Novartis Phase 3 cancer drug Panobinostat may correct Niemann Pick Type C cholesterol defect through inhibiting histone deacetylase (HDAC)

I almost fell off my chair a few minutes ago. I just posted a blog on news from Notre Dame and Cornell about HDAC inhibitors correcting the Niemann Pick Type C defect in cell culture.

I just read on PNAS that the Novartis cancer drug Panobinostat (LBH-589), a Phase 3 drug developed for the treatment of cancer, may be able to halt the progression of Niemann Pick Type C disease, a fatal genetic cholesterol metabolism disorder that affects my twins. Panobinostat inhibits one or more of the histone deacetylase (HDAC) enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.

Here is the abstract — I don’t have the full paper.

Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts

• Niemann-Pick type C (NPC) disease is predominantly caused by mutations in the NPC1 protein that affect intracellular cholesterol trafficking and cause accumulation of unesterified cholesterol and other lipids in lysosomal storage organelles. We report the use of a series of small molecule histone deacetylase (HDAC) inhibitors in tissue culture models of NPC human fibroblasts. Some HDAC inhibitors lead to a dramatic correction in the NPC phenotype in cells with either one or two copies of the NPC1I1061T mutation, and for several of the inhibitors, correction is associated with increased expression of NPC1 protein. Increased NPC1I1061T protein levels may partially account for the correction of the phenotype, because this mutant can promote cholesterol efflux if it is delivered to late endosomes and lysosomes. The HDAC inhibitor treatment is ineffective in an NPC2 mutant human fibroblast line. Analysis of the isoform selectivity of the compounds used implicates HDAC1 and/or HDAC2 as likely targets for the observed correction, although other HDACs may also play a role. LBH589 (panobinostat) is an orally available HDAC inhibitor that crosses the blood–brain barrier and is currently in phase III clinical trials for several types of cancer. It restores cholesterol homeostasis in cultured NPC1 mutant fibroblasts to almost normal levels within 72 h when used at 40 nM. The findings that HDAC inhibitors can correct cholesterol storage defects in human NPC1 mutant cells provide the potential basis for treatment options for NPC disease.

Interestingly, Gleevec, another cancer drug developed by Novartis also works in the NPC mouse model (modestly) and was reported by Paul Greengard to have an effect in the Alzheimer’s model.

Wow. Panobinostat may also work in other neurodegenerative diseases as well such as Alzheimer’s, Huntington’s, ALS, SMA……many others where HDAC inhibition is showing some success!

HDAC Inhibition Therapy to Stop Neurodegeneration? Notre Dame and Cornell Scientists PNAS Paper To Show How Histone Deacetylase Inhibitor (HDIs) Corrects Niemann Pick Type C Cholesterol Defect

Notre Dame and Cornell researchers are reporting a major breakthrough in Niemann Pick Type C disease research that has major relevance to other progressive neurological conditions such as Alzheimer’s, Huntington’s, and ALS.

A paper coauthored by Olaf Wiest and Paul Helquist of the University of Notre Dame’s Department Chemistry & Biochemistry and Frederick Maxfield, Chair of Biochemistry at Cornell University Weill College of Medicine, is apparently going to appear in the Proceedings of the National Academy of Sciences this week according to a press release issued by Notre Dame.

The paper apparently shows how the use of a histone deacetylase inhibitor corrects the damage done in Niemann Pick Type C,  a fatal genetic cholesterol metabolism disorder, and allows once-diseased cells to function normally. The press release discusses the “effectiveness of the drug” but no compound is named.

Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics.  In more recent times, HDIs are being studied as a treatment for neurodegenerative diseases so the fact these researchers are having such success in NPC cells is very promising.

Interestingly, our neurologist Dr. Daniel Birnbaum at Children’s Hosptial Research Center Oakland started Addi and Cassi on Valproic Acid, an anti-seizure medicine that is also classified as an HDAC inhibitor.  We have had good success with Valproic Acid over the past three months.

Trichostatin A, suberoylanilide hydroxamic acid (SAHA), Phenylbutyric Acid and Butyric Acid can all act as HDAC inhibitors as well.  Maybe it’s one of these compounds that is showing success in the Niemann Pick Type C cells?

The press release does not say whether testing was done in NPC mice or NPC cats or if the HDAC inhibitors worked in NPC animal models.  I hope the paper discusses animal work.  The good news is that many HDAC inhibitors are in advanced clinical trials or even approved drugs.  I hope these compounds can also easily cross the blood brain barrier!

HDAC inhibition therapy — is this the miracle we have all been waiting for?   I hope so and if  it is Notre Dame and Cornell researchers will be heros for their in work that will extend beyond NPC disease.

More information on Histone deacetylase is here.

National Center for Advancing Translational Sciences (NCATS) Announced By National Institutes of Health (NIH) Director Francis Collins

The Global Genes Project, a rare disease patient advocacy organization, was invited to present a giant handmade denim genes ribbon to Dr. Francis Collins on February 28 — Rare Disease Day 2011.

This year the NIH Office of Rare Disease Research (ORDR) encouraged everyone to wear jeans to show support for the campaign of using a genes and jeans concept to educate the public on the prevelance of rare genetic diseases and the lack of available drug treatments.

I was invited to speak at Pfizer in Boston about Niemann Pick Type C disease and our medical odyssey over the past three years getting FDA approval to treat Addi and Cassi with a potentially life-saving sugar compound called cyclodextrin.

I wish I could have been in two places at the same time. I would have liked to meet Dr. Collins to thank him for supporting our campaign and to find out more about the NIHs plans for the National Center for Advancing Translational Sciences (NCATS).

Apparently, the National Institutes of Health’s Scientific Management Review Board (SMRB) recommended that the NIH open a new center this fall in an effort to spur creation of medications for rare diseases.  Read the SMRB report here.  Collins says that the NIH is not going to turn into a “drug-development company” but will move research forward so it will be more attractive to commercial investments.

With fewer than 200 of 7,000 rare diseases have any available therapies creating a center like this at the NIH is long overdue.

It’s encouraging that the Director of the NIH is taking action and recognizes the seriousness of the problem we have with drug development for rare diseases.

I hope the strategy works because it’s the only chance for millions of rare disease patients to have treatments developed to save their lives.