| IT'S ALL ABOUT THE
BIOMARKERS |
|
Allison Bradbury, PhD and Staci
Kallish, DO,
Co-editors |
|
bi·o·mark·er
The
National Institutes of Health Biomarkers
Definitions Working Group defined a
biomarker as "a characteristic
that is objectively measured and evaluated as an
indicator of normal biological processes,
pathogenic processes, or pharmacologic responses
to a therapeutic intervention."
Biomarkers
may provide useful markers of disease severity
and progression, which can be used to show
stabilization or improvement as therapies move
into clinical
trials.
|
BIOMARKERS IN FELINE
SANDHOFF DISEASE
Published in the journal
"Experimental Neurology" January
2015
Dr. Douglas
Martin's lab at Auburn University published an
article in the journal of Experimental Neurology
in January, 2015 entitled "Biomarkers for
disease progression and AAV therapeutic efficacy
in feline Sandhoff disease."
In this
study, the authors looked for markers of Sandhoff disease (SD)
progression in affected cats throughout the
duration of their lifespan by assessing
cerebrospinal fluid (CSF), blood, and other
peripheral tissues, and conducting clinical
evaluations including magnetic resonance imaging
(MRI) and analysis of hearing and sight.
A group of
SD cats were also treated with AAV gene therapy
by direct brain injection, and the same
biomarkers were compared to the untreated
affected SD cats and normal cats to see if
therapy was alleviating signs of disease.
Results of AAV-treated cats are reported up to
16 weeks of age, or the equivalent lifespan of
an untreated SD cat.
The study
found that two analytes in the CSF, aspartate
aminotransferase (AST) and lactate dehydrogenase
(LDH), were significantly elevated with SD and
continued to increase with age. Importantly, AAV
gene therapy restored levels to
normal.
Analysis
of 18 routine blood analytes revealed several
that were significantly altered with SD
including AST, albumin, calcium, and
cholesterol. AAV gene therapy partially or
completely corrected changed analytes in the
blood.
A subset
of white blood cells was analyzed with a
fluorescent dye called LysoTracker that
selectively labels lysosomes. There was a
significant increase in the number of
LysoTracker positive cells by 12 weeks of age in
SD cats, which continued to increase until
humane endpoint. AAV gene therapy led to a minor
reduction in LysoTracker.
Red blood
cells of SD cats were analyzed for a population
of abnormally shaped cells called echinocytes,
which were significantly increased when compared
to normal cats. AAV gene therapy showed little
to no correction of altered red blood cell
morphology.
In the
absence of Hexosaminidase, other lysosomal
enzymes are increased by an unknown mechanism.
Analysis of a subset of white blood cells in SD
cats showed a 2-fold increase in the enzyme
β-galactosidase and a 2.5-fold increase of
α-mannosidase. AAV gene therapy decreased both
enzymes, but to varying degrees.
MRI was
used to measure alterations in the brain of SD
cats at endpoint and AAV-treated cats 16 weeks
post-treatment. Significant alterations in
signal intensity were seen in multiple areas of
the brain in SD cats and AAV gene therapy lead
to improvement in all areas analyzed.
To read more about
the AAV gene therapy with the feline model of
Sandhoff disease, download the paper here. To date,
NTSAD has funded over $500,000 to support animal
studies at Auburn University. |
BIOMARKERS IN GM1 and
GM2
Published "Molecular
Genetics and
Metabolism"
Drs. Jeanine Utz, a doctor of pharmacy, and
Chet Whitley, a geneticist, published an
article in the journal "Molecular Genetics and
Metabolism," titled "Biomarkers of central
nervous system inflammation in infantile and
juvenile gangliosidoses".
In this study, the authors looked for
markers of the disease severity in children with
infantile and juvenile forms of GM1
gangliosidosis and GM2 gangliosidosis (GM2
gangliosidoses include Tay Sachs disease and
Sandhoff disease).
They included 12 children with these
diseases: 2 with infantile SD, 3 with infantile
TSD, 2 with juvenile TSD, 3 with infantile GM1,
1 with late-infantile GM1, and 1 with juvenile
GM1. They looked at both blood and cerebrospinal
fluid (CSF; fluid from a spinal tap) from these
children. Children had blood and CSF samples
collected between 1 and 5 times each.
The blood and CSF samples were evaluated for
72 different chemicals (called analytes) which
can be measured and may be signs of inflammation
or other disease processes.
Results from the children with GM1 and GM2
diseases were compared with normal values and
with those from children with similar but
unrelated lysosomal diseases, the
mucopolysaccharidoses (MPS diseases).
They found 5 analytes that were consistently
elevated in CSF from infantile-onset
gangliosidoses but not elevated in samples from
children juvenile gangliosidosis or from healthy
patients. These analytes were all markers of
inflammation. The elevations in infantile but
not juvenile patients may reflect the increased
severity of earlier-onset diseases.
These analytes were also normal in samples
from patients with MPS diseases, indicating the
elevation may be a signal of an abnormal process
in gangliosidoses rather than lysosomal disease
in general.
Additionally, these analytes were normal in
blood samples, which seems consistent with
central nervous system involvement being the
predominant feature of these diseases.
This was a small study and further research
is needed. Biomarkers may provide useful markers
of disease severity and progression, which can
be used to show stabilization or improvement as
therapies move into clinical trials.
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|
NTSAD Science Symposium &
Workshop |
April 16, 2015 - Hyatt
Regency
Reston, VA ~
8am-6pm |
|
NTSAD is hosting a science symposium
and workshop for researchers and healthcare
professionals in Reston, VA on April 16, 2015 at
the Hyatt Regency hotel.
The co-chairs are Frances Platt, PhD,
and Cynthia Tifft, MD,
PhD. The meeting
will cover advances and new avenues of research
toward treatments for diseases affecting the
CNS. Workshop topics include newborn screening,
gene therapy, novel small molecules, and
clinical trial readiness.
The symposium and workshop agenda is
available here.
There
is space for 10 more attendees. If you are
interested in attending,
please contact
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 |
Anxious to get your bike on the
road this spring after all the snow? Celebrate
the melting and sign up for the 2015
Ride on May 9th!
Join Team NTSAD to raise at
least $20,000!
A
matching grant from the Center of Orphan Rare
Disease Research at University of Pennsylvania
School of Medicine may lead to a successful
treatment!
Register to ride
with
Team NTSAD in
the
Million Dollar Bike Ride at
www.milliondollarbikeride.org.
Don't forget to select Team NTSAD on the drop down
menu!
Email Allison Bradbury with
registration confirmation or questions at allisonbradbury@gmail.com
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