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Project:
Development and validation of a rapid,
MS/MS-based method to detect Hexosaminidase
deficiency in Tay-Sachs disease.
Principal
Investigator: Denis C. Lehotay,
PhD
Institution:
University of Saskatchewan College of
Medicine
Goals
of the proposal:
*
Validate an existing high through-put MS/MS method for detection of
reduced hexosaminidase activity (that was
developed for Sandhoff disease) using dried
blood spots (DBS) in normal patients and
patients affected with Tay-Sachs disease
(TSD). *
Determine hexosaminidase activity in 1000
de-identified DBS from normal patients and in
10-20 samples from known TSD patients to
establish reference ranges and cut off values.
*
Conduct a pilot-screening study using ~5000 DBS
from an area of Quebec with high carrier
frequency (~1/25) among French Canadians, which
is similar to that found among Ashkenazi Jewish
populations.
Impact
of Research: Once treatment for
TSD becomes available, detecting TSD by early
screening, including newborn screening, and
initiating early treatment will become essential
to preventing the devastating consequences of
this currently incurable condition. Developing,
validating, and testing a rapid MS/MS based
assay for measuring hexosaminidase activity in
populations with a high incidence of the disease
are part of the essential steps that will lead
to an established newborn screen and an eventual
cure.
Project:
Intravascular gene therapy for feline GM2
gangliosidosis
Principal
Investigator: Douglas R.
Martin, PhD
Institution:
Auburn University
Goals
of the proposal:
*
Optimize intravascular (IV) gene therapy
to treat both central nervous system (CNS) and
peripheral (rest of body) manifestations of
feline Sandhoff disease (SD). *
Conduct short-term (6 week) studies to compare
different delivery routes (i.e. carotid artery and cephalic vein) for optimal
therapeutic effect in the CNS and minimized
vector levels in the periphery. *
After selecting optimal delivery route, the
therapeutic effect of pretreating cats with
mannitol to temporarily open the blood brain barrier and
possibly permit use of a lower dose of vector
for long-term therapy will be evaluated.
Impact
of research: NTSAD has
previously supported efforts of the Tay-Sachs Gene Therapy
Consortium to develop an effective gene
therapy protocol for TSD and SD. Previous
studies with direct intracranial injection of Adeno-associated virus (AAV)
vectors expressing hexosaminidase
dramatically increased the life span and quality
of life in SD cats. While these proof-of-concept
studies continue to support human application of
intracranial gene therapy for TSD and SD, it is
desirable to develop a less invasive and
presumably safer approach that will also better
address peripheral disease.
Project:
Defining the Natural History
of
Canavan
Disease through Development
of
an
International Registry
Principal
Investigator: Heather A.
Lau, MD, MS
Co-Investigator:
Paola Leone, PhD
Institution:
New York University
Goals
of the proposal:
*
Create an international electronic database to
gather data prospectively in order to enhance
the understanding of clinical variability,
further define the relationship between genotype
and phenotype, and delineate the progression of
natural history of patients with Canavan disease
(CD).
*
Maintain a bio-repository of blood and urine
specimens collected from CD patients for
potential evaluation of biomarkers. *
Provide the medical community treating patients
with CD with recommendations for monitoring and
managing patients in order to optimize patient
care.
*
To define and categorize clinical endpoints that
may be used for the development of clinical
therapeutic trials.
Impact
of research: A disease registry
is integral to elucidate the natural history of
the disease and its varied clinical
presentations so that appropriate clinical
endpoints are obtained to show efficacy of
potential therapies. These efforts will also
harmonize the efforts of Dr. Annette Bley at the
University Medical Center Hamburg-Eppendorf, Dr.
Florian Eichler at Massachusetts General
Hospital, and other clinical sites around the
world to increase the power of individual
studies.
Project:
Late Onset Registry and
Repository
Principal
Investigator: Florian S.
Eichler, MD
Institution:
Massachusetts General Hospital
Goals
of the proposal:
*
Perform a comparative review of literature
reports and patient surveys for natural history
data and outcome measures to establish an
inventory for TSD with participation from
various sources.
*
Determine optimal outcome measures in LOTS
patients through a prospective pilot project at
MGH. Outcome measures will be judged based on
variability of data, change over a 6-month
period, and patient ranking of importance.
*
Create and implement electronic case report
forms based on outcome measures to allow several
centers to participate in future trials using
NeuroBANK.
*
Perform prospective studies of longitudinal
outcome measures and biomarkers in LOTS
patients.
Impact
of research: This proposal will
retrospectively and prospectively determine
optimal outcome measures in LOTS patients and
thereby assist in protocol development and trial
design. Specifically, this proposal will
identify the target population and clinical
endpoints in the LOTS subpopulation of the
disorder and will be vital in responding to
questions of patients, families, medical
practitioners, industry and regulatory bodies
alike.
Project:
Generation of a knock-in mutant Hexb
mouse model
Principal
Investigator: Eric R.
Sjoberg, PhD
Institution:
OrPhi Therapeutics
Goals
of the proposal:
*
Create a specific missense point mutation in the
beta chain of hexosaminidase that can be rescued
by pharmacological chaperones,
small molecules that selectively bind and
stabilize certain point mutations, in order to
test efficacy of chaperones that are being
developed for Late Onset Tay-Sachs and Sandhoff
disease. *
Compare brain levels of beta-hex, GA2, and GM2
levels in disease-causing homozygous knock-in
mice to determine if a biochemical phenotype
similar to Late Onset Tay-Sachs and Sandhoff
diseases presents in the mouse model.
Impact
of research: Pharmacological
chaperones represent a new class of treatment
for patients with diseases that result from
destabilization, unfolding, or misfolding of a
protein. The current GM2 mouse model is a
hexosaminidase knock-out (hex-/-), which does
not produce any of the target protein and
therefore cannot be used to evaluate various
chaperones ability to bind and stabilize the
protein. Creation of a knock-in mouse with a
point mutation, which is equivalent to a known
human late onset mutation, will allow analysis
of in vivo dosing effects of specific chaperones
that have already been developed. The mouse
model will be made available for other late
onset
research.
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