The NNPDF does a wonderful job of keeping families and people interested up to date on how things are progressing in the disease community for Niemann-Pick Type C. You can visit updates on their page here: http://www.nnpdf.org/aboutus_14.html

Cyclodextrin

A few families have taken a different approach in individually seeking the approval of the FDA to start an individual trial. Some of their hard work contributed in helping promote the upcoming Cyclodextrin trial.  Cyclodextrin could be one of many therapies needed in the future to help NPC patients manage the disease progression.

Letter From TRND

Dear families and friends of the NPC community,

The collaborative group planning a cyclodextrin clinical trial at the National Institutes of Health (NIH) for the treatment of Niemann-Pick type C (NPC) disease met with the Food and Drug Administration (FDA) on Tuesday, December 13, 2011 as a follow up to the recently held November pre-IND meeting.  On November 1, we met with the FDA Review Division staff to discuss the proposed development plan for cyclodextrin and needs for the IND application package.

Representatives from the Therapeutics for Rare and Neglected Diseases (TRND) group at the NIH, as well as several NPC researchers, Johnson & Johnson, and consultants from RRD International, LLC, participated in this meeting.

While the November meeting focused on the drug safety and toxicology data, the purpose of the December meeting was to discuss the proposed clinical trial design.  Overall, the feedback from FDA was very positive and their comments and guidance will assist us in the generation of an IND application that is agreeable to FDA, thus allowing us to move forward with the initial clinical trial as soon as possible.

Preclinical toxicology and safety studies in animals are ongoing, and additional studies will be initiated shortly.  These required nonclinical studies will guide the selection of drug doses for the initial trial and will provide essential safety information.   In the upcoming months, we will be evaluating these study results and will incorporate them into the  IND application and initial clinical protocol, which will then be submitted to FDA and the NIH Institutional Review Board (IRB).  Once we have agreement from FDA and approval from the NIH IRB, we can share the specific details of the initial clinical trial, such as patient inclusion/exclusion criteria.

We are very excited about the progress we have made thus far and are encouraged by our recent meetings with FDA.  We understand that the community is eager to start this initial trial as soon as possible and we do not have time to waste.  Following the meeting, we believe that FDA shares our sense of urgency and we are grateful that they are willing to work closely with us to get this important initial trial started.  As always, your support of NPC research is the final piece that will help us impact this disease.  Thank you for your enthusiasm, your patience, and especially for trusting that we are making every effort to help individuals and families affected by NPC.

The TRND Team

Press Release:

NIH Therapeutics for Rare and Neglected Diseases Program announces next round of drug development projects

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Niemann-Pick Type C is essentially a generic flaw keeping lipids trapped in the cell and prevents cells from using the lipids appropriately. The destruction of brian cells, which is the most crucial area, typically kills the affected individuals by their teenage years. NPC strikes approximately one in every 150,000 births. NPC is a genetic inherited neurological disorder that involves the lack of cholesterol metabolism within the cells.

A recent claim published by Olaf Wiest and Paul Helquist of the Univeristy of Norte Damn and Frederick Maxfield of Cornell University says that a histone deacetylase inhibitor (HDAC) corrects the damage done by NPC and allows the previous diseased cells to function normally.

This obviously would appear like wonderful news except we have to remember not to jump to premature conclusions drawn from this press release. This whole disease and finding a suitable treatment is so complicated. There have been many times in the past that something in the lab has shown to cure NPC but only to later show that it wasn’t feasible in actual humans or animal studies.

One of the leading Niemann-Pick Type C experts 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, urged caution on 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.

If there was ever a time to have a child or loved one with Niemann-Pick Type C, it would be in our current timeline. Research is making head way but that head way has to be weighed by the fact that in research time it might be moving fast but to parents that timeline will never be fast enough to help their dying children now.

To view more detailed information about this press release and feedback: http://www.nnpdf.org/npdisease_14.html#ValproicAcid

Photo used under Creative Commons from jepoirrier.

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In Rockville, MD on June 3-4th many of the researchers looking into different areas and avenues for Niemann-Pick Type C came together to discuss promising therapies. Although research is making progress, parents of NPC patients never feel that research is happening fast enough. That is greatly to be expected. The NPC community is  making large strides in the right direction!

The National Niemann Pick Disease Foundation was very kind in putting together a recap of that meeting in a pdf format which is viewable here: Promising Therapies for Niemann-Pick Type C Disease.

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In January of 1983, the Orphan Drug Act (ODA) was passed into law in the United States with consistent pursuit by the National Organization for Rare Disorders. The ideal behind this is to encourage pharmaceutical companies to look into smaller markets with development of drugs for orphan diseases. Niemann-Pick Type C (NPC) certainly falls into this category (around than 500 diagnosed ever worldwide). The benchmark on how to determine an orphan disease is one that affects less than 200,000 people.

As Nadine Hill, director of family services of the National Niemann Pick Disease Foundation (NNPDF) stated in an email to families this week, “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.”

Chemical structure of the three main types of cyclodextrins.

Cyclodextrins are a sugar compound which was first described in 1891 by A. Villiers. Currently the food industry uses cycodextrins in preparing cholesterol free products. The concept is to help reduce the intercellular cholesterol that becomes the main culprit in NPC. By reducing the size of the lysosomes and in theory reducing cholesterol, it can help prolong the life of a child or adult suffering from the death sentence of NPC. Although there currently is no formal clinical trial, these actions are a step in the right direction. There still is a lot of unknowns and work that will need to take place.

Behind the push to get to this point is Chris & Hugh Hempel who has twin daughters suffering from NPC. In conjunction with other NPC families they formed their own Virtual BioTech they named S.O.A.R. (Support of Accelerated Research). Through the work of much collaboration, this has shown to help move research quicker.

As of today there is no known cure or effective treatment for Niemann-Pick Type C. The future outcome looks bright even though time is not on our side. The Niemann-Pick Children’s Fund looks to provide support in the areas of research, education/awareness, and family support through existing channels.

Read the WSJ.com story here: FDA Grants Mom’s Wish; Gives Orphan Drug Designation

To learn more please visit NNPDF’s website: http://www.nnpdf.org/Cyclodextrin.html

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Authors: James E Wraith, Jackie Imrie
Published Date November 2009

James E Wraith, Jackie Imrie

Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, UK

Abstract: Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain.

Read the full abstract here.

*This post does not reflect the views and opinions of Niemann-Pick Children’s Fund, Inc. This article is for informational purposes only. The sole credit of this article belongs to the author/website listed above.

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Researchers have used a modified AIDS virus to halt a devastating brain disease in two young boys. The treatment, in which the virus delivered a therapeutic gene, marks the first time gene therapy has been successfully used against X-linked adrenoleukodystrophy (ALD)–a disorder that is always fatal if untreated. With this proof of principle, scientists hope versions of the AIDS virus engineered to carry different genes can now be applied to a variety of other diseases.

ALD is caused by a defect in an X chromosome gene that produces a protein called ALD. Cells need this transporter protein to break down certain fats; without it, the fats build up and damage the myelin sheathing that protects nerves. In X-linked ALD, which strikes mainly boys, patients develop neurological symptoms such as seizures and loss of vision around age 6 to 8, and within months they become paralyzed, deaf, and eventually die. In the 1980s, the parents of a boy with ALD developed a mixture of fatty acids they called Lorenzo’s oil that may have delayed the disease in their son (and inspired a 1992 movie). But the only widely accepted way to stave off ALD is a bone marrow transplant, which is risky–20% to 30% of patients die or have serious complications–and works best if the donor marrow comes from a sibling.

In search of an alternative, pediatrician Patrick Aubourg of INSERM in Paris, the French biomedical research agency, and the University Paris-Descartes, along with collaborators in France and Germany, tried gene therapy on two 7-year-olds with ALD who couldn’t be matched with a bone marrow donor. They removed blood cells from each boy and treated the cells with a so-called lentiviral vector, a modified HIV virus carrying the gene for the enzyme they lacked. The virus could not replicate, but it stitched the gene into the DNA of the blood cells.

To provide the treated cells room to take hold and multiply, the researchers wiped out each patients’ bone marrow with chemotherapy. Then they infused the repaired cells back into the patient, and the cells began cranking out ALD protein. The idea was that, after a few months, some of these cells would migrate into the brain.

As expected, parts of the patients’ brains that already showed signs of myelin damage initially got worse after the gene therapy, because the modified cells did not migrate into the brain right away. But after 14 to 16 months, the boys’ blood cells were still making ALD, and brain images showed that their disease had stabilized or improved, suggesting the protein was being produced there. One boy did worse on a non-verbal IQ test, and the other lost some vision, but their verbal test scores did not drop the way they do in patients who don’t get any therapy. The results were comparable to a bone marrow transplant, the researchers report tomorrow in Science.

“It’s a real milestone in the field,” says neurologist Florian Eichler of Massachusetts General Hospital in Boston. He cautions, however, that the therapy should not be attempted until a patient shows signs of ALD. That’s because many boys with the defective gene do not develop the brain disease, and thus they should not be subjected to such a severe treatment regimen.

The study is also important because it suggests that a lentiviral vector may be safer than some other viruses used for gene therapy, says gene therapy researcher David Williams of Harvard Medical School and Children’s Hospital Boston. In the best-known example, another viral vector cured about 20 patients with “bubble boy” immune disease, but it caused leukemia in several of them by inserting its DNA near a cancer gene. An analysis of the ALD patients’ blood cells suggested the lentiviral vector is less likely to land in the wrong spot. Williams expects that lentiviral vectors will now be used to treat other genetic diseases that involve blood cells, such as sickle cell disease.

Go To Science NOW

Email response to this article from:

Cate Walsh Vockley, MS, CGC
Coordinator of Education, Referral and Advocacy
National Niemann-Pick Disease Foundation
Senior Genetic Counselor
Medical Genetics
Children’s Hospital of Pittsburgh

In addition, Karen Quandt, Vice-Chair of the NNDPF Board, asked Dr. Vanier about the studies and whether this technique can be applied to NPC. Dr. Vanier’s response was as follows:

“Unfortunately the procedure described for adrenoleukodystroph y (ALD) is NOT applicable to NPC1 patients, because this strategy has a chance to work only in diseases where bone marrow or cord blood transplantation has proven efficient. In ALD, bone marrow transplantation (BMT) has been shown quite efficient, provided it is done early enough. The big advance in the trial has been to use the patient’s own cells, after correction by gene therapy. In NPC1 we know that bone marrow transplantation (BMT) has no effect on the neurological disease.

(Note that BMT has some chances to work in NPC2, although it is still too early to conclude in the one patient who survived the transplantation procedure).”

*This post does not reflect the views and opinions of Niemann-Pick Children’s Fund, Inc. This article is for informational purposes only. The sole credit of this article belongs to the author/website listed above.

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