April 28, 2011

Rare Diseases: Will push for new drugs pay off?

Cassidy Hempel, 6, waves at hospital staff with the help of her mother, Chris, at the Children's Hospital and Research Center in Oakland, Calif., Friday, March 18, 2011. Cassidy and twin sister, Addison, are being treated for a fatal disorder called Niemann Pick Type C disease. (Credit: AP Photo)

(CBS/AP)Call it the rare disease gap. Scientists have identified more than 7,000 diseases that affect fewer than 200,000 people, but treatments are available for just 200 of the diseases.

But now there's a move to close the gap. The National Institutes of Health this fall will open a center to speed genetic discoveries into usable therapies, doing some of the riskiest early-stage research in hopes companies then will step in.

A new International Rare Diseases Research Consortium is pushing for at least 200 more treatments by 2020, in part by pooling the work of far-flung scientists and families.

Rather than starting from scratch, the FDA is pointing the way for manufacturers to "repurpose" old drugs for new use against rare diseases, publishing a list of those deemed particularly promising.

And legislation recently introduced in the Senate, called the Creating Hope Act, would offer drug makers another financial incentive - a voucher promising fast FDA evaluation of their next blockbuster drug in return for developing a therapy for a rare or neglected disease that disproportionately affects children.

"We have to give drug companies a reason to go into this market," says Nancy Goodman of Kids v Cancer, a group pushing the legislation. Her son Jacob died at age 10 from a type of brain cancer that has no good treatment.

Pharmaceutical giants are starting to show some new interest in rare diseases, traditionally a niche market for small biotech companies. The practical reason: Blockbusters are drying up, says Dr. Ed Mascioli of Pfizer Inc., the world's largest drug company.

Some other companies, including Novartis AG and GlaxoSmithKline PLC, also have begun rare-disease programs.

But NIH Director Dr. Francis Collins says all the activity reflects a larger promise. "Getting a home run with a rare disease sometimes points you in a direction that will be beneficial for common diseases," he told The Associated Press.

That's the argument put forth by Chris Hempel, of Reno, Nev. Her 7-year-twin girls have been getting injections of an experimental drug for Niemann-Pick Type C (HPC), a disease that causes cholesterol and other fats to build up inside cells, harming the brain and other organs until patients lose the ability to talk, walk and swallow. Only 500 children worldwide are known to have it. But a drug that could flush out that build-up, Hempel contends, just might point to a new route to fighting heart disease or Alzheimer's.

Hempel isn't alone in her quest to repurpose common drugs. Consider progeria, a disease that rapidly ages children until they die of a heart attack or stroke, usually before their teens.

Collins' lab at NIH uncovered the gene defect behind progeria, research that he says he pursued only because of meeting another mom, Dr. Leslie Gordon, founder of the Progeria Research Foundation, and her son, Sam, who has the disease. Today, clinical trials are under way using a failed cancer drug named lonafarnib that promises to block some of the progeria mutation's effect.

There are an estimated 150 progeria patients worldwide, but Gordon points to growing evidence that the culprit protein may play a role in the heart disease that comes with regular aging, too.

** Taken from CBS News Health Watch **

Rare Diseases in the Spotlight

By Marissa Cevallos, HealthKey

1:55 p.m. EDT, April 27, 2011

Rare diseases are likely to get more attention now that an international consortium of patient advocacy groups and research funders has vowed to deliver 200 new therapies by 2020. For people with these diseases, such attention must seem long overdue.

Drug companies currently don’t have much incentive to develop drugs for diseases that affect fewer than 200,000 people, but almost 7,000 rare diseases exist affecting a total of about 25 million Americans.

Many are caused by mutations in a gene. The National Institutes of Health is opening a center in the fall to translate research findings in genetics to usable therapies, the Associated Press reports.

The NIH already has grant programs to spur research in rare diseases. The NIH's Therapeutics for Rare and Neglected Diseases program has a pipeline of projects. Its pilot projects offer a glimpse into some of the diseases that, though rare, can nonetheless have debilitating consequences.

Schistosomiasis (also known as bilharzia or snail fever): Infection begins when a parasitic worm carried by freshwater snails penetrates the skin and lays eggs in blood vessels. First come rashes, then fever and chills, followed by liver and other organ damage over time. Researchers recently decoded the genomes of two schistosomiasis-causing parasites, which may allow researchers to find ways to inhibit the parasites’ growth. About 200 million people worldwide have the disease, and 280,000 die from it each year.

Niemann-Pick Type C: In this condition, fatty deposits accumulate in the spleen, liver, lungs, bone marrow and brain. Type A, the most common, is fatal in infants. Type C can appear early in life or in young adulthood; it causes brain damage and ultimately can affect walking, swallowing, seeing and hearing. Only about 500 children in the world are known to have Type C. Researchers have found two genes that can contribute to Type C and Type D, but progress is slow.

—Hereditary inclusion body myopathy: Usually starting in young adulthood, the disease causes muscle-wasting, leading to severe disability in 10-20 years. A clinical trial in 2006 found mild benefits from intravenous immune globulin, essentially antibodies from blood plasma. A small gene therapy trial is underway, and stem cell therapies are being considered.

Sickle cell disease: Crescent, or sickle-shaped, blood cells block blood flow in vessels, and can lead to stroke, organ failure or death. The disease affects about 70,000 to 100,000 people in the U.S., mostly African Americans. Only one effective medication exists to help prevent deaths. But a few children and adults have been cured by blood and bone marrow transplants.

Chronic lymphocytic leukemia : This is the most common type of leukemia, a cancer of the bone or blood, found in adults. About 15,000 people are diagnosed each year (and about 101,000 people live with it).

The new consortium’s goal is to have 200 new therapies in nine years. Many people, in seemingly isolated disease groups, are waiting.

** Taken from the Baltimore Sun **

Ty was up for the Challenge

Yes it's that time of year again....Spring, which means Special Olympics Challenge day! But remember we do live in the Midwest so it was a good thing the event was held indoors because it snowed most of the day!! That sure didn't stop Tylor...even though he slept through his first event, team basketball. After his little rest he was ready to take on the rest of the events. He had a huge fan club that followed him throughout the day. His Dad, Step mom, sister, Liv and Kate, brothers, Will and Drew, Grandma Terri, Aunt Rach, Mom, Sy and his helper for the day Samy (his friend from school). He also was a torch bearer in the Opening Ceremonies...they read a bio about him and he passed the torch on to start the games. This was Tylor's third year participating in the Challenge day and he absolutely loved it.

Our little torch bearer

Warming up to YMCA

Making a cool picture frame with Samy and my sisters

You like??

Look Ty is awake

My FAN club

Look at all his ribbons and medal
God Bless

April 14, 2011

What has Ty been up to??

Hello Everyone!

Tylor has been a very busy little (or should I say big??) boy. A few weeks ago he had a speech evaluation to find out if there is a better way for him to communicate with us. Because the disease is not progressing like we thought it would he is still interacting very well but verbal communication is hard for him. The speech therapist suggested we look into DynaVox. This device looks kind of like the iPad, it is all touch screen but it talks for him. He will be able to take pictures with it and add descriptions. We got to try it out with a DynaVox sales rep last week and I think this will work great for Ty. Tylor should receive his in about three weeks. We have four weeks to try it and make sure that it is the right fit for Ty and if it is it's his!!! I am so excited about this...

Last weekend we took a road trip to Milwaukee so watch the Cubs/Brewers game! Of course the Cubs lost but being the die hard Cubs fans that we are you get use to it! Even though they got beat 6 to 0 Tylor had a great time. He was girl watching most of the game. On our way home we visited Tylor's Great Grandma Pearl, Aunt Janet, and Uncle Terry in Rosco, Illinois. He slept most of the time...he was tried after chasing all the girls at the game.

This week Tylor received a bike from therapy, they are letting us keep it for the summer. He lights up every time he is on it. He rides for about 45 minutes everyday....he is pretty tired when we are done. He thinks it's funny to go fast so I have to run along side of him, what a little stinker!

April 9, 2011

More on Histone Deacetylase Inhibitor

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.

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/.