect in a lethal, rare disease called Niemann-Pick Type C (NPC).
The researchers found that a compound called LBH589, part of a group of drugs called histone deacetylase (HDAC) inhibitors, corrected the defect in human NPC cells in a lab setting. The LBH589 compound is being studied in clinical trials to treat several forms of cancer, including brain cancer. The idea of repurposing drugs used in more common diseases to try to treat rare conditions is an increasingly popular approach to drug development.
The finding, published this week in the Proceedings of the National Academy of Science, is considered early stage since the experiments were done in tissue culture models of NPC, a genetic cholesterol-metabolism disorder that is ultimately fatal. Typically, promising compounds are then tested in an animal model before being tried in humans. Compounds that work in cells are not always effective in animals or humans.
Paul Helquist, one of the authors of the PNAS paper and a professor of chemistry and biochemistry at Notre Dame, says the researchers are hopeful that the class of inhibitors might be useful not only in NPC disease but in other neurodegenerative disorders where lipids inappropriately accumulate in cells. He said that they would like to test the compound in a cat model of NPC disease.
The paper comes at a time when the NIH is gearing up for a clinical trial involving another promising compound, cyclodextrin, that has been tested in animal models and is being given experimentally to a small number of children. Last week, NIH director Francis Collins discussed the NIH’s NPC efforts in a webinar sponsored by the FasterCures organization.
It isn’t easy to get clinical trials going in rare diseases like NPC, which affects only an estimated 500 people world-wide. The number of patients is so small that it is difficult to attract pharmaceutical company interest. As a result, unusual partnerships are sometimes needed between patient advocacy organizations and researchers to try to drive research and trials.
The PNAS paper represents one such partnership. The research was funded in part by the Ara Parseghian Medical Research Foundation. Parseghian, the former Notre Dame head football coach, had three grandchildren who died from NPC.
Last summer, the Notre Dame College of Science dean and his wife biked over 2000 miles from Tucson — where the Parseghian Foundation is based — to Notre Dame to raise awareness about NPC. The foundation set up an endowment at Notre Dame last year to support research into and an annual scientific conference about the disease.
Among the programs, Notre Dame offers an undergraduate course at its Center for Rare and Neglected Diseases to teach undergraduates how to collect and analyze data from NPC patients. Notre Dame also has a program open to researchers who want to synthesize potential drugs for use in experiments or trials in rare or neglected diseases, including NPC.
Photo: Associated Press
March 4, 2011
Leah's story
AN ITV crew spent two-and-half years filming Leah Garfitt, who suffers from the genetic illness Niemann Pick Disease Type C, and her family in Fleetwood.
Leah, who is nine years old and attends Red Marsh School, Thornton, is one of only 500 children in the world suffering from the disorder which attacks the nervous system.
It has already robbed the pretty youngster of the ability to talk and walk, and she now has numerous other problems including dementia.
And tragically, the illness is likely to cost the youngster her life before she reaches the age of just 15.
However, from Leah’s heart-breaking story film maker Chris Malone has created a film which he says is uplifting and carries a message of love, bravery and down-to earth determination.
The programme, Leah’s Dream, was broadcast on Tuesday, March 1, at 9pm on ITV1.
Manchester-based Chris told the Weekly News: “There is a sad story at the heart of it because of Leah’s illness, but in many ways it is uplifting.
“It is a love affair between a little girl and her devoted mother, Lindsey Patterson, who has to come to terms with her daughter’s illness, and the strength of their family when things are tough.
“Lindsey then also has to face up to her own illness when she is diagnosed with a brain tumour and almost dies on the operating table.”
Chris added: “The film is also about the community of Fleetwood.
“When I started filming in Fleetwood I fell in love with this place; the community is so warm and down to earth.
“Everyone seems to know Leah and there is a lot of love for her in the town.”
Well known places in Fleetwood were featured in the film, including the Ferry Cafe, the beach and promenade.
The TV film also touched on Leah’s trip to Disney World on Florida.
Funds for this once-in a lifetime trip were during a Weekly News campaign which raised an astounding £10,500 plus over 2007/8.
Fleetwood’s community responded magnificently with fundraisers and donations large and small, ensuring that Leah could enjoy the special trip while she was well enough.
Tragically, today such a trip would be impossible because Leah is not well enough.
The film starts at Leah’s seventh birthday where she is celebrating and singing along to High School musical, and follows her for the next two-and-half years.
Lindsey tells the programme about how Leah was diagnosed with Niemann-Pick as a baby after she noticed her little girl seemed tired and fragile.
Both Lindsey and Leah’s father, Michael Garfitt, carry the gene but were unaware of it.
Lindsey, of Wansbeck Avenue, Fleetwood, says in the documentary: “Not too sure what the future holds for Leah. To be honest and true, your living in limbo.”
And dad Michael says of his precious daughter: “She has taught me to care for people more, I think.
“Just to enjoy what you’ve got.”
A Father speaks about their struggle with NPC
Carl and Emma Burdon, like most parents, want to fill their child's life with as much love as they can.
Every moment with their six-year-old son Calum is particularly precious to the Freckleton couple, though, because he has a rare genetic disorder.
Calum has Niemann-Pick condition (NPC) which is likely to claim his life before he reaches his 10th birthday.
Mr Burdon said: "We have had to accept that unless there is a miracle, Calum is going to die young.
"Children don't usually survive past the age of eight or nine."
Calum was born with an enlarged spleen, one of the symptoms of the condition, but he was almost two when he was diagnosed with Niemann-Pick type C.
'In denial'
The couple were concerned he was not running or jumping about like normal toddlers and doctors did genetic tests on him which confirmed he had the disease in May 2006.
Mr Burdon said it was very difficult to accept. He said: "The hardest thing is the feeling that you can't do anything about it, that gets to you. There's no cure and no treatment and you feel useless."
The family have concentrated their efforts "on squeezing a lifetime of love in whatever time we have with him" and fundraising for children with the disease.
Both singers, the couple have done countless charity gigs for good causes in the past. "It really hits home, though, when you are doing events for your own child."
They stage an annual charity golf day and evening meal at Garstang Golf Club which is being held on 15 July this year and they are aiming to raise £10,000.
The trauma of living with a death sentence hanging over Calum's head has brought the couple closer.
"It's very tough to deal with but we're very committed to Calum and to each other."
Calum Burdon is going to Disneyworld in May through Hopes and Dreams charity His two children from a previous marriage Ricky and Derry, who do not have the condition, are equally supportive.
"They dote on Calum and make a real fuss of him. He always perks up when they're around."
According to the Niemann-Pick Disease Foundation, there are just 500 cases diagnosed worldwide - yet there is another child with the disorder from the Fylde coast.
Nine-year-old Leah Garfitt, the subject of Tuesday night's ITV documentary Leah's Dream, lives less than 20 miles from Calum in Fleetwood.
The two families have formed a bond and Calum and Leah meet up when they go to Brian's House at Trinity Hospice.
As well as support from Brian's House, the family say they also get much needed support from the Niemann-Pick Disease UK.
The charity's executive director, Toni Mathieson, has personal experience of the condition. Three of her children had it.
Now one of the UK's leading authority on the disorder, she said: "Sadly it is always fatal at the moment and it is a very difficult and challenging time for the families of children with the disease. It is never easy."
Mr Burdon glows with pride at his son. "We are so proud of Calum and his achievements but it isn't the usual things you would be proud of your children for - it can be him getting off the couch or finishing a sentence."
A snooker fan, Calum has met his heroes, including a home visit from three-times World Champion John Higgins through his cue doctor Kevin Muncaster who is from Freckleton.
"The look on his face when he realised it was John Higgins was fantastic."
Sports presenter Andy Goldstein has organised it for the couple to take Calum to Disneyworld in May through the Hopes and Dreams charity.
It will be a poignant, though. "We're creating memories for him but we're aware it will probably be his last trip."
Despite the inevitability of his condition, Calum is not short of giving or receiving affection. "I don't know any child who has had as much love and kisses as Calum has."
"He knows he is special, but he just doesn't know why," added Mr Burdon.
NIEMANN-PICK TYPE C FACTS
The disease is inherited. Both parents have to be carriers of the faulty gene and there is a 25% chance that they will pass on the condition to their child
It occurs when the body cannot break down cholesterol and other fats, leading to excessive levels of cholesterol in the liver, spleen and the brain
The condition is characterized by eye movement abnormalities, difficulty in swallowing and slurred, irregular speech, lack of muscle control and intellectual decline leading to dementia
Yum Yum
This week Tylor got a very special package in the mail from Rich, a counselor from Albrecht Acres. He lives in the UK. He sent Tylor a ton of British candy and a letter.
Thank you Rich!! Tylor's face lite up when I read him your letter. He was so happy to hear from you and he loved the candy. And yes Tylor is going back to camp. Take care and we will see you this summer.
Thank you Rich!! Tylor's face lite up when I read him your letter. He was so happy to hear from you and he loved the candy. And yes Tylor is going back to camp. Take care and we will see you this summer.
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