Report on the Second International Conference on NPC
May 29-31, 2003
Tucson, Arizona
Sponsored
and Hosted by: the Ara Parseghian Medical Research
Foundation
Co-sponsored
by: the Office of Rare Diseases,
NIH
|
Report on the Second International Conference on NPC May 29-31, 2003
Tucson, Arizona Sponsored
and Hosted by: the Ara Parseghian Medical Research
Foundation Co-sponsored
by: the Office of Rare Diseases,
NIH |
|
Reported
by NNPDF Director of Research, Janet Ward Pease, with assistance from
Bill Owen
and Susan Green, Niemann-Pick Disease Group-UK, and Douglas Pease, NNPDF
The Second International Conference on Niemann-Pick Type C drew over 140 participants and continued the tradition of encouraging strong cooperation and collaboration among scientists. There were 29 speakers and over 50 poster presentations during the conference. Representatives of NPC families from the U.S., the U.K. and Germany attended and shared their personal stories with researchers at mealtimes and during breaks. Posters on clinical research findings were also presented by Dr. M. Pineda (Fundacion Niemann-Pick de Espana); by Dr. Hans Klunemann (Niemann-Pick Selbsthilfegruppe); and by Jackie Imrie, clinical nurse specialist (Niemann-Pick Disease Group-UK).
A summary given on the final day of the conference by Dr.
Marc Patterson provided an overview of NPC therapies – current and
potential. It gives a good
introduction to the conference material for interested laypersons:
Dr. Patterson explained that the term “therapy” can be used
to describe a treatment which is “curative” (restores normal function by
restoring the cells to health); “definitive” (works on the primary
physiological problem); or “symptomatic” (reduces or eliminates symptoms
without removing the primary cause of the illness). While we all hope for a “curative” treatment, all three of these
types of therapies are useful and, it should be noted that many diseases (like
diabetes) are not cured but are controlled with symptomatic treatments.
A number of symptomatic treatments currently exist for NPC:
There are a number of special challenges in going beyond
symptomatic therapies to provide curative or definitive therapies for NPC. These include:
Dr. Patterson categorized the possible types of therapeutic
strategies as:
1)
gene repair or replacement
2)
cell replacement (i.e. stem cell therapy)
3)
delivery of the healthy protein through the bloodstream
using a virus (possible for NPC2 but not for NPC1 due to its size)
4)
downstream interventions
a)
reduction of sequestered modules (i.e. free the trapped cholesterol
and glycolipids);
b)
stimulation of cholesterol and glycolipid trafficking;
c)
replacement of deficient molecules;
d)
synergy (multiple approaches used together).
5)
other strategies (anti-inflammation; inhibit the process
which programs neuronal cell death; inhibit tau phosphorolation -i.e. the
formation of neurofibrillary tangles which is a symptom of both NPC and
Alzheimer’s disease).
Finally, to move toward more effective therapies, Dr.
Patterson suggested some future directions for NPC research:
Dr. Robin Lachmann, supported by the Niemann-Pick Disease
Group-UK and recently given transitional funding by the NNPDF, reported progress
on his work to correct defective NPC1 genes in mice using the herpes
simplex virus as a vector (i.e. a delivery mechanism).
Preliminary findings by Dennis Ko, who created a “chimeric
mouse” with some healthy and some NPC-diseased Purkinje cells, indicate that
if 20-40% of the Purkinje cells in the animal are normal, neurological disease
symptoms can be largely erased.
This suggests that any strategy for gene therapy or stem cell therapy
for NPC would not need to “fix” 100% of the diseased neurons to provide
significant therapeutic benefits. Work
is continuing to verify results.
A number of researchers, working at the cellular level, have successfully reduced cellular storage of cholesterol using various substances:
It must be emphasized that the substances listed above are
being tested on cells, not on animals or on human beings. Work on all these substances is ongoing and
much more work is necessary before a therapeutic agent could result from any of
them.
Dr. Synthia Mellon’s lab has been exploring the idea that
NPC disrupts the synthesis of neurosteroids in the brain. Neurosteroids have many functions including
modulation of neurotransmission receptors and alteration of neurons and
synapses during development. In NPC,
Dr. Mellon has noted the reduction of various neurosteroids and, specifically,
a very substantial reduction of the neurosteroid allopregnanolone
(“allo”).
Dr. Mellon has
found that treatment of NPC mice with allo substantially increases their
lifespan as well as improving motor skills and delaying weight loss. Treated mice have substantially more
Purkinje cells than untreated mice.
Experiments are continuing to see whether continuous treatment is better
than one shot; whether giving allo to mice at earlier ages is better (appears
to be); and whether even better results would be obtained by prenatal treatment
(i.e. giving allo to pregnant mothers).
Dr. Mellon is also interested in testing a combined treatment of allo
and OGT-918 to see if this is more beneficial than either substance alone. Other avenues for research include learning
how allo preserves the Purkinje cells; and determining how allo treatment
affects the presence of other neurosteroids, glycosphingolipids like GM2 and
GM3, and cholesterol.
Dr. Fran Platt’s studies
on NPC mice showed the presence of some markers of inflammation, in a pattern
similar to that seen in prion diseases, a rare group of neurodegenerative
disorders that includes 'mad cow' disease. Modest (not statistically
significant) effects on survival were seen after giving the mice an
anti-inflammatory drug (ibuprofen). There are no data to indicate that
ibuprofen would have an effect in human NPC, and this drug should not be used
without supervision, as it can produce a number of adverse effects, including
gastrointestinal bleeding and impairment of kidney function. However, Dr. Platt suggested that eventual
NPC therapies might include a combination of compounds: for example, a
glycosphingolipid inhibitor (like OGT-918) in conjunction with an
anti-inflammatory or anti-oxidant.
In a poster presentation, Dr. Hans Klunemann and colleagues
presented information derived from their study of nine NPC1 patients aged 12 to
39 years. By PET-neuroimaging they
documented hypometabolism in the brain’s frontal lobe, basal ganglia,
cerebellum, parieto-occipital lobe, and thalamus. Clearly diminished thalamic hypometabolism was such a
common finding that they suggest it as a possible diagnostic clue for NPC1.
Research continues to show that NPC1 & NPC2 work in
coordination with one another rather than as stand-ins or substitutes for
one another. Dr. Marie Vanier said she
agrees with this hypothesis based upon the fact that there is no phenotypic
(symptomatic) difference in brain and liver tissues from individuals with NPC1
and NPC2.
The importance of the accumulation of glycolipids in the
NPC brain appears now to be widely accepted although there is disagreement
about how this phenomenon relates to cholesterol accumulation. In a new hypothesis, Dr. Steve Walkley
proposed that glycosphingolipid accumulation may actually be the primary defect
of NPC affecting neurons and that the accumulation of cholesterol might be a
secondary effect.
Regarding cholesterol storage in the brain, Dr.
Vanier said that it accumulates in NPC
neurons but not in the mass quantities seen in other types of cells of the
body. On the other hand, Dr. Jean Vance
felt that in NPC there is no additional cholesterol in NPC neurons but that
it’s distribution may be different from that in healthy neurons (i.e. NPC
neurons have a higher than usual amount of cholesterol in the cell body and a
lower than usual amount in distal axons).
Dr. Vance also noted that NPC cells show more cholesterol accumulation
at the neuron’s synapse than healthy cells do. This may have implications for
neurotransmitter release in NPC.
Several researchers discussed the possibility that NPC
disrupts neuronal synapse formation.
Dr. Robert Maue, in his work on cerebellar Purkinje neurons in NPC mice,
concluded that synapse formation appeared to be normal but that electrical
activity was disrupted. Specifically,
electrical activity in Purkinje cells of normal mice show regular firing
patterns whereas those of NPC mice have many
stops and starts in their activity.
Dr. Maue says there are two components of the electrical current
that flows through neurons: transient and persistent. Transient current flows only when a particular action is taking
place in the neuron whereas persistent current is constant and helps the neuron
get ready for the next action. His
studies indicate that the persistent component of the electrical current may
never develop properly in NPC Purkinje cells.
Dr. Joan Blanchette-Mackie has shown that material is
exchanged between the late endosome and the lysosome in cells through tubules
that form on the late endosome and connect to the lysosome at the time of
exchange. The NPC1 and NPC2 proteins
can be seen moving through these tubules.
She has also found that the presence of cholesterol affects the mobility
of the tubules and that tubules in NPC-diseased cells show significantly
less mobility. She believes that
this immobility may be the reason that lipids remain stuck in the lysosome,
eventually causing cell death.
A number of papers were presented on NPC2 with one proposing the 3D structure of the protein, how it may accommodate a cholesterol molecule, and describing its location as being within lysosomes. The importance of this is that it is not only a further piece in the NPC jigsaw, but it provides an opportunity to define new therapeutic strategies
The conference was a first in showing cholesterol
trafficking in the central nervous system (“CNS”) although this is not
new. (A paper was published last year
which discussed the role of apoE/HDL interaction in the CNS). In the past, work on fibroblasts and CHO
cells have been presented. However, the
diagrams presented in Tucson showed apoE mediated transport between astrocytes
and neurons and between oligodendrocytes and microglia. The main point is that the cells of the
CNS are now becoming the focus of attention. This is important in that the body seems to tolerate NPC, except
of course for severe mutations, but the brain does not.
Dr. Peter Lobel, who discovered the NPC2 gene, has created a
mouse model of NPC2 disease.
In yeast, it has
been noted that when the Ncr1 gene in yeast (which is comparable to the NPC1
gene in humans) is defective, it does not seem to cause the yeast to die or
sicken. Consequently, Dr. Stephen
Sturley has concluded that another gene (or genes) must take over the work of
the Ncr1 when it is not functional. Dr.
Sturley has 55 candidates for “stand-in genes” for Ncr1. If such a gene can be found, the next step
would be to find the comparable gene in humans and see if it could be “turned
on” to compensate for the defective NPC1 proteins in those with Niemann-Pick
Type C.
A poster from Marie Vanier's lab proposed that improved
models of NPC mice should be developed containing milder, more common mutations. This is likely to provide a better insight
into protein trafficking and the mice would survive longer giving scientists
time to obtain more extensive results.
Dr. Robert Maue’s presentation included work using his hybrid
mouse model (“NPC1-GFP fusion gene”).
The NPC mouse ‘s Purkinje cells have been altered so they are
fluorescent green, making them easier to monitor in research. It is hoped that the mouse model will
improve understanding of neuronal function in NPC and help in investigating
possible treatment strategies. The
mouse line, which Dr. Maue described in his address at the NNPDF Family
Conference last year, are available for use by other NPC researchers. Hybrid
mice development was co-funded by the NNPDF and NIH.
On behalf of all NNPDF members, we thank the hosts,
sponsors, organizers and others who made this important gathering possible:
Also, many thanks to Bill Owen and Susan Green of the Niemann-Pick Disease Group-UK and to Doug Pease of the NNPDF who contributed to this summary.
Tucson Conference Abstracts (Adobe Acrobat Reader required)