Leading the worldwide fight to treat and cure
Tay-Sachs, Canavan, GM1 and Sandhoff diseases

Emma's Fund for Families

When we look back on our time with Emma we don't focus on the medical equipment, the seizures, the medications, or the feedings.  We remember all the memories we made with her.  We were determined to give Emma as normal of a life as possible and tried to do as much with her as we could.  From trips to the zoo, baseball games, days at the beach, apple picking, going to the top of the Empire State Building, and having tea at the Plaza with Eloise, we have so many things to choose from and numerous pictures to remind us of the good moments.

Emma’s Fund for Families is established to enable families to have memory making opportunities in honor of Emma.  The purpose of the fund is to allow affected families to apply for grants to use towards enrichment activities.  It can be used any way a family feels would be beneficial for creating their memories, such as trips to the zoo, photo shoots, tickets to an event, an overnight in a hotel with a pool, etc.  Anything that your family feels would provide a break from the routine and some fun times with your child is eligible.  We hope all families have the opportunity to make amazing memories. 

To apply for grant, please download and fill out the form document here (82 KB) .

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Download an application here.

  

Emma with Daddy at a Mets game

Resting on the beach

 

Emma at Frozen on Ice

 

Apple Picking 

Relaxing poolside  

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Research Review 7-14-2017 - Full Reports

Novel combined gene/cell therapy strategies to provide full rescue of the Sandhoff pathological phenotype

Principal Investigator: Angela Gritti, PhD

San Raffaele Scientific Institute, San Raffaele Telethon Institute (two year study)

Reporting period: 12/15/16 – 6/14/17

The goal of this study is to evaluate gene and cell therapy approaches in the mouse model of Sandhoff disease (SD). Specifically, this study is comparing 3 therapeutic methods 1) direct intracranial lentiviral gene therapy, 2) neural stem cell transplantation (with or without gene correction of cells), 3) and bone marrow transplantation (BMT). These therapies will initially be tested individually and subsequently in combination. The investigators identified 3 milestones to be completed during the first 6 months of the project. Progress has been made on each milestone as described below:

 1. To optimize BMT in neonatal SD mice.

The investigators have conducted BMT in 13 SD and 10 unaffected littermates at postnatal day 7, following myeloablation (reduction of host bone marrow to allow engraftment of donor bone marrow) at postnatal day 6. Engraftment of the donor stem cells ranged from 40-100%. The investigators are currently optimizing the myeloablation protocol to uniformly achieve the target of >70% engraftment.

A small group of BMT-treated SD mice were sacrificed at 4 months of age, corresponding to the average lifespan of untreated SD mice. Preliminary data in mice sacrificed at 4 months of age show that GM2 storage is not normalized in the central nervous system (brain and spinal cord) of BMT-treated SD mice. The remaining BMT-treated SD mice were allowed to live until humane endpoint (mice unable to walk and feed) to be monitored for survival. These mice show significant enhancement of lifespan (155 +/- 4 days) as compared to untreated SD mice (116 +/- 1 days; p<0.005). Analyses of these mice are ongoing.

2. To generate high titer lentiviral vectors expressing mouse hexosaminidase genes.

The investigators have generated 2 lentiviral vectors, one encoding the HEXA gene and the other encoding the HEXB gene. These vectors have been validated in cell culture and are now being tested in a small cohort of SD mice that will be sacrificed and analyzed 1-month post brain injection. 

3. To optimize vector transduction of neural stem cells (NSCs).

The investigators transduced SD and wildtype NSCs with the lentiviral vectors mentioned above and showed a dose-dependent increase in hexosaminidase. The Hex enzyme produced in the NSCs proved to be functional as it reduced GM2 storage as compared to untreated SD NSCs.

 

Development and Validation of an MS-MS Method for the Detection of Hexosaminidase Deficiency in Tay-Sachs Disease

Denis Lehotay, PhD, Queens University

Description:

The aims of the project are to develop a mass spectrometry-based method for rapid screening of babies with Tay-Sachs or Sandhoff disease using dried blood spot (DBS) samples collected as part of the routine, newborn screening, usually within the first week of life. 

Progress & Status:

The investigators looked at the enzyme assay protocol used for measuring hexosaminidase. In examining the enzyme assay conditions, they realized that the conditions that were used in their earlier publication describing the assay to detect Sandhoff disease in northern Saskatchewan did not work for samples from patients with Tay-Sachs disease. So, they examined every aspect of the earlier assay, and embarked on re-developing an assay that will work in the detection of both Tay-Sachs and Sandhoff patients. This work is essentially complete.

The next step is to validate this assay using about 500 normal blood spots, as well as blood spots from both Tay-Sachs and Sandhoff patients. Almost all of these blood spots have already been collected and are ready to be analyzed. The goal is to establish reference ranges for total hexosaminidase, Hex-A and Hex-B for normal patients as well as for those affected by either Tay-Sachs, or Sandhoff disease. The investigators anticipate this work to proceed quite rapidly, since the assay they developed is capable of analyzing many samples per day.

Next Steps:

The plan for the future therefore includes completing the validation of the method. This will be followed by analyzing the approximately 10,000 blood spots that they hope to receive from the Quebec newborn screening program. They are awaiting approval from the Ethics Review Board in Quebec for this study, which they hope to receive in the near future.

 

Rapid Identification of New Biomarkers for the Classification of GM1 and GM2 Gangliosidoses: A HNMR-linked Metabolomics Strategy

Principal Investigator: Martin Grootveld, PhD

Leicester School of Pharmacy, De Montfort University, UK (one year study)

The objective of this study is to identify biomarkers of GM1 and GM2 in plasma, CSF (cerebrospinal fluid), and/or urine that have been sampled repeatedly from affected individuals over time. This will contribute to an overall goal of a greater understanding of disease pathogenesis as well as identification of potential drug targets. The study is utilizing nuclear magnetic resonance (NMR)-linked metabolomics to screen for biomarkers in samples from GM1 and GM2 patients followed by advanced multidimensional datasets to extract detailed information. The study aims to further identify and validate potential NMR targets by liquid chromatography-mass spectrometry (LC-MS), a technique that has a higher level of sensitivity.

More than 80, 50 and 30 metabolites were detectable in the spectra acquired on urine, blood plasma and CSF respectively. The investigators are initially focused on both metabolomics comparisons of the plasma profiles of GM1 type 2 patients with those arising from a healthy human control population. 32 significantly higher and 8 significantly lower plasma levels of metabolites in the GM1 type 2 group of blood plasma samples were found and further analyzed. The key metabolic modifications up regulated in the blood plasma concentrations of GM1 type 2 group included: 3-aminobutyrate, valine, citrate and lipoprotein-associated traicylglycerols, and neuroactive amino acid glutamine. The significant down regulations included urea level, an intermediate-to-long chain function of a currently unidentified biomolecule, and an aromatic amino acid protein. Further investigations to determine the identities of these two GM1 type 2 - reduced signals are currently in progress. Some of these alterations may arise from imbalances in BCAA and/or thymine catabolism and modifications to lipid homeostasis in GM1. Metabolic distinctions between the CSF and urinary NMR profiles are currently being investigated.

 

Identifying Novel Therapeutics for Treating GM2 Gangliosidoses

Investigator: Beverly L Davidson, Ph.D.

The drug Miglustat (approved for Gaucher disease in 2002) does not cross the blood-brain barrier to an extent that could mediate benefit in a clinical trial in patients with late onset Tay-Sachs disease. In this study, the investigators are using a powerful drug discovery approach to identify FDA approved drugs that have improved brain penetrance while simultaneously share the same efficacy as Miglustat.

Status: They have submitted 49 samples to the University of Iowa, Genomics division for high-throughput RNA-sequencing. These samples represent 7 donors treated with the three drug treatments and controls at two different doses.

Next Steps: The investigators will query the LINCS database with the RNA-seq data, identify drugs and validate hits over the next 4-6 months. Importance: These important preliminary studies will help identify additional, brain penetrable drugs that may find use in substrate reduction therapy for the gangliosidoses.

2019 Ninth Annual Day of Hope

What is a Day of Hope?
It is a time for our rare and mighty community to come together to make a difference and show that there is always hope.

All proceeds go to the research that NTSAD funds including the work leading to clinical trials. We are closer than ever and together we can be sure to be ready!

Our goal for 2019?

To surpass $500,000! We can do it! Our total since 2011 is now $439,000. If you're interested in participating, please take a moment and email Becky This email address is being protected from spambots. You need JavaScript enabled to view it.. Thanks! 

Now, how can you be part of a Day of Hope?

There are many ways!

  • Create your own custom Day of Hope t-shirt campaign with our friends at CustomInk. (Email This email address is being protected from spambots. You need JavaScript enabled to view it. to sign up for your own campaign!)
  • Spread awareness about being the risks of being a carrier.
  • Share your family story and how being rare has impacted your family.
  • Host a lemonade stand in your neighborhood.
  • Create your own giving page and encourage friends to make it go viral for what is important to you.
  • Check out some of the ideas (in the box to the right), or come up with an idea of your own, and let us know and we'll be sure to send you some fun swag!
  • Whatever you do, be sure to post and tag your photos on Facebook, Twitter or Instagram with #NTSAD #MoveMountains #2019DayofHope.

Let's Rally & Raise Funds for Research!

Let's Make Treatments and a Cure Happen. Now!

2016 Research Initiative Grants

Martin Grootveld, PhD
Leicester School of Pharmacy
De Montfort University, UK

Co-Principal Investigator: Cynthia Tifft, MD, PhD

Rapid Identification of New Biomarkers
for the Classification of GM1 and GM2
Gangliosidoses: A HNMR-linked
Metabolomics Strategy

The objective of this study is to identify biomarkers of GM1 and GM2 in plasma, CSF (cerebrospinal fluid), and/or urine that have been sampled repeatedly from affected individuals over time. This will contribute to an overall goal of a greater understanding of disease pathogenesis as well as identification of potential drug targets.

The study will use nuclear magnetic resonance (NMR)-linked metabolomics to screen for biomarkers in samples from GM1 and GM2 patients and used advanced multidimensional datasets to extract detailed
information. The study will further identify and validate potential NMR targets by liquid chromatography-mass spectrometry (LC-MS), a technique that has a higher level of sensitivity


Angela Gritti, PhD
San Raffaele Scientific Institute
San Raffaele Telethon Institute for Gene Therapy (Italy)

Novel combined gene/cell therapy
strategies to provide full rescue of the
Sandhoff pathological phenotype

This study will evaluate gene and cell therapy approaches in the mouse model of Sandhoff disease. 

Specifically, this study will compare three therapeutic
methods:

1) direct intracranial lentiviral gene therapy,

2) neural stem cell transplantation (with or without gene
correction of cells)

3) and bone marrow transplantation.

These therapies will initially be tested individually and subsequently in combination. A combination of these therapies has demonstrated a synergistic effect and extension of lifespan in a mouse model of a similar disease providing the rationale to assess these therapies for Sandhoff and Tay-Sachs diseases.


Cynthia Tifft, MD, PhD
National Human Genome Research Institute
National Institutes of Health

Clinically Relevant Outcome Measures
for Patients with Late Onset Tay-Sachs
disease Ascertained Real-Time Through
Patient Wearable Technology

Funded by Katie & Allie Buryk Research Fund of NTSAD

This study is a next step in identifying relevant outcome measures for clinical trials. This six month exploratory study will use 5-8 ambulatory or partially ambulatory adult patients with late onset Tay-Sachs or Sandhoff disease to collect patient data on ambulation, falls, wake/sleep cycles, and other patient input that can be tested as potential clinically relevant outcome measures for future clinical trials. Data is collected through a wearable device and transmitted through a mobile app to Dr. Tifft for analysis. The data collected will be compared to clinical testing including gait lab metrics to be conducted at the NIH Clinical Center at the time of initial evaluation and at the six month endpoint.


Beverly Davidson, PhD
Children's Hospital of Philadelphia

Fran Platt, PhD
Oxford University (UK)


Identifying Novel Therapeutics for
Treating GM2 Gangliosidoses

Co-funded with the Katie & Allie Buryk Research Fund and the Vera Pesotchinsky Research Fund of NTSAD

Substrate reduction therapy (SRT) has the potential to be broadly applicable to several lysosomal storage diseases, including the gangliosidoses. However, the SRT drug Miglustat (approved for Gaucher disease in 2002) does not cross the blood-brain barrier to an extent that could mediate benefit in patients with Tay-Sachs disease.

This study will analyze Miglustat and the closely related drug Lucerastat using human macrophages (a type of white blood cell that digests cellular debris and foreign objects). This comparison will allow identification of common pathways affected by both Miglustat and Lucerastat and determination of other drugs that act in a similar manner. Drugs that share common features, but have improved central nervous system penetrance for treating the gangliosidoses (including GM-1), will then be tested for their ability to reduce stored substrate levels when applied to patient-derived cells. As Miglustat has
additional anti-inflammatory properties relative to Lucerastat, this analysis may also shed light on the inflammatory pathways targeted by Miglustat.


 

Current and Past Grants

Advancing Research

NTSAD's Annual Request for Proposals, 2022 Pre-application will be due in February 18, 2022. Learn more: Request for Proposals (RFP) 2022

NTSAD awards grants for innovative research projects that may lead to treatments for lysosomal storage diseases or leukodystrophies impacting the central nervous system.

These grants went on to receive over $20 million in funding through the National Institute for Health. 

Explore the Impact

On the following pages, explore current research underway, and the impact past grants have made. 

  • 2018 Research Initiative Grants +

    Research is Underway

    The following 3 grants were awarded for 2018. Research updates will be posted when available.

    1. Role of Plasma membrane-ER Contact Sites in GM1-mediated Neuronal Cell Death
      Alessandra D'Azzo, PhD

      With these studies we plan to evaluate in the mouse model of GM1-gangliosidosis how GM1 accumulation affects the membrane contact sites formed between cellular components and the neuronal outer membranes. This will help us to understand the role of calcium and calcium-binding proteins at these contact sites in causing the damage to neurons.
    2. Role of microglia in Sandhoff disease pathology
      Tony Futerman, PhD

      Microglia are inflammatory cells found in the central nervous system. They are known to play a role in the pathophysiology of Sandhoff disease but the inflammatory pathways activated are not known. This study aims to better understand these pathways to delineate potential targets for therapeutic intervention in Sandhoff and Tay-Sachs diseases.
    3. Oligosaccharide Biomarkers for Disease Progression and AAV Therapeutic Efficacy in GM1 Gangliosidosis
      Xuntian Jiang,PhD

      In this proposal, we will identify the structure of the oligosaccharide biomarker and evaluate this marker as a surrogate outcome measure of treatment for GM1. This project will provide a much-needed tool for assessing GM1 disease severity and therapeutic efficacy.
    Read More
  • 2017 Research Initiative Grants +

    Research is Underway

    The following 3 grants were awarded for 2017. Research updates will be posted when available.

    1. Proof of concept study of HSC gene therapy for Tay-Sachs disease
      Alessandra Biffi, MD

      The project will test a novel gene therapy approach for Tay-Sachs and Sandhoff Disease by establishing a stable population of brain cells, which will serve as a sustained and balanced supply of the deficient enzymes in the patients.
    2. Minimally invasive delivery of AAV gene therapy in the Tay-Sachs Sheep
      Heather Gray-Edwards

      The study will evaluate the efficacy and biodistribution of the state-of-the-art gene therapy in Tay-Sachs Disease sheep.
    3. Development of a quantitative method for the determination of a pentasaccharide in GM1-gangliosidosis patient cells to assess the potential therapeutic efficacy of a beta-galactosidase pharmacological chaperone drug candidate
      Tim Wood / Stephane Demotz

      This study's goals are to develop a quantitative, sensitive, and robust method to determine a biomarker for GM1-gangliosidosis, and to explore treatment conditions of a drug candidate for GM1 patient cells.
    Read More
  • 2016 Research Initiative Grants +

    Research is Underway

    1. Rapid Identification of New Biomarkers for the Classification of GM1 and GM2 Gangliosidoses: A HNMR-linked Metabolomics Stragegy
      Martin Grootveld

      By identifying the markers of GM1 and GM2 in plasma, cerebrospinal fluid, and urine, a greater understanding of the disease will contribute to identification of treatments.
    2. Novel Combined Gene/Cell Therapy Strategies to Provide Full Rescue of the Sandhoff Pathological Phenotype
      Angela Gritti

      This study will evaluate Sandhoff Disease gene and cell therapy approaches, comparing three therapeutic methods to assess these therapies for Sandhoff disease.
    3. Clinically Relevant Outcome Measures for Patients with Late Onset Tay-Sachs disease
      Ascertained Real-Time Through Patient Wearable Technology
      Cynthia Tifft

      This study will collect patient data to identify outcome measures for future clinical trials for Late Onset Tay-Sachs.
    4. Identifying Novel Therapeutics for Treating GM2 Gangliosidoses
      Beverly Davidson

      This study will analyze the drugs Miglustat and Lucerastat, and drugs that act in a similar manner, testing their ability to be used as a treatment for GM2.
    Read More
  • 2015 Research Initiative Grants +

    Research is Underway

    1. Development and validation of a rapid, MS/MS-based method
      to detect Hexosaminidase deficiency in Tay-Sachs disease
      Denis Lehotay

      Advancing research for Tay-Sachs screening, this study furthers the work to establish newborn screening and an eventual cure.
    2. Intravascular Gene Therapy Studies to Improve Methods of Delivery
      Douglas Martin

      This research advances work into developing a less invasive and safer approach to treating Tay-Sachs and Sandhoff Disease.
    3. Defining the Natural History of Canavan Disease through Development of an International Registry
      Healther Lau / Paola Leone

    4. An international registry of Canavan Disease will contribute to showing the effectiveness of potential therapies and provide more data for future studies.
    5. Registry and Repository for Late Onset GM2 Gangliosidoses
      Florian Eichler

      This study will take steps to accumulate and organize information, leading to improved trial design for Late Onset GM2 patients. It includes review of literature and surveys, determination of optimal outcome measures for a pilot project, and creation of electronic case report forms.
    6. Generation of a knock-in mutant Hexb Mouse Model
      Eric Sjoberg

      Advancing Late Onset research, this study will focus on creating a model environment equivalent to a human Late Onset condition. The model will be made available for other Late Onset research.
    Read More
  • 2014 Research Initiative Grant +

    Research Completed

    Lectin-Assisted Transnasal Delivery of Corrective Enzyme for GM1 Gangliosidosis

    This grant funded research into Transnasal delivery, exploring this alternative as a method of delivering enzyme replacement therapy. With its distinctive advantage of being convenient and non-invasive, Transnasal delivery offers potential for treating brain disorders like GM1.

    Read More
  • 2012-2013 Research Initiative Grants +

    Research Completed

    Studies of the Molecular and Biochemical Bases of Neurodegeneration in Sialidosis
    NEU1 is a key lysosomal enzyme in brain cells. Patients with Sialidosis, a rare pediatric lysosomal storage disease, have too little or no NEU1 enzyme. Scientists from d’Azzo Lab analyzed the effects of NEU1 deficiency and identified new genes that may help develop therapies for both Sialidosis and Alzheimer's disease. Read More
  • 2011 Research Initiative Grants +

    Research Completed

    1. Clinical Outcome Measures for a Gene Therapy Trial in Infantile and Juvenile GM2
      Florian Eichler

      Neurological and neuropsychological evaluations of children with GM2 resulted in a Severity Scale that will help scientists further clinical trial design for GM2 gene therapy.
    2. Optimization of Efficacious Gene Therapy for Canavan Disease
      Guangping Gao

      Advancing gene therapy for Canavan disease, this research examined the efficiency of deliverying therapy by injections to the central nervous system. Both systematic intravenous (IV) injections and direct-to-brain intracerebroventricular (ICV) injections were studied.
    3. Studies of Taurine-Conjugated GM2 in Tay - Sachs Disease
      Yu-Tah Li

      This study explored lipids in the brain of Tay-Sachs patients.
    Read More
  • 2010 Research Initiative Grants +

    Research Completed

    1. The Therapeutic Potential of Human Induced Pluripotent Stem Cells (IPSCs)
      in the Sandhoff Disease Mouse Model of Lysosomal Storage Disorders
      Jean-Pyo Lee

      Advancing development of stem them therapy for Tay-Sachs and Sandhoff disease, this pilot study examined the benefits of using transplanted stem cells with a protein factor.
    2. Developing a High Throughput Screening Assay to Identify Potential Drugs for Metachromatic Leukodystrophy
      Gustavo Maegawa

      Researchers developed expertise to convert skin cells to brain cells, to be used as a model system to test potential drugs for neurological diseases.
    3. Sheep as a Model of Tay-Sachs Disease
      Doug Martin

      This research characterizes the disease progression of Tay-Sachs to assist with therapeutic strategies.
    4. Optimizing the Therapeutic Potential of Anti-inflammatory Therapy in
      Tay-Sachs and Related Diseases: Targeting IL-β Generated by Aberrant NLRP3 Inflammasome Activation
      Fran Platt

      The impact of inflammation on the symptoms of lysosomal storage diseases was researched to further potential therapies in treating Tay-Sachs and Sadhoff diseases.
    5. Development of an in vitro approach to identify molecular pathways of Canavan disease
      Maria Traka

      From this research into the rare leukodystrophy Canavan disease, it was determined the loss of key enzyme ASPA function did not lead to the death of oligodendrocyctes neuron cells. This study ay help identify new pathways for treating Canavan disease.
    Read More
  • 2009 Research Initiative Grants +

    Research Completed

    1. Investigator-Initiated Clinical Trial of Pyrimethamine
      Joe Clarke & Edwin Kolodny

      This study examined the potential clinical benefit of a therapy called PYR (Pyrimethamine) for the treatment of late-onset Tay-Sachs Disease and Sandhoff Disease. Further studies are needed to evaluate the benefits and safety.
    2. A Biomarker for Disease Progression in GM2 and Other Neurolipidoses
      Florian Eichler

      This research studied the use of Magnetic Resonance Imaging (MRI) techniques to examine cerebral blood flow changes, providing more data to detect diseases at an early stage.
    3. Novel Therapy for Tay-Sachs Disease, Sialidosis and Ggalactosialidosis
      Using Metabolic Bypass Catalyzed by the Lysosomal Sialidase Neu4
      Alexey Pshezhetsky

      This research provided an explanation as to why the Tay-Sachs disease is severe in humans, but not in mice up to one year of age. The results contribute to further study of the treatments for Tay-Sach disease.
    4. Combination Therapy for Krabbe Disease
      Mark Sands

      This study combined Bone Marrow Transplantation (BMT) with gene therapy for the treatment of Globoid-cell leukodystrophy (GLD, Krabbe disease), proposing this viabile and less invasive way to treat the disease.
    Read More
  • 2002 - 2008 Research Initiative Grants +

    On this page:

    Resulting Publications

    2008
    2003
    2002

    Research Initiative Grants
    2008
    2007
    2004-2005
    2003
    2002

    2008 Research Initiative Grants

    Angela Gritti, PhD and Alessandra Biffi, PhD
    San Raffaele Telethon Institute for Gene Therapy
    “Evaluation of Combined Approaches Using Hematopoietic and Neural Stem Cells for the Treatment of Globoid Cell Leukodystrophy”

    Stephanos Kyrkanides, PhD
    Stony Brook University
    “Retrograde transfer of therapeutic vectors enabled by the trigeminal sensory system”

    2008 Research Grants - Resulting Publications

    Gentner, S, et al., Therapy of Globoid Cell Leukodystrophy Sci Transl Med 2, 58ra84 (2010)

    Kyrkanides, S, et al., The trigeminal retrograde transfer pathway in the treatment of Neurodegeneration, Journal of Neuroimmunology, 209 (2009) 139–142 pdf Journal of Neuroimmunology Pathway Treatment Neuro Kyrkanides 2009 (1.08 MB) (.pdf)

    2007 Research Initiative Grants

    Susan L. Cotman, PhD
    Massachusetts General Hospital
    “Small molecule screening to identify modifiers of lysosomal trafficking, a putative therapy for Batten”

    Doug Martin, PhD
    Auburn University
    “Pre-clinical gene therapy for GM2 in a feline model”

    Miguel Esteves, PhD
    Massachusetts General Hospital
    “AAV-mediated gene therapy for Tay-Sachs: Vector selection for pre-clinical development”

    Aryan Namoodiri, PhD
    Uniformed Services University of the Heath Sciences
    * “Preclinical Research toward Acetate Supplementation Therapy for Canavan Disease”

    This grant was made possible by through the generous

    Read More
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