Sunday, November 19, 2017

FDA Filing Made Requesting Use of Medtronic SynchroMed Pump To Deliver Cyclodextrin To Brain

April 13, 2011 by  
Filed under Featured Stories

To say I am pumped up  today is an understatement!  We’ve reached another historic milestone in our effort to treat Addi and Cassi with cyclodextrin!  Dr. Caroline Hastings at Children’s Hospital Research Center Oakland filed a 400+ page document with the FDA yesterday on behalf of the twins seeking a permanent solution to deliver hydroxyl-propyl-beta-cyclodextrin (HPBCD) past the blood-brain barrier and into the cerebrospinal fluid (CSF) by utilizing a Medtronic SynchroMed® II Drug Infusion Pump System.

We believe that combination therapy of intravenous (IV) and intrathecal (IT) HPBCD is the most effective way to target both the brain (IT) and organs/peripheral tissues (IV) in Niemann Pick Type C disease.

The FDA has been very helpful throughout this process but the FDA filings are incredibly time consuming and take months and months of work.  The amount of detail necessary for a new drug treatment protocol is mind blowing — even if it’s for two children with an ultra rare disease.  The reason is everything we do has implications for all other children with Niemann Pick Type C, not to mention other diseases where cyclodextrin may work.  I think it could work in the ‘Lorenzo’s Oil’ disease called adrenoleukodystrophy.  Check out this paper where cyclodextrin is having an effect in ALD:  ADRENOLEUKODYSTROPHY Cyclodextrin Paper.  I hope  ALD families are making their researchers pump this into their mice models.  HPBCD is safe — if it has an effect on VLCFA, it could go into ALD kids as well with this pump idea!

We’re proposing to the FDA to use a new drug (hydroxyl-propyl-beta-cyclodextrin) in an existing device (a SynchroMed pump).  This requires two FDA divisions to be involved in the approval process — the Division of Gastroenterology Products (DGP) which is part of the Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH), which is responsible for regulating firms selling medical devices in the United States.

I am sure anyone who works in the drug development field can appreciate the complexities involved when seeking FDA approval for a new drug in a device.  We don’t have time on our side and getting agreement from two FDA divisions is not easy.  But our plan is solid and makes sense and I am confident we’ll get the approval to move forward.

Once we get the Medtronic pump solution approved by FDA, Dr. Peter Sun, Chief of Pediatric Neurosurgery at Children’s Hospital & Research Center Oakland, will surgically implant a SynchroMed® II Drug Infusion System into Addi and Cassi.  We are proposing placing the catheter in the mid-thoracic region of the spine at the T6—T7 level rather than at the typical T11—T12 level.  Then HPBCD will be pulsed in bolus doses into the twins’ central nervous system so it can reach their brains.

To understand how this works, think about how a diabetic pump works.  Instead this pump is surgically implanted on inside of the body and is programmable from outside the body.  Generally, Synchromed pumps are used to deliver a drug called Baclofen used to control pain or spasticity.  In our case, we want to fill the pump with HPBCD monthly and deliver it just like you would Baclofen.

We have now completed 11  intratehcal injections of hydroxyl-propyl-beta-cyclodextrin into the twins’ spines via lumbar punctures. Intrathecal treatments are going very well but the travel from Nevada to California every other week is exhausting.  In addition, the sedations with propofol (yes, the one Michael Jackson used) take a toll on the twins. We really need a permanent solution and we believe SynchroMed is it!

Thanks to the amazing doctors and medical pros at Johnson & Johnson and Medtronic who have donated their time pro-bono to help us create this ground breaking treatment protocol.  The support we have received from people outside the Niemann Pick Type C community has been remarkable to say the least.

Now we wait to hear from the FDA to find out when we can schedule a teleconference call to discuss our proposal.



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Insulin Therapy and Alzheimer’s – Could Cyclodextrin Sugar Act on Insulin and Glucose Metabolism?

April 10, 2011 by  
Filed under Uncategorized

Recently reports in the news shows how insulin therapy may be a treatment for Alzheimer’s.  Basically, a low dose of insulin has been found to suppress the expression in the blood of four precursor proteins involved in the pathogenesis of Alzheimer’s disease, according to research by University at Buffalo endocrinologists.  Paresh Dandona, MD, PhD, University at Buffalo is a senior author on the study.

I am very interested in insulin therapy for Addi and Cassi and I have been looking into this along with a drug called Rosiglitazone.  I wonder if I am already doing insulin therapy by giving the twins the sugar compound cyclodextrin into their bodies and brains?  I think I’ll email Paresh Dandona about it.

Addi and Cassi have major disruption in glucose metabolism in their brains. Dr. Harry Chugani and his team at Children’s Hospital of Michigan discovered this a few years ago in the twins and it is spreading out of control based on our last PET scan.  Dr. Chugani and team are publishing a paper about the glucose metabolism PET based brain biomarker in Niemann Pick Type C disease.

For over a year, I have been looking into whether or not hydroxy-propyl-beta-cyclodextrin (HPBCD) might have some sort of effect on insulin and glucose metabolism in the body and brain.

I found these very interesting references:

  • International Journal of Molecular Sciences (2009): The objective of this study was to elucidate the effects of hydroxylpropyl- B-cyclodextrin (HPBCD) on the in vitro stability of insulin. It was found that HPBCD had positive effects on the stability of insulin in acid and base and under high temperature conditions. Furthermore, use of HPBCD could also increase the stability of disulfide bonds which are important to the conformation of insulin. Through 1H-NMR experiments it was found that the protective effect of HBPCD was due to complexation with insulin. The results suggest that the presence of HPBCD could improve the stability of insulin in different environments.
  • Abulrob et.al. (J Neurochem. 2005 Mar;92(6):1477-86) demonstrated the neuroprotective activity of some cyclodextrin derivatives against oxygen-glucose deprivation (OGD), N-methyl-D-aspartic acid (NMDA) and glutamate in cortical neuronal cultures. Although all Cyclodextrin complexed with NMDA or glutamate, only beta-, methylated beta-and sulfated beta-CDs displayed neuroprotective activity and lowered cellular cholesterol.

I have been asking our researchers to see if they can conduct microPET on the Niemann Pick Type C mice to see if they can find a hypometabolism issue in the brains of the mice like they find in my identical twins.  If  found, researchers could give the NPC mice the cyclodextrin and test as to whether or not it has an effect on insulin and glucose metabolism in the brain.  If so, this could be a very important finding that could bolster the University at Buffalo’s work.

Also, one of the things I find really interesting is there is a rare disease called Ataxia – telangiectasia that I think provides further clues to neurodegeneration.   In Ataxia – telangiectasia, there are issues with glucose and insulin receptors: http://www.ncbi.nlm.nih.gov/pubmed/651946

Both Niemann Pick Type C and Ataxia – telangiectasia  there is massive loss of Purkinje cells in the brain — loss of Purkinje cells in one of the first signs in NPC disease.  Why the massive loss of Purkinje neurons in Niemann Pick Type C and Ataxia – telangiectasia?  What is the connection point causing loss of Purkinje neurons?  I think it might be glucose metabolism or insulin utilization.

Given the glucose metabolism issue we have found in Addi and Cassi’s brains and the ataxia which is one of the first symptoms of the disease, maybe glucose metabolism and insulin issues are a core issue in NPC?  I read that the cerebellum is largely fueled by glucose and the cerebellum is where Purkinje neurons are located!

Steve Walkley’s work shows that cyclodextrin rescues Purkinje neurons in the NPC mouse model  – could it be acting on glucose metabolism or insulin?  Could cyclodextrin rescue Purkinje cells in Ataxia – telangiectasia?

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

April 2, 2011 by  
Filed under Featured Stories

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.

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