Friday, JUNE 12, 2015

NTSAD Monthly Research Review
2015 NTSAD Research Initiative Grants
Allison Bradbury, PhD, and Staci Kallish, DO, co-editors

NTSAD has maintained a strong commitment to funding research over the years to advance its mission to lead the fight to treat and cure Tay-Sachs, GM-1, Sandhoff, Canavan, and other related genetic diseases.


This year NTSAD is pleased to announce the 2015 Research Initiative Grants totaling $266,000 thanks to many generous research supporters.


This year NTSAD solicited proposals for innovative research projects that involve basic research, translational studies or clinical studies (the full RFP can be seen here). Grant awards were based on final proposal evaluations by a Research Evaluation Subcommittee of NTSAD's Scientific Advisory Committee and other scientists who generously volunteered their time. Grants were made for a one to two year period for up to $40,000 per year. (Funding for a second year is predicated by adequate progress during year one.)


NTSAD would like to thank all of those that submitted an application this year. The pool of applicants was highly competitive and numerous proposals were conducive to the NTSAD mission. At this time NTSAD congratulates the five awardees for the 2015 research grants and includes their summaries below.

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.

The following two grants are made possible by the Katie & Allie Buryk Research Fund of NTSAD:

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.

NTSAD Scientific
Advisory Committee
NTSAD's Scientific Advisory Committee (SAC) is comprised of world-leading experts in lysosomal and leukodystrophy disease research and clinical care. We thank them for their guidance and sharing their expertise. Read about SAC here.
Fran Platt, PhD (Chair)
Jodi Hoffman, MD (Vice chair)

Miriam Blitzer, PhD
Robert Desnick, PhD, MD
Florian Eichler, MD
Mark Haskins, VMD, MS, PhD
Michael Kaback, MD, FACMG
Edwin Kolodny, MD
Heather Lau, MD
Paola Leone, PhD
Gustavo Maegawa, MD, PhD
Marvin Natowicz, MD, PhD
Swati Sathe, MD, MS
Thomas Seyfried, PhD
Barbara Shapiro, MD, PhD
Evan Snyder, MD, PhD
Cynthia Tifft, MD, PhD, FACMG
Steven Walkley, DVM, PhD
Michael Watson, PhD, FACMG
NTSAD Corporate
Advisory Council
The Corporate Advisory Council (CAC) advises NTSAD about its efforts to direct, fund and promote the development of treatments and cures for the NTSAD family of diseases.Read more about CAC here.
Marion Howard, MD, PhD (Chair)
Oved Amitay
Ritu Baral
Michael Gladstone
Kate Haviland
Joan Keutzer, PhD
Greg Licholai, MD
Events Benefiting Research

Friday, June 19th, 2015
12th Annual Drive for Dylan
Honey Brook Golf Club
Honey Brook, Pennsylvania

This annual golf outing honors
Dylan Manning's memory and funds raised will go to NTSAD's Research Initiative to further support research. Last year's outing raised $23,000 for research!

Click here to support the outing.

Sunday, June 21, 2015
Dance for a Cause
Sycamore Junior High School
Cincinnati, Ohio

This special performance is dedicated to a little boy, Maanas, who had Sandhoff disease. His big sister, Ria, and his family are starting a Sandhoff disease research fund in his memory - all proceeds will benefit the fund.

Click here to support Ria's efforts.
Canavan Researcher Highlighted
Dr. Guangping Gao of UMass Medical profiled in International Innovation

This article highlights Dr. Guangping Gao, what led him to study gene therapy and the work he is doing that focuses on Canavan disease. You can read the full article by downloading it here.

Dr. Guangping Gao has been working on a gene therapy treatment for Canavan disease at the University of Massachusetts Medical Center in Worcester, MA. His work has been funded by NTSAD and a final report can be downloaded here.

NTSAD appreciates the generosity of 1,200+ donors who have made gifts in support of our annual Day of Hope events and Research Funds in the last year. 

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