Cholesterol and Autism – Can Eggs In The Diet Save the Autistic Brain? Will SLOS Provide Clues To Autism?

Will it be the Mom’s and Dad’s with children with autism who will finally help educate the public on how serious cholesterol is when it comes to brain function in children?

This week researchers at The Ohio State University Medical Center announced they are studying whether a simple nutritional intervention – adding cholesterol to the diets of children with autism spectrum disorders after a test to see if they need it – can improve core autism symptoms. These studies are being led by Dr. L. Eugene Arnold, a child psychiatrist at Ohio State’s Nisonger Center who specializes in researching and treating autism.

According to the article, Arnold is teaming up with Dr. Elaine Tierney of Johns Hopkins University/Kennedy Krieger Institute and Dr. Forbes D. Porter of  the National Institutes of Health to conduct a phase I/II double-blind study for children ages 4-11 who have been diagnosed with autism spectrum disorders: autistic disorder, Asperger’s disorder, or pervasive developmental disorder – not otherwise specified (PDD-NOS).

60 children who are found to have abnormally low cholesterol will participate in a 12-week double-blind study in which they will be fed cholesterol …. or a placebo … to see in increasing dietary cholesterol has an impact on brain function.

I first heard about the role of cholesterol in autism from Dr. Porter a few years ago. Unfortunately, I was at the NIH for a week long visit with my identical twins, Addi and Cassi, who are suffering from a fatal brain disorder called Niemann Pick Type C.  Addi and Cassi have a genetic cholesterol defect on chromosome 18 and don’t process any cholesterol in their cells.  As a result this causes a “childhood Alzheimer’s” type of condition.  My twins appear to make cholesterol fine — but cholesterol gets stuck inside their brain cells, destroying their neurons, and causing this fatal condition.

During my visit, I was taking with Dr. Porter about dietary cholesterol concerns I had with the twins and that I put my twins on a low cholesterol diet.  Dr. Porter mentioned a genetic cholesterol condition called SLOS — or Smith-Lemli-Opitz syndrome. SLOS is a metabolic disorder caused by a genetic mutation in the DHCR7 (7-dehydrocholesterol reductase) gene on chromosome 11. This gene codes for an enzyme that is involved in the production of cholesterol.  Dr. Porter treats both NPC and SLOS kids and explained that SLOS kids have a high degree of autism and many SLOS kids with low levels of cholesterol.

I have heard from Dr. James Hildreth, a leading HIV-AIDS researcher I know,  that the expression of a key transcription factor could be disrupted in both NPC and Autism.  Dr. Hildreth has established a connection between Niemann Pick Type C and  HIV.  Basically cells affected by Niemann Pick Type C, which have the disrupted cholesterol trafficking I mentioned, were unable to release HIV, suggesting NPC cells would not spread the virus.  As it turns out, cholesterol is somehow essential to HIV because HIV relies on specialized structures known as lipid rafts, which are rich in cholesterol, to infect new cells.  Maybe this transcription factor is another key to the puzzle?

I hope this simple nutritional intervention of adding cholesterol into the diet has a positive effect on some of these kids’ brain function.  But if I was in the Autism Community, I wouldn’t be putting all my eggs in one basket just yet.

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.

Dr. Stephen Groft of NIH Visits Global Genes Project In Advance of Rare Disease Day 2011

Monday, Feb. 28, is Rare Disease Day 2011.  Here is a great story from the Orange County Register, which is helping to raise awareness for rare diseases and our efforts to spread awareness through our blue denim jeans ribbon and “Wear That You Care” campaign.

Local advocates looking to kick-start research to help patients with rare diseases got a boost Wednesday afternoon when an official with the National Institutes of Health stopped by to talk.

Dr. Stephen Groft, director of the NIH’s Office of Rare Diseases Research, visited with a Dana Point nonprofit group aimed at building a community for people with rare diseases. A rare disease is defined as one that affects fewer than 200,000 Americans.

Groft informally talked with people who went to meet him at an office in La Plaza shopping center off Pacific Coast Highway that houses the RARE Project (Rare Disease Advocacy Research Education). As he did, children created blue denim ribbons similar to the red ones for AIDS awareness or the pink ones for breast-cancer awareness.

“It’s symbolic that the NIH is coming to speak to this organization. It shows they recognize the power it has,” said Beth Anne Baber, a San Diego cancer researcher and mother of a child with a rare pediatric cancer.

Baber spent hours talking to Groft about what can be done to make advances in rare-disease research.

Monday is Rare Disease Day, and the RARE Project plans to present a 3-foot denim ribbon to NIH Director Francis Collins at a ceremony at NIH headquarters outside Washington, D.C.

The NIH Office of Rare Diseases Research, which stimulates research and acts as an information center, has been around since 1993, but rare-disease research has taken a step into a faster lane in the past five years. Groft attributes that to a greater sense of collaboration among patients groups, researchers, pharmaceutical companies and government. In 2009, NIH dedicated $24 million to pave the way for new treatments for rare diseases. Soon after, the U.S. Food and Drug Administration began providing more grants to encourage researchers to produce more rare-disease treatments.

But Groft’s office is one of many NIH branches. Of the NIH’s $31 billion budget, the Office of Rare Diseases Research gets about $18 million a year. Patients advocates say more money is needed for research, but it can be tough to persuade the government or private pharmaceutical companies to spend money on products when a small number of people have a particular disease. It costs about a billion dollars for a company to develop a new drug.

Groft said he often plays the role of myth-breaker when he talks to the pharmaceutical and medical communities. Many think there is little information about rare diseases and that research is scarce. Groft said that’s not true.

About 1,100 advocacy groups worldwide, including the one in Dana Point, are working to increase awareness of diseases most people have either never heard of or wouldn’t think of as rare. Childhood cancers, for example, are considered rare. So, too, are developmental disorders with names such as campomelic dysplasia and pachygyria.

The RARE Project began in 2008 as an umbrella organization to connect multiple rare-disease groups. Though each disease affects a small number of people, almost 7,000 rare diseases affect 30 million people in the United States, 75 percent of them children, advocacy groups say. Most rare diseases don’t have a drug designed to treat them.

Nicole Boice began the RARE Project after a friend had a child with a rare disease. She saw how isolated the family felt and how worried they were. After some research, she learned how many people have rare diseases.

“I saw how large the community was and was just absolutely blown away,” Boice said. “I thought with so many people, why are they not talking to each other?”

Advocacy groups for patients of rare diseases often focus on a specific disease, making their numbers small. If the groups had an organization to connect them, Boice thought, they would have more power in numbers.

Numbers are often what it takes to get research done. Baber, who started an advocacy group for childhood cancer research called the Nicholas Conor Institute (after her 7-year-old son), joined forces with Boice. They figured they could play a role in showing scientists a large number of patients willing to be tested.

“We have to make it easy. That’s how this community will win,” Boice said.

Advocates aren’t expecting cures, she said. “We’re just looking for treatments, something to help these kids feel better for a while, maybe even live normal lives.”

This year her group launched the Global Genes Project, a campaign to increase awareness of children’s rare diseases. The group is encouraging supporters to wear denim ribbons or jeans on Rare Disease Day.

The group plans to start its first round of fundraising for research by this summer. The dream is to get as big as the Susan G. Komen for the Cure breast-cancer foundation.

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