Eye On NPC


The National Institutes of Health is launching the first integrated, drug development pipeline to produce new treatments for rare and neglected diseases. The $24 million program jumpstarts a trans-NIH initiative called the Therapeutics for Rare and Neglected Diseases program, or TRND.

The program is unusual because TRND creates a drug development pipeline within the NIH and is specifically intended to stimulate research collaborations with academic scientists working on rare illnesses. The NIH Office of Rare Diseases Research (ORDR) will oversee the program, and TRND's laboratory operations will be administered by the National Human Genome Research Institute (NHGRI), which also operates the NIH Chemical Genomics Center (NCGC), a principal collaborator in TRND. Other NIH components will also participate in the initiative.

A rare disease is one that affects fewer than 200,000 Americans. NIH estimates that, in total, more than 6,800 rare diseases afflict more than 25 million Americans. However, effective pharmacologic treatments exist for only about 200 of these illnesses. Many neglected diseases also lack treatments. Unlike rare diseases, however, neglected diseases may be quite common in some parts of the world, especially in developing countries where people cannot afford expensive treatments. Private companies seldom pursue new therapies for these types of illnesses because of high costs and failure rates and the low likelihood of recovering investments or making a profit.

"NIH is eager to begin the work to find solutions for millions of our fellow citizens faced with rare or neglected illnesses," said NIH Acting Director Raynard S. Kington, M.D., Ph.D. "The federal government may be the only institution that can take the financial risks needed to jumpstart the development of treatments for these diseases, and NIH clearly has the scientific capability to do the work."


The drug development process is complicated and expensive. Studies suggest that it currently takes more than a dozen years and hundreds of millions of dollars to take a potential drug from discovery to the marketplace. And the failure rate is high.

"This initiative is really good news for patients with rare or neglected diseases," said ORDR Director Stephen C. Groft, Pharm.D. "While Congress has previously taken important steps to help these patients, such as providing incentives for drug companies under the Orphan Drug Act, this is the first time NIH is providing support for specific, preclinical research and product development known to be major barriers preventing potential therapies from entering into clinical trials for rare or neglected disorders. While we do not underestimate the difficulty of developing treatments for people with these illnesses, this program provides new hope to many people world-wide."

Typically, drug development begins when academic researchers studying the underlying cause of a disease discover a new molecular target or a chemical that may have a therapeutic effect. Too often, the process gets stuck at the point of discovery because few academic researchers can conduct all the types of studies needed to develop a new drug. If a pharmaceutical company with the resources to further the research does get involved, substantial preclinical work begins with efforts to optimize the chemistry of the potential drug. This involves an iterative series of chemical modifications and tests in progressively more complex systems - from cell cultures to animal tests - to refine the potential medicine for use in people. Only if these stages are successful can a potential treatment move to clinical trials in patients.

Unfortunately, the success rate in this preclinical process is low, with 80 to 90 percent of projects failing in the preclinical phase and never making it to clinical trials. And the costs are high: it takes two to four years of work and $10 million, on average, to move a potential medicine though this preclinical process. Drug developers colloquially call this the "Valley of Death."

TRND will work closely with disease-specific experts on selected projects, leveraging both the in-house scientific capabilities needed to carry out much of the preclinical development work, and contracting out other parts, as scientific opportunities dictate. Its strategies will be similar to approaches taken by pharmaceutical and biotechnology companies, but TRND will be working on diseases mostly ignored by the private companies. Importantly, TRND will also devote some of its efforts to improving the drug development process itself, creating new approaches to make it faster and less expensive.

If a compound does survive this preclinical stage, TRND will work to find a company willing to test the therapy in patients. There are several stages to the clinical trials process that can take several years before the safety and efficacy of a new drug is determined. FDA will only approve a drug for general use after it passes these trials. The clinical trials process is also expensive, but the failure rate is lower at this stage.

"NIH traditionally invests in basic research, which has produced important discoveries across a wide range of illnesses," said NHGRI Acting Director Alan E. Guttmacher, M.D. "Biotechnology and pharmaceutical companies have enormous strength and experience in drug development, but to maximize return-on-investment work primarily on common illnesses. TRND will develop promising treatments for rare diseases to the point that they are sufficiently "de-risked" for pharmaceutical companies, disease-oriented foundations, or others, to undertake the necessary clinical trials. NIH's goal is to get new medications to people currently without treatment, and thus without hope."

NIH already has many components of the drug development pipeline within its research programs. TRND will begin its work in collaboration with the NIH Chemical Genomics Center (NCGC), a center initially developed as part of the NIH Roadmap for Medical Research. NCGC has developed a robotic, high-throughput screening system and a library of more than 350,000 compounds that it uses to make basic discoveries and probe cellular pathways. NCGC also has developed a team of researchers skilled in developing assays representing disease processes that can be tested in its screening system, and has extensive experience building collaborative projects with investigators from across the research community. Molecules with potential therapeutic properties that emerge from the NCGC screening process could be fed into the TRND drug development pipeline.

"With this new funding, TRND will develop teams of scientists who can do the hard work of optimizing chemicals that we or others discover that may treat rare diseases and turn them into actual drugs," said NCGC Director Christopher P. Austin, M.D., who is also the Senior Advisor for Translational Research to the NHGRI Director. "This will still be hard work and it will take time and produce failures. Unlike traditional drug development, however, where only successes are published, we will publish our failures as well, so everyone in the drug development community can learn from them. That alone could be revolutionary."

If all the preclinical hurdles can be crossed, a possible treatment must still be tested in a series of clinical trials. TRND will seek to take advantage of several NIH resources that can help launch human studies, including the NIH Clinical Center, the NIH Rapid Access to Interventional Development (NIH-RAID), and the Clinical and Translational Science Awards (CTSA) program.


Numerous obstacles impede the development of new drugs for rare and neglected diseases. In addition to the reluctance of private companies to risk their capital on a potentially low return, relatively few basic researchers study rare diseases, so the underlying cause of the illness frequently remains unknown. And, because rare diseases are rare, researchers often have difficulty recruiting enough people with the disorder to participate in a clinical trial once a candidate compound reaches the stage where it can be tested in people. Moreover, for many rare diseases, the natural history of the disease is poorly understood, so researchers lack the needed clinical measures (such as blood pressure) that can demonstrate whether a treatment is working.

To address these difficulties, TRND will seek a wide range of collaborations with academic researchers, as well as partnerships with patient advocacy organizations, disease-oriented foundations and others interested in treatments for particular illnesses. TRND's leaders hope that the collaborations will help lay the groundwork for clinical trials once that point in drug development is reached.

TRND is currently setting up an oversight process to help it decide which projects that address thousands of rare and neglected diseases will be pursued. Leadership currently envisions a small number of diseases being studied each year, with strict criteria used to determine which molecules will be studied for which diseases. NIH expects to use existing intellectual property policies to transfer licenses for TRND-discovered drugs to private companies or others for development, clinical testing and marketing.

Frequently asked questions about this new program are available online at:

-- FAQ on the Therapeutics for Rare or Neglected Diseases (TRND) program: www.genome.gov/27531965

-- TRND FAQ on Neglected Diseases: www.genome.gov/27531964

-- TRND FAQ on Rare Diseases: www.genome.gov/27531963

Follow this link for full-resolution b-roll clips from the NCGC facility which will be involved in TRND, www.genome.gov/pressDisplay.cfm?photoID=20030

The Office of Rare Diseases Research is one of the programmatic offices in the Office of the Director of the NIH. For more about ORDR, visit http://rarediseases.info.nih.gov/.

The Office of the Director, the central office at NIH, is responsible for setting policy for NIH, which includes 27 Institutes and Centers. This involves planning, managing, and coordinating the programs and activities of all NIH components. The Office of the Director also includes program offices which are responsible for stimulating specific areas of research throughout NIH. Additional information is available at http://www.nih.gov/icd/od/.

The National Human Genome Research Institute is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site, www.genome.gov.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.



Why Rare Diseases OUR Important

March 21st, 2010 | Author: Michael G. Stults (Dad)
How many times have you been looking for something at your house but you accidentally find something you previously were missing? Wouldn’t it be a shame if the prize you were seeking was within reach but you discounted that it could be that easy? What if understanding Niemann-Pick Type C disease opened up the door to help millions of Americans with other disorders involving cholesterol? Of course nothing in life is easy nor will it always be within reach. With being human comes the tendency to make oversights.
It has been almost 13 years in July 2010 that the NPC1 gene, on Chromosome 18 for Niemann-Pick Type C was shared with the world on its discovery. This was a huge step and monumental discovery with associating cholesterol with a certain gene/chromosome at that time. To arrive at this point, it took decades of work which shed an abundant light into how a cell metabolizes cholesterol. In short, Niemann-Pick Type C causes progressive deterioration of the nervous system by blocking the movement of cholesterol within cells.

From a press release dated July 10, 1997 from Bethesda, MD:
“This discovery is an excellent example of how research on rare brain disorders often pays off in other ways,” says Zach W. Hall, Ph.D., Director of the National Institute of Neurological Disorders and Stroke (NINDS). “By identifying this gene, we not only take a crucial step forward in understanding this devastating disorder, but also gain insights into problems that affect every one of us.”

In 2001, cardiovascular disease was responsible for more than 39 percent of all deaths in the United States (American Heart Association: Heart Disease and Stroke Statistics 2004). Atherosclerosis is a disease where plaque builds up in your arteries. We all know those aren’t important to our lively hood at all. OK, just joking but plaque is made up of fat, calcium, cholesterol, and other substances found in our blood that over time builds up but hardens in the passage ways of our arteries. Imagine if you’re driving through a two way tunnel but one side is now closed off?  It would be kind of hard to get through to the other side in a timely and relaxing manor with additional objects in your way? Just like that situation, this affects how we get our blood to important areas in our bodies. With millions of people dying each year, this is a huge number of people. What if Niemann-Pick Type C could provide some insight?

Other diseases such as Adult onset Alzheimer’s, Stroke, Cystic Fibrosis, Duchenne Muscular Dystrophy, and even HIV-Aids will benefit from the research into Niemann-Pick Type C. Did you know that children can experience dementia to? Crazy to imagine because most of us think that only our elderly family members get that! With the combination of deaths due to these diseases, could you imagine if we had a more collaborative research environment? Unfortunately big companies aren’t going to sacrifice revenue opportunities to help a blip on the radar screen but they will invest if they see it helping thousands of people; this means a return on their investment. This reality is sad but true.
Rare diseases OUR important to you, me, and everyone we know. Each of us has a Chromosome 18 that is vital to us being a living human being.  I encourage you to help out in some way. That could be donating to several charities that fund research for NPC like the National Niemann Pick Disease Foundation, Ara Parseghian Medical Research Foundation, Hide and Seek Foundation or the Niemann-Pick Children’s Fund. That could be becoming and advocate in lobbying our government for better health care. It could be you just passing the word and spreading awareness.
We all are in this together and have been affected in some way by one of the diseases mentioned in this post. One person can make a difference in the world and that person could be you.

 FDA Grants Mom’s Wish; Gives Orphan Drug Designation 
By Amy Dockser Marcus

A mother from Reno, Nev. who was a force behind an application for an orphan drug designation has gotten good news: the FDA approved the request.

Chris Hempel, whose twin daughters have a fatal cholesterol metabolism disorder known as Niemann-Pick Type C (NPC), said that the designation was approved last week. An official at the FDA’s Office of Orphan Products Development confirmed the designation, for a form of a compound called cyclodextrin. The FDA’s move is the first step in the process of developing drugs for rare diseases that affect fewer than 200,000 Americans.

In March, the WSJ reported about a new effort by the FDA to get more applications by holding  workshops offering on-the-spot advice. The first one, held in February at the Keck Graduate Institute in California, was attended by Hempel and Ron Browne, a scientist hired by a group of families with children who have NPC. The next one is slated for August, at the University of Minnesota.
At the workshop, Hempel stuck out from a crowd consisting mainly of pharmaceutical and biotech company representatives; the binders that held her application were hot pink, her daughters’ favorite color.

The approval is important for a few reasons. Last year, only 160 applications — out of 250 requests –received an orphan drug designation. So cyclodextrin is now in an elite group. Moreover,”ultra orphan” diseases — affecting fewer than 6,000 patients in the U.S. — such as NPC face particularly steep challenges. These ultra orphans make up less than 15% of orphan designations even though they represent more than 80% of identified rare diseases, according to data prepared by the Kakkis EveryLife Foundation and BioMedical Insights.

Hempel hopes the designation will attract pharmaceutical and biotech companies or investors who might develop cyclodextrin into a drug to help treat NPC. The FDA’s move makes the group eligible to pursue special tax credits that could apply to clinical trials and research. “The designation helps legitimize what we are doing,” says Hempel. “It’s no longer just a mom saying it — the FDA is saying this is a promising compound.”

 FDA Approval Received! 
Children’s Hospital Oakland Receives FDA Clearance to Begin World’s First Cyclodextrin Administration Into the Brains of Twins with Rare and Deadly Cholesterol Disease

Sugar Molecule Used In Common Food and Household Products Like Febreze® Fabric Refresher Called Hydroxypropyl Beta Cyclodextrin (HPßCD) Will be Delivered into Twins’ Central Nervous System in an Attempt to Stop Neurological Progression of Niemann Pick Type C Disease 

September 23, 2010 – Oakland, Calif. – Children’s Hospital & Research Center Oakland announced today that the US Food and Drug Administration (FDA) has granted clearance of an Investigational New Drug (IND) application to introduce Trappsol® Cyclo™ (Hydroxypropyl Beta Cyclodextrin or HPßCD) into the brains of six year old identical twin girls dying of a rare brain-destroying cholesterol disease called Niemann Pick Type C (NPC). Known as “childhood Alzheimer’s,” NPC is a deadly progressive neurological condition that causes severe dementia and other debilitating symptoms in children. The FDAs approved use of Trappsol® Cyclo™ marks the first time in medical history that HPßCD will be delivered directly into the brain of a human being in an attempt to arrest a progressive and fatal neurological condition.

Within days, Addison and Cassidy Hempel will travel from their home in Reno, Nev., to Children’s Hospital Oakland to start ongoing injections of Hydroxypropyl Beta Cyclodextrin (HPßCD) into their central nervous systems. Initially, the twins will receive six cyclodextrin treatments of Trappsol® Cyclo™ via lumbar injection over a 12-week period. If Trappsol® Cyclo™ is well tolerated and no adverse side effects occur, the twins are then expected to undergo brain surgery to implant access ports allowing HPßCD to be delivered into the brain’s ventricle system.

HPßCD is a ring of seven sugar molecules known as a cyclic oligosaccharide that is derived from starch. Derivatized cyclodextrins are used extensively in research labs to remove cholesterol from cultured cells and are well known in the pharmaceutical industry for their ability to solubilize drugs. Underivatized cyclodextrins are used throughout the food industry to make cholesterol-free products, such as fat-free butter, eggs and milk products. HPßCD is recognized as a GRAS (Generally Recognized As Safe) material for use in food products in Asian and European countries and is being considered for similar certification in the United States. Hydroxypropyl Beta Cyclodextrin, the chemical compound that will be administered into the twins’ central nervous system, is also an active ingredient found in Procter & Gamble’s Febreze® Fabric Refresher and is used to help eliminate odors from fabrics. Millions of people worldwide are exposed to small amounts of cyclodextrin compounds every day in food, cosmetics and household products.

“It is remarkable to be in position to try a genuine medical intervention that may retard or restore neurological function in children suffering from Niemann Pick Type C disease,” said Caroline Hastings, MD, the Children’s Hospital Oakland pediatric hematologist/oncologist who diagnosed the twins. Dr. Hastings also manages the satellite hematology/oncology clinic at Renown Regional Medical Center in Reno where the girls receive much of their treatment. “This family’s tremendous courage to move forward with this groundbreaking treatment to deliver cyclodextrin into the brains of their twins provides real hope for all children afflicted by this mind-robbing condition and possibly others suffering from cholesterol and lipid related disorders.”

In April 2009, the FDA approved an Investigational New Drug protocol that allowed Addison and Cassidy Hempel to undergo weekly intravenous infusions of Hydroxypropyl Beta Cyclodextrin into their bloodstreams through a Medi-Port catheter implanted in their chest walls. However, research conducted by David Begley, PhD, a leading blood-brain barrier expert at Kings College London, discovered that Hydroxypropyl Beta Cyclodextrin does not cross from the bloodstream into the brain. While the Hempel twins have shown improvements with ataxia and have less difficulty swallowing following intravenous intervention with HPßCD, they continue to decline neurologically and there are no other treatment options available to save their lives. The twins have lost most of their ability to speak and are experiencing intermittent seizures and dementia; however, the girls can still walk, see, and communicate to their parents with a range of sounds and gestures.

On June 13, 2010, Dr. Hastings filed a revised protocol to the Hempel twins’ Investigational New Drug applications with the FDA requesting permission to deliver Trappsol® Cyclo™ directly into the central nervous system of the twins in order to bypass the blood-brain barrier. Researchers studying Niemann Pick Type C afflicted cats and mice have discovered that when HPßCD is delivered directly into the brains of these animals, HPßCD has a remarkable life extending effect and appears to arrest the progression of this deadly neurological condition. It is currently unknown exactly how HPßCD is working to achieve these astonishing neurological effects in NPC animals or if it will have the same effect in humans.

For Chris Hempel, mother of the twins, the start of cyclodextrin treatments into the central nervous system of her twins “creates new hope that was unimaginable even a few years ago for an ultra rare disease with a certain death sentence.” Since receiving the NPC diagnosis in October 2007, Ms. Hempel has worked tirelessly with doctors and researchers around the world to search for a lifesaving treatment for her twin daughters. In May 2010, she worked with Dr. Hastings to receive one of the few orphan drug designations granted by the FDA for the compound Trappsol® Cyclo™.

“It’s extraordinary to think that a sugar compound used in common products found in my refrigerator and laundry room could have such a profound effect on human cholesterol metabolism and may actually save our daughters lives,” said Hempel. “We are incredibly grateful for the support we have received from the medical, regulatory, pharmaceutical, and academic communities who have worked to help us bridge the scientific gap and turn a treatment idea into a treatment reality.

Approximately 500 children worldwide have been diagnosed with double genetic mutations on the Niemann Pick Type C cholesterol gene, yet what scientists learn about these children may have implications that reach far beyond this ultra rare genetic cholesterol disease. Recent published research reports of the role for the NPC1 gene in Alzheimer’s disease and human immunodeficiency virus infection (HIV) make Niemann Pick Type C disease and gene research relevant to millions of people worldwide.

Genetic Counseling
Genetic Counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. This process integrates:
The interpretation of family and medical histories to assess the chance of disease occurrence or recurrence;
Education about inheritance, testing, management, prevention, resources, and research;
Counseling to promote informed choices and adaptation to the risk or condition.
A genetic counselor is a health professional with specialized graduate degrees and experience in the areas of medical genetics and counseling. Genetic counselors provide supportive counseling to families, serve as patient advocates, and refer individuals and families to community or state support services. They serve as educators and resource people for other health care professionals and for the general public. Some counselors also work in administrative capacities. Many engage in research activities related to the field of medical genetics and genetic counseling.
To learn more general information about genetic counseling, tips on how to prepare for a genetics clinic appointment, and details about different specialties in the field of genetics, please see the new Genetic Alliance collaborative publication Making Sense of Your Genes: A Guide to Genetic Counseling.
The National Niemann-Pick Disease Foundation has contracted for the services of a board certified Genetic Counselor, Cate Walsh Vockley, MS, CGC as Coordinator of Education, Referral and Advocacy and a member of the Family Services team. Cate is available to immediate and extended families and to their health care providers to provide initial genetic counseling, assistance in arranging diagnostic and molecular testing, referrals to local genetic and health-related services, supportive counseling, and a wide range of assistance on other issues.
NNPDF has a variety of educational and resource materials that are available on this web site including:
  • Information about Niemann-Pick disease types A, B, and C for health care providers, and for family and friends
  • Diagnostic and Genetic Testing
  • Middle and high school curriculum supplement about Niemann-Pick disease
  • Material on the education of the child who has a neurodegenerative disorder
  • Information about bone marrow transplantation and stem cell transplantation
  • Approaches to care of the caregiver
  • Hospice and respite care resources
  • Grief Support information
  • Teens and chronic illness, and transition to adult care

For more information, contact NNPDF or contact Cate Walsh Vockley, MS, CGC, NNPDF Coordinator of Education, Referral and Advocacy. 


CYCLO (Cyclodextrin) CYCLO research is only in the very early stages but it is something we are watching very closely. The Hemple twins are currently receiving Cyclodextrin infusions now.

Compound that releases trapped cholesterol identified

1 March 2009
Researchers at University of Texas Southwestern Medical Center have identified in mice a compound that liberates cholesterol that has inappropriately accumulated to excessive levels inside cells.
The findings shed light on how cholesterol is transported through the cells of the body and suggest a possible therapeutic target for Niemann-Pick type C disease (NP-C), an inherited neurodegenerative disorder characterised by abnormally high cholesterol levels in every organ. 

"What we've shown is that very quickly after administration of this compound, the huge pool of cholesterol that has just been accumulating in the cells is suddenly released and metabolised normally," said Dr John Dietschy, professor of internal medicine at UT Southwestern and senior author of the study appearing online and in an upcoming issue of the Proceedings of the National Academy of Sciences. "With just one dose, you excrete a large portion of this pool of cholesterol." 

Cholesterol in the body comes from dietary sources and is also made by the body itself. It is essential for many biological processes, including the construction and maintenance of cell membranes. Cholesterol normally is transported through cells and is excreted by the body. 

People with Niemann-Pick type C have a genetic mutation that causes excessive amounts of cholesterol to accumulate in compartments within cells called lysosomes. This cholesterol accumulation leads to liver disease, neurodegeneration and dementia. There is no specific level at which cholesterol levels become abnormal, but the vast majority of children diagnosed with NP-C die before they are 20 years old and many before age 10. Late onset of neurological symptoms such as clumsiness, mild retardation and delayed development of fine motor skills can lead to longer life spans, but few people diagnosed with NP-C reach age 40. 

In the current research, researchers injected a single dose of a cholesterol-binding agent known as CYCLO into 7-day-old mice with the Niemann-Pick mutation. Shortly after administration, the mice that received CYCLO began to process cholesterol just as their healthy counterparts did. After 49 days, the mice treated with a single injection continued to show substantially lower tissue cholesterol levels than the untreated mice, as well as improved liver function and decreased neurodegeneration. 

Dr Dietschy, who has been studying cholesterol metabolism for nearly 50 years, cautioned that the findings in no way represent a Niemann-Pick disease cure. 

"The key idea is that we appear to have overcome the transport defect in the lysosome that is brought about by the genetic defect or mutation," Dr Dietschy said. "We do not yet understand what is happening at the molecular level, but it is clear that this compound somehow overcomes the genetic defect that causes individuals to accumulate cholesterol." 

The next step in Dr Dietschy's investigation is to determine the concentration of CYCLO needed to trigger the cholesterol's release. Researchers also hope to determine in animals the additional lifespan CYCLO administration provides, as well as how long the drug's affects lasts. 

"By treating at seven days, we eliminated approximately one-third of the accumulated cholesterol almost immediately," Dr Dietschy said. "Now we want to see what happens if we give it every week. Can we maintain low cholesterol levels? That's what we're looking at now." 

Other UT Southwestern researchers involved in the research were Dr Benny Liu, lead author of the study and postdoctoral researcher in internal medicine; Dr Stephen Turley, professor of internal medicine; Dr Dennis Burns, professor of pathology; Anna Miller, student research assistant; and Dr Joyce Repa, assistant professor of physiology. 

The work was funded by the US Public Health Service, the Harry S. Moss Heart Trust, the Ara Parseghian Medical Research Foundation and the Dana's Angels Research Trust.

(Source: University of Texas Southwestern Medical Center: Proceedings of the National Academy of Sciences: March 2009)

No comments:

Post a Comment