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

2017 Research Initiative Grants

We are proud to announce the 2017 Research Initiative grant awards. Through an intensive review process, six were invited to submit full applications.  After evaluations by Scientific Advisory Committee (SAC) members, a grant recommendation from a subset of the SAC group was made to NTSAD's Executive Committee for approval. As a result, three (3) grants have been awarded to the following researchers. 


Alessandra Biffi, MD
Director, Gene Therapy Program
Dana-Farber/Boston Children’s Hospital Cancer and Blood Disorders Center
Boston, MA

 

Proof of concept study of
HSC gene therapy for Tay-Sachs disease

Goals of the Proposal

  • To assess the feasibility and efficacy of an innovative gene therapy based on hematopoietic stem cells (HSCs) and lentiviral vectors (LVs) in the mouse model of Sandhoff disease (SD)
  • To conduct a proof-of-concept study that could be translated into a larger scale study and future clinical development

Impact of the Research

The project will test a novel gene therapy approach for TSD and SD with the potential for clinical translation. This gene therapy works by establishing a stable population of brain cells, which will serve as a sustained and balanced supply of the deficient enzymes in the patients.

Dr. Biffi and her research team accumulated extensive experience in preclinical development and clinical translation of gene therapies for lysosomal storage disorders (LSDs) and TSD. The proposed study has a high likelihood of achieving transformative outcomes in TSD/SD due to the investigators’ expertise and the well-developed research plan.


Heather Gray-Edwards, PhD
Scott-Ritchey Research Center
Auburn University, Auburn, AL

 

Minimally invasive delivery of
AAV gene therapy in the Tay-Sachs Sheep

Goals of the Proposal

  • To evaluate efficacy of adeno associated viral (AAV) gene therapy after cerebrospinal fluid (CSF) delivery in the sheep model of Tay-Sachs disease (TSD)
  • To confirm previously proposed biomarkers of TSD, including MRI image, lipidomic signatures, cognitive testing, and neurologic evaluation
  • To study the biodistribution and clearance of CSF delivered AAV gene therapy in the Tay-Sachs sheep

Impact of Research

Gene therapy, is one of the most promising treatment options in development. 

The study will evaluate the efficacy and biodistribution of the state-of-the-art gene therapy in TSD sheep. Tay-Sachs sheep is one of the most relevant animal models of the disease, due to its large brain size and suitability for various biomarker studies.

The findings in this proposal will aid in expanding our knowledge on the treatment’s administration and biodistribution. The efficacy profile from the work with be necessary and helpful for future regulatory application before FDA. Most importantly, this study will generate useful data and insight about TSD biomarkers and contribute to future clinical studies in human patients.


Tim Wood, PhD, Greenwood Genetic Center. Greenwood, South Carolina and 
Stephane Demotz, PhD, Dorphan, Lausanne, Switzerland

 

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


Goals of the Proposal

  • To develop a quantitative, sensitive, and robust mass spectrometry based analytical method for the determination of a potential biomarker for GM1-gangliosidosis
  • To explore treatment conditions of a drug candidate for GM1 in GM1-gangliosidosis patient cells using the analytical method developed in the first part of the project

Impact of the Research

GM1-gangliosidosis and mucopolysaccharidosis IVB (MPS IVB) are two diseases caused by beta-galactosidase deficiency. A biomarker that indicates the severity and progression of the disease and a convenient analytic method to determine the biomarker will significantly enhance the clinical trial design in the therapeutic development.

A preliminary study found a potential biomarker for both GM1 and MPS IVB. The level of the biomarker, a sugar molecule, was elevated by 10 to 100 fold in the urine samples of GM1 and MPS IVB patients than samples of normal donors. This compound has the potential to be utilized as a biomarker for future clinical trials.

The findings from the proposed work will develop a quantitative method to analyze the sugar molecule, validate its role as biomarker for the diseases. In addition, researchers will explore the optimal treatment conditions of an investigational pharmacological chaperone drug candidate for GM1-gangliosidosis.


 

All about Lysosomal Storage Disorders

Overview

Individual lysosomal storage disorders are classified as rare genetic disorders. However, when taken as a group, they are far more common.

The prevalence rate is estimated to be 1 per 7,700 births in some countries (Meikle, PJ et al, Prevalence of Lysosomal Storage Disorders, JAMA 1999; 281:249-254)

 

Frequently Asked Questions

Which NTSAD diseases are lysosomal storage disorders?

Tay Sachs, Sandhoff, GM1, Fabry, Gaucher, Niemann-Pick, Pompe are lysosomal storage disorders. Tay Sachs and Sandhoff are both categorized as GM-2 gangliosidoses. This is because they are both caused by the build up of GM-2 gangliosides, as described below.

 

*Pompe is also a glycogen storage disorder.

What is a lysosome and what is a lysosomal storage disorder?

Lysosomes are the cell’s recycling center. They contain digestive enzymes; responsible for breaking down debris in the cell into reusable parts.

 

 

The Cell. Image from: https://awbionotes.wordpress.com/tag/animal-cell/ 

 

lysosomal storage disorder occurs when one of these enzymes is not functioning correctly. When the enzyme does not function correctly, there is a build up of undigested debris (substrate) in the lysosome. This substrate is usually a fatty substance called a sphingolipid. This build up eventually leads to cell degeneration. This then results in the accumulation of substrate in various tissues and organs of the body, causing these organs to function less efficiently, resulting in progressive deterioration in physical and/or mental state, and eventually death.

 

A visual representation:

a) In most individuals the substrate (water) can be degraded efficiently by adequate enzyme volume (hole in sink).

b) In affected individuals the amount of enzyme is insufficient to efficiently degrade the substrate and it accumulates. It is this accumulation that causes the disease.

 

 

Why does the enzyme not function correctly?

The enzyme is made incorrectly if both copies of the gene that codes for the enzyme contain a spelling error, which is called a mutation. Mutations in the gene can change the way the enzyme is made, and it therefore is unable to do its job. Sometimes the mutations in the gene cause the enzyme to not be made at all. When the enzyme cannot do its job, the substrate builds up.

Which enzyme is deficient in each lysosomal storage disorder?

Disease Name

Enzyme affected

Gene containing mutation

Substrate that accumulates

Tay Sachs

Beta- hexosaminidase A

HEXA

GM2 Ganglioside

Sandhoff

Beta-Hexosaminidase A & Beta-Hexosaminidase B

HEXB

GM2 Ganglioside

GM-1

Beta-galactosidase

GLB1

GM1 Ganglioside

Fabry

Alpha-galactosidase A

GLA

Globotriaoslyceramide

Gaucher

Beta-glucocerebrosidase

GBA

Glucocerebroside

Niemann-Pick Types A & B

Acid-sphingomyelinase

SMPD1

Spingomyelin

Niemann-Pick Type C*

 

NPC1 or NPC2

 

Pompe**

Acid alpha-glucosidase (acid maltase)

GAA

Glycogen

 

*Mutations in the NPC1 or NPC2 genes cause a problem with the transport of lipids (fatty substances) in the cell. These lipids then build up in the cells, which causes cell dysfunction. There is further cell dysfunction because the lipids are not taken to the location where they are needed in the cell.

**Pompe is also a glycogen storage disorder.

Why are some lysosomal storage disorders more severe than others?

The severity of a Lysosomal storage disorder depends on the amount of enzyme activity that is present, and where in the body the substrate (debris) is accumulating. If some enzyme activity is present, symptoms usually begin later on (as in juvenile or adult onset version of the diseases.) The most severe disorders are where the debris builds up in the central nervous system, such as in Tay Sachs, Sandhoff and GM-1.

 

FreeStyle FAQ Testing

Carrier Screening FAQ

General Topics

My partner isn’t Ashkenazi Jewish. Should we still have carrier screening?

Yes! Anybody could be a carrier. Even if your partner is not Jewish it is still possible that you are both carriers for the same recessive condition. Discuss screening options with your doctor or genetics professional (geneticist or genetic counselor) to determine the best screening method for you and your partner.

I’ve heard carrier screening can be done at home. Is that true?

It’s important for you to speak with a genetics professional prior to having carrier screening. Through some programs, a saliva sample can be collected at home and sent to a laboratory for analysis. Saliva testing does not include Tay-Sachs enzyme analysis, but may provide sequencing of multiple genes.

For more information, visit the Screening Centers page.

If I already have a healthy child, do I still need to have carrier screening?

Yes. If you and your partner are carriers for the same recessive disease, there is a 25% chance with each pregnancy that your child will be affected with the disease as well as a 75% chance of having an unaffected child. Two carrier parents could have several healthy children before having an affected child.

Where can I get carrier screening?

It is best to talk with your doctor or make an appointment with your genetics professional to discuss your interest in carrier screening. Each of these medical professionals can explain the screening, submit an order, and interpret the results for you.

For locations, visit the Screening Centers page.

Why are natural history studies and the Patient Insights Networks (PIN) important to clinical trials?

Natural history studies document the progression of the disease. The more data there is about the progression of the disease from medical data and patient experience, the clearer the endpoints are to determine whether a therapy is working or not. The PIN is a format to help families contribute this information. Therefore, participating in the PIN and natural history studies is important and critical.

Join the GM2 Tay-Sachs & Sandhoff PIN here or the GM1 PIN here as soon as you can!

Why do patients have to meet certain criteria to be accepted into the trial?

Inclusion criteria are necessary for a successful clinical trial. Inclusion criteria also help minimize risk in a clinical trial and ensure the proposed therapy is safe and effective. Having a successful trial in which risks are minimized and success of the therapy can be shown is important to allow therapies to continue in future trials and to lead to eventual approval.

Tay-Sachs Disease

I’m concerned that I may be a carrier for Tay-Sachs disease. What type of carrier screening will offer the most accurate results?

A combination of DNA and enzyme testing is strongly recommended for Tay-Sachs screening for the highest level of detection. Most labs only offer DNA testing for Tay-Sachs. Be sure to request a laboratory that performs both DNA and enzyme testing.

It is also important that your genetic screening is tailored to you and your family history. For example, individuals of Ashkenazi Jewish ancestry are known to have different mutations than individuals from the French Canadian population. It’s important to make sure that you do carrier screening specific to your ancestry.

Some labs offer expanded panels with many conditions aimed at couples with mixed or unknown ancestry. Discuss your interest in carrier screening with your genetics professional and determine which testing is best suited for you.

For more information, visit the Types of Screening page.

Only one of my grandparents is Jewish. Do I still need carrier screening for Tay-Sachs disease?

Yes, it’s important to remember that anyone could be a carrier for Tay-Sachs disease. You are at risk of being a carrier of a Jewish mutation based on your Jewish ancestry. Individuals of Irish, Cajun, French Canadian, and Pennsylvania Dutch descent are also at increased risk of having a Tay-Sachs disease mutation. It may be a good idea for you to have an expanded panel that includes screening for other recessive conditions. Discuss your options with your genetics professional prior to testing.

I’m pregnant and I just found out that I have a family history of Tay-Sachs disease. Can I get carrier screening while I’m pregnant?

Yes, you can get carrier screening for Tay-Sachs disease while pregnant. When women are pregnant or taking birth control pills, detection is best using leukocytes. Make sure that the genetics professional ordering your carrier screening knows that you are pregnant so that the correct testing is ordered. The father of the pregnancy can also pursue carrier screening to determine if he is a carrier. If the father is not found to be a carrier, your baby is at very low risk for Tay-Sachs disease. If he is carrier, you can consider doing an amniocentesis or CVS. These are diagnostic tests that will be able to tell you if your current pregnancy is affected with Tay-Sachs disease or is unaffected. Speak with your obstetrician or genetics professional about this testing.

For more information, visit Family Planning.

I have a “pseudodeficiency allele”. What does this mean?

A “pseudodeficiency allele” reduces enzyme activity but does not cause a disease. A pseudodeficiency allele does not cause Tay-Sachs disease in a carrier or in the children who inherit the pseudodeficiency allele. Even if a person has one Tay-Sachs mutation and one pseudodeficiency allele, they will not develop Tay-Sachs disease. Approximately 30% of non-Ashkenazi Jewish and 3% of Ashkenazi Jewish individuals who are identified as carriers by enzyme analysis have a benign pseudodeficiency allele.

My enzyme carrier screening for Tay-Sachs disease came back as inconclusive. My provider wants me to have genetic testing for Tay-Sachs disease. Is it possible that I’m not a carrier?

Yes. Tay-Sachs disease enzyme analysis is very sensitive but can be affected by pregnancy status, medications, and transport temperature. DNA mutation analysis may help clarify whether an individual is truly a carrier for Tay-Sachs disease. Typically DNA and enzyme testing are performed at the same time to allow for optimal interpretation of results.

A genetics professional can help you to understand what this result means for you and your family. Visit Genetic Counseling to get in contact with a provider near you.

 

Genetic Testing Terminology

What does “gene sequencing” mean?

If you think of a gene as a page in a book, “gene sequencing” refers to reading across each letter of that page to see if there are any “spelling mistakes” in the genetic code. Gene sequencing would detect if “cat” in the book is misspelled as “ctt”. Some coding changes are normal and make us unique individuals. Other coding differences can result in disease.

My doctor told me that I have a “variant of uncertain significance.” What does that mean?

A “variant of uncertain significance” or VUS is a coding change in your genes that has not been seen in enough people to thoroughly understand. We all have genetic variants that make us unique individuals. Some “variants” in your genes are normal and do not affect your health. It is also possible that a variant will eventually explain a disease in your family or increases your chance of having a child with a genetic disease.

Researchers are working to classify these variants and clarify what they mean for your family’s health. Most often a variant of uncertain significance is eventually determined to be “benign” or normal. It is a good idea to check-in with your genetics professional every few years to see if there are updates on your specific variant.

Known Carrier of Tay-Sachs Disease

If I am a carrier for Tay-Sachs disease or an allied disease, does that mean that I will get the disease?

No. Carriers do not express the symptoms of the disease. You need two mutated copies of a particular gene, one inherited from each parent, to develop an autosomal recessive disease.

For more information about autosomal recessive inheritance, visit the About Inheritance page.

I am a carrier for Tay-Sachs disease. Can I test my kids to see if they are also carriers?

Carrier screening is not recommended for children under the age of 18, as it is not helpful in the medical care of healthy children. Once your children are 18 or older they can decide if they would like to pursue carrier screening, prior to considering reproductive options.

My partner and I are both carriers for Tay-Sachs. We do not feel that we could handle the emotional burden of having a baby with Tay-Sachs disease. Is there anything we can do to ensure that we will have a healthy baby?

There are many reproductive options available to increase your chance of a having a healthy baby, specifically a baby that does not have Tay-Sachs disease. Some people choose adoption, others use sperm, egg, or embryo donation from non-carriers, some pursue a natural pregnancy with prenatal testing by amniocentesis or CVS, while others consider in vitro fertilization with pre-implantation genetic diagnosis (PGD).

For more information, visit the Family Planning page.

I am a carrier for Tay-Sachs disease and my husband is not. Is it possible for our children to be affected with Tay-Sachs disease?

Both parents need to be carriers for a child to be affected with an autosomal recessive disease like Tay-Sachs. However, there is a 50% chance with each pregnancy that your child will be a carrier (like you) and a 50% chance that your child will inherit two normal copies of the Tay-Sachs gene.

For a graphic explanation, please visit the About Inheritance page.

I am 12 weeks pregnant and I just found out that I’m a carrier for Tay-Sachs disease. What do I do?

Finding out that you are a carrier while pregnant can be anxiety-provoking. Fortunately, you have several options that will help you better understand the risk to your baby.

The father of the pregnancy can pursue carrier screening to determine if he is also a carrier. If the father is not found to be a carrier, your baby is at very low risk for Tay-Sachs disease. If he is carrier, you can consider doing an amniocentesis or CVS. These are diagnostic tests that will be able to tell you if your current pregnancy is affected with Tay-Sachs disease or is unaffected.Speak with your obstetrician or genetics professional about this testing.

For more information, visit the Family Planning page and the About Inheritance page.

More Answers

My relative had a baby with Tay-Sachs. Should I be concerned?

If your relative had a baby with Tay-Sachs disease, he or she is a carrier. If this is a blood relative, you may be at increased risk to be a carrier. It’s a good idea to discuss this family history information with your doctor or genetics professional. Remember, you are only at risk of having a child with Tay-Sachs disease if both you and your partner are carriers.

I’m French Canadian. My biochemical testing came back inconclusive and my sequencing came back normal. What should I do?

Carriers of French Canadian descent are more likely to have a mutation called a deletion; this means that a region of the HEXA gene is missing. If you think of the HEXA gene as a page in a book, screening by sequencing is only looking for single letter typos, but can fail to detect missing paragraphs. If you are French Canadian, ask your doctor or genetics professional to order genetic testing that will be able to find a large deletion, if present.

If I have late onset Tay-Sachs disease (LOTS), could I have a child with infantile or early onset Tay-Sachs disease?

All individuals with Tay-Sachs disease have a mutation in both copies of their HEXA genes. Some individuals with late onset Tay-Sachs disease have one late onset mutation and one infantile onset mutation. Others have two late onset mutations. If you have one infantile onset mutation and your partner does too, there is a 25% chance with each pregnancy that your child will have infantile or juvenile Tay-Sachs. If you have two late onset mutations and your partner is a carrier for late onset Tay-Sachs disease, your children are at risk for LOTS, but not early onset disease.

See the About Inheritance page for more information about autosomal recessive inheritance.

 

Lacie's Legacy

Join us for a fun filled day of a 1-mile walk, silent auctions, raffles, lunch and door prizes. All proceeds will be donated to National Tay-Sachs & Allied Diseases Association, Inc. (NTSAD) in memory of our daughter Lacie who passed away in 2005 of Tay Sachs Disease.

Carroll Valley Park
5685 Fairfield Road
Carrolll Valley, PA

Registration begins at 10:00 a.m. Rain or Shine!

$10.00 for each participant. 

Donate Today

 

Helping Hand Grant Fund FAQs

Helping Hand Grants FAQ

We have received a grant in the past, can we apply again?
Yes, but award priority is given to families who received their diagnosis or have a loved one who had passed since the last in person Annual Family Conference in 2019. 

Our family needs a grant for all our expenses, including travel, is that possible?
Unfortunately, in most cases NTSAD is not able to cover travel expenses. If you have extenuating circumstances that you would like the grant committee to take into consideration, please list them in the final question of the form.

We live outside the US; are we eligible for a Helping Hand Grant?
Yes! But again, we are not able to cover travel expenses so you would need to be able to make your way to the US, and we can help from there.  

Do I need to pay for my affected child?
No. We never charge for affected children.  All other family attendee’s fees are as follows:  
Ages 0-4             FREE!
Ages 5-12           $100
Ages 13 and up   $200

Are there limits to how much I can ask for?
While we ask all families to make every effort possible to seek out conference funding before applying for a Helping Hand Grant, we must also limit the amount we grant to each family to ensure we can help as many families as possible. Therefore, we ask you to please only request funds that are absolutely necessary for attendance.

What is the application funding limits?
While there are no limits, per se, there are general guidelines the Family Services Committee uses when determining how much to award:

Newly diagnosed families and individuals attending for their first time, and newly bereaved families attending for their first time will be given priority status for grant considerations up to the amounts as follows:
$1500 Family/$1000 Individual for registration and hotel.

How/when will I know if I was awarded a grant?
We will notify you of your grant award status after the grant approval process is complete. Grants will be awarded on a rolling basis as they are received and we will aim to notify awardees within two weeks of the date of submission of their application. All grantees will be notified no later than Monday, June 15, 2022.

What do I need to do if I am approved?
You will receive an award letter and contract of attendance to accept, sign and return to NTSAD no later than June 16, 2022.  At that time, any additional fees owed for registration will be due to NTSAD. You must make your own hotel reservation, for standard rooms only within the NTSAD room block with your own credit card (to leave on file with the hotel for incidentals). The hotel will then notify NTSAD of your reservation. You will not be charged for the approved hotel room nights, but you are responsible for any additional charges made to your room.

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