Friday, MARCH 13, 2015

NTSAD Monthly Research Review
Allison Bradbury, PhD and Staci Kallish, DO, Co-editors

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. 
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 ?-galactosidase and a 2.5-fold increase of ?-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 hereTo date, NTSAD has funded over $500,000 to support animal studies at Auburn University.


    Published "Molecular Genetics and Metabolism" 

    Drs. Chet Whitley, a geneticist, and Jeanine Utz, a doctor of pharmacy, 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.


    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 
    Sue Kahn, Executive Director at
    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


    Don't forget to select Team NTSAD on the drop down menu! 


    Email Allison Bradbury with registration confirmation or questions at 


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