1. “Childhood Alzheimer's”
Niemann Pick Type C
“Childhood Alzheimer's”

2. Niemann Pick Type C
NPC is caused by an inherited change, or mutation, in one of two genes: Npc 1 or Npc 2
The two genes working together produce a protein that moves and recycles fatty molecules through the cells. When the proteins do not work the fatty molecules or cholesterol and lipids become trapped in the cell and stored in a small cellular compartment known as a lysosome.
This happens because the NPC proteins are located in the cell membrane of these small compartments known as lysosomes.
This classifies Niemann Pick Type C Disease as a lysosomal storage disorder

3. Lysosomes role in Cellular function
Lysosomes are the garbage disposal system of a cell.
They are bound by a single membrane that enables them to contain enzymes and facilitate breakdown and recycling of materials processed through them.

4. Overview of NPC as an LSD
Lysosomal Storage Diseases
Niemann Pick Type C
Caused by storage of fatty materials in the membrane of a cells lysosome.
Inherited Chromosomes are responsible for causing particular proteins to express and properly recycle waste from the cells
An NPC patient inherits a mutated copy of Chromosome 18 from each carrier parent.
Most cause mutations in the NPC1 protein (95%).
The cells are unable to recycle cholesterol and lipids through the cell. They get trapped and cause system wide failure.
Did you know…..? You only need 1 functioning Chromosome 18 to be a carrier instead of an afflicted patient.

5. Autosomal Recessive Inheritance
Chromosomes are found in pairs
Each parent passes one of each chromosome to their offspring to result in a new pairing.
In each pregnancy there is a 25% chance the resulting offspring will receive mutated chromosomes from each parent “carrying” one mutation.
The Mutation that causes
NPC is on Chromosome #18

6. NPC Onsets with Variability
Infantile Onset normally presents with severe liver disease and ascites at birth or major respiratory complications from infiltration in the lungs and is fatal early.
The most common form of NPC or the Classic presentation occurs in early childhood and presents as developmental delay, ataxia, dystonia, supra-nuclear gaze palsy, dementia, seizure and dysphagia & dysarthria that eventually make feeding and swallowing impossible. Death commonly occurs from aspiration pneumonia
Adult onset presents with dementia and psychiatric symptoms, this form is the least common
All form result in early death. Once onset occurs all forms follow the same general path and cause complete neuro-degeneration.

7. Treatment Options
NO FDA APPROVED TREATMENT
EXPERIMENTAL THERAPIES
Off Label prescription of Miglusat, used to treat Gaucher LSD
Supportive care
Parent Driven Compassionate Use Trials of HPBCD underway since12/09
Formal NIH trial underway since 1/13
Very promising new treatments on the horizon in lab settings

8. Supportive Treatment Options
Physical Therapy for low tone and loss of ability to stand, walk or sit
Speech Therapy to add in swallowing difficulties and loss of speech, swallowing ability
Occupational Therapy to teach use of adaptive tools
Seizure Medications to control seizure and cataplexy
PT to move secretions and clear the lungs of mucus brought on by aspiration pneumonia and foamy macrophage infiltration
Comfort measures like pain medication and palliative care

9. Hydroxy Propyl Beta Cyclodextrin
Medical Grade is an 8 ring sugar molecule. Commercial a 7ring sugar molecule
Active ingredient in Febreeze ©, which vaporizes instead of masking odors
Thought to work the same way in NPC by cleaning up excess storage in cells and excreting in waste.
Parents got HPBCD Orphan Drug Status in 2009.
Doesn’t cross the blood brain barrier to reach accumulation in the brain so its presently being infused in 5 US kids aged 3-14 via chest implanted Medi ports and delivered to 4 of their brains by injection into the Cerebral Spinal Fluid.
The NIH launched a 9 patient trial putting it into patients brains via an Ommaya port in January of 2013

10. Diagram of Ommaya Reservoir
Please note the trial at the NIH infusing cyclodextrin via an Ommaya port was halted in Spring of However, there is one US patient with one in and several in Brazil , Spain and Japan. The trial
at the NIH has resumed as of September 2013 injection cyclodextrin into the cerebral spinal fluid of NPC patients. It is called an
Intrathecal lumbar puncture. If you are familiar with epidurals given to women in labor it is the same concept.

11. Diagram of a Medi-Port for IV Infusions
Chase DiGiovanni & Scout
during a typical infusion.
Medi Ports are commonly used for Chemotherapy infusions. They are about
the size of a quarter and are under the skin. The area over the port is numbed
with a freezing cream or spray and the port is accessed with a disposable needle.
These are an excellent alternative to traditional IVs that commonly occlude and are
more visually disturbing for children. Placement is typically an outpatient surgery
and these ports are designed to last for many years.

12. HDAC Inhibitors
A focus of study at Notre Dame is HDAC inhibitors, presently used to treat Cancers
Some of these drugs cause the NPC proteins to express
The hypothesis is that finding the right one to work on certain mutations can cause the cells to begin to recycle the excess cholesterol and lipids accumulating in the cells.
Work on HDACs is accelerating rapidly

13. rhHSP70 Little is known & the researchers aren’t being overly generous with information sharing at this time regarding data on this drugs potential.
This is a drug by Danish Company Orphazyme
Orphazyme’s lead lysosomal storage disease program, Orph-001, a recombinant version of human HSP70 (rhHSP70) is being developed as a therapy for Niemann-Pick disease type C.
One of the main features of rhHSP70 is its cytoprotective capacity which involves its ability to rescue lysosomal function and integrity and maintain proper protein folding and recycling during cellular stress. The molecular mechanisms of rHSP70 ameliorates significantly lysosomal dysfunction. (Kirkegaard et al. Nature 2010, 463:549-53)
As HSP70 is a bona fide chaperone, it is not restricted to act on only specific mutations but can potentially act on all mutations.
One of the main receptors involved in rHSP70 uptake is LRP-1, a well-characterised blood-brain barrier trans-cytosis receptor. rHSP70 thus has the capacity to cross the blood-brain barrier and can potentially address lysosomal storage diseases with significant neurological involvement.