Friday, MAY 1, 2015

NTSAD Monthly Research Review
Allison Bradbury, PhD, Diane Golebiowski 
and Staci Kallish, DO, co-editors

The symposium and workshops gave researchers and clinicians an opportunity to consider ways in which we can partner to make progress together.  The presentations and workshops helped to identify critical issues in our current path and fostered collaboration among scientists, clinicians, as well as patients and their families.  The next steps envisioned may include turning to patients and their families to help collect information, which will then be used to help measure and improve patient outcomes and quality of life measurements for future clinical trials. Highlights of the topics discussed were as follows:

Common Elements of the Pathogenesis of Neurodegenerative diseases

Fran Platt, PhD, University of Oxford

  • Looking at common pathways in neurodegenerative disorders such as inflammation can identify a common target for the treatment of multiple diseases.
  • These pathways will potentially allow us to utilize existing drugs to treat current patients and improve their quality of life.
  • For example, deregulation of inflammasome activation has been shown to occur in mouse models of lysosomal diseases; therefore, existing and new small molecules that inhibit inflammasome activation could be therapeutic. 
Clinical trial design and outcome measures for diseases affecting the CNS: FDA perspective

Yao-Yao Zhu, MD, PhD Division of Clinical Evaluation and Pharm/Tox (DCEPT), Office of Cellular, Tissue, and Gene Therapy (OCTGT), Center for Biologics Evaluation and Research (CBER), FDA

  • Approximately 200 investigational new drug applications (INDs) are submitted to OCTGT per year and have been growing since initiated in 2003. Gene therapy studies are held  to a higher standard because the therapy can exhibit delayed effect; the delivery is an invasive procedure; it can elicit an immune response; and it can result in unwanted adverse reactions such as tumor formation.
  • Phase I trial design should have preclinical safety and bioavailability data, include dose escalation, avoid multiple dosing, and include data and safety monitoring.
  • Stressed importance of natural history studies to identify biomarkers and measurable quality of life outcomes.

Specific issues relating to the gangliosidoses

Alessandra d'Azzo, PhD, St. Jude Children's Research Hospital

  • Described detailed mechanism studies into GM1 and beta-galactosidase cellular location, functions, and associated molecules. 
  • Discussed preliminary data on a new enzyme replacement therapy using a beta-galactosidase-lectin fusion protein and potential delivery routes including intravenous, intranasal, or intracranial injection (also discussed with Drs. David Radin and Carole Cramer at the Research Update at conference).

Specific issues in the leukodystrophies

Adeline L. Vanderver, MD, Children's National Medical Center

  • Described the Global Leukodystrophy Initiative (GLIA): Their goal is to define & classify leukodystrophies & leukoencephalopathies to assist with patient referral and support data collection for clinical trials.
  • Described method of improved diagnostics of white matter diseases by use of an algorithm that uses pattern recognition to detect differences in MRI patterns and associate MRI alterations with clinical presentation of patient. If a patient cannot be diagnosed by this method then whole exome sequencing is conducted.
  • "Leukodystrophies are incurable, but are treatable."



Small Molecule Approaches

Gustavo Maegawa, MD, PhD, Johns Hopkins University School of Medicine, and Steven U. Walkley, DVM, PhD, Albert Einstein College of Medicine

  • Discussion of small molecules currently in clinical trials including cyclodextrin and Vorinostat for treatment of Niemann-Pick type C disease.  
  • The lack of natural history and reliable endpoints have weakened clinical trial robustness to date. Need to develop superior outcome measures to inform future clinical trials.
  • There was agreement on the need for a biobank of samples to support development of biomarkers of disease progression and subsequently used to measure therapeutic efficacy.
  • Compounds currently in development may have a great propensity to cross the blood-brain barrier.

Gene therapy: current status and future

Miguel Sena-Esteves, PhD, University of Massachusetts School of Medicine, and Douglas McCarty, PhD, Nationwide Children's Hospital

  • Overview of the current status of intracranial delivery of AAV for lysosomal storage disorders as well as the second generation of gene therapy through IV delivery.
  • Discussion on benefit and success of lentiviral mediated ex-vivo hematopoietic stem cell treatment for these disorders.
  • Discussion on appropriate age and stage of disease to administer treatment as well as including immune suppression drugs with AAV administration.

Newborn   Screening   : What is the role of NBS in developing therapies for pediatric neuro-degenerative diseases?

Joan Keutzer, PhD, Genzyme, a Sanofi Company

Michael S. Watson, PhD, FACMG, American College of Medical Genetics

  • A virtual central repository for patient samples exists in participating states for researchers and clinicians to promote collaboration.
  • Important to develop inexpensive screening test for use in pilot studies.
  • Discussion on how long after treatment becomes available to add diseases to newborn screening, especially since early intervention may improve therapeutic success.

NTSAD's diseases: What are the outstanding issues in clinical trial readiness?

Florian Eichler, MD, Massachusetts General Hospital, Harvard Medical School, and Cynthia Tifft, MD, PhD, National Institutes of Health

  • Collaboration and sharing of resources will allow us to make progress together more quickly as well as avoid duplication of data.
  • Interfaces such as NeuroBANK™ act as a platform for clinical research and virtual biobank and allow others to easily search for information (such as age, gender, MRI, gait assessment) and acquired samples (including sample type, patient ID, and volume) without the need for a central repository.
  • Take a patient-centered approach for fast clinical trial readiness. Measurable quality of life outcomes may be more important than biomarkers.
  • Patient portals have been implemented in NeuroBANK™ for ALD patients and will be important because the FDA increasingly wants consensus among patients (i.e. what is clinically meaningful).  We should try to introduce new technology into data collection such as smart phones apps to monitor patient outcomes and collect natural history data.
  • Importance of natural history studies that may uncover different subtypes within a disease or stages of disease progression; accurately categorizing patients will be critical for assessing outcomes in clinical trials. 
  • Although some biomarkers, such as measuring specific lipids by mass spec in CSF, appear to trend appropriately, they do not always correlate with clinical improvement and thus must be evaluated carefully.
NTSAD's 2015 Annual Family Conference Research Session
Highlights from Roundtable Discussions
What's New in Carrier Screening

Mimi Blitzer, PhD, Shari Ungerleider, Jewish Genetic Disease Consortium, and Kevin Romer, Mathew Forbes Romer Foundation, NTSAD affiliate


Discussed quality control for TSD enzyme testing:

  • Screening has improved because 1) improved technology, 2) decreased costs, and 3) improved assessment of results.
  • Broad range carrier screening can allow detection of numerous disorders and whole geneome sequencing allows for more robust detection of carrier status since not just searching for the most common mutations
  • JScreen is an at-home carrier screening program based at Emory University. A saliva sample provides DNA to analyze patients for >40 diseases with the Jewish panel or > 80 diseases with the extended panel.  A certified laboratory analyzes the DNA and results are reviewed and reported to participants by a genetic counselor. The use of JScreen is not limited to people with Jewish ancestry. JScreen should eliminate the need for supplemental blood tests and costs are as low as $99 with insurance subsidies. More information can be found at:
  • Education of health professionals is also key to helping prevention of these rare inheritable diseases

NTSAD-funded project: "Lectin-assisted transnasal delivery of corrective enzyme for GM1 gangliosidosis"

David Radin, PhD, Carole Cramer, PhD, and Alessandra d'Azzo, PhD

  • Drs. Radin and Cramer have produced a beta-galactosidase (β-gal) fusion protein using a sugar-binding lectin called RTB (β-gal:RTB) with hopes that the lectin may help carry β-gal from the nose directly to the brain.
  • The fusion protein has been produced in plant leaves, proving speed, safety, and cost advantages.
  • The next step is to assess the short term biodistribution of β-gal:RTB fusion protein in the brains of GM1 mice after intranasal delivery.
  • Subsequently long term experiments will be conducted in which GM1 mice will receive β-gal:RTB via nasal delivery and the affect on reducing GM1 substrate and improving disease phenotype will be evaluated.
  • Lastly intranasal delivery of β-gal:RTB will be compared to more traditional intravenous administration of the same compound.
  • Read an executive summary of the six-month progress report here.


Gene Therapy: Tay-Sachs Gene Therapy Consortium (NTSAD-funded) and GM1 Gene Therapy Douglas Martin, PhD, Auburn University

  • After previous gene therapy vectors for GM2 proved toxic in non-human primate (NHP) studies, new vectors were developed in the lab of Miguel Sena-Esteves. Three new formulations were tested in a 90 day study. Of the three AAV vector formulations tested, two provide safe overexpression of enzyme in the NHP brain. More on these studies can be seen in a recent research review here.
  • Now the two vectors producing the most appropriate levels of enzyme are being tested in mice to determine if they are therapeutically beneficial.
  • Lastly, a new final toxicity study in primates has been designed and submitted to the FDA for approval.
  • Concurrently gene therapy studies are continuing at Auburn University in the lab of Doug Martin in GM1 cats, GM2 cats (Sandhoff disease), and Tay-Sachs sheep.
  • GM1 cats treated by direct brain injection of adeno-associated virus (AAV) gene therapy continue to do well and treated cats are now living beyond 5 years of age (untreated cats live to ~8 months of age).
  • Recently, LYSOGENE, a biotechnology company from Paris, France, entered into collaboration with the University of Massachusetts Medical School and Auburn University to develop preclinical data to support translation of AAV therapy towards a clinical trial. A press release of this collaboration can be found here.
  • In order to decrease surgical risks, intravenous delivery of AAV is now being assessed in the GM1 cat model and shows great promise.

The Importance of Natural History Studies, Registries, and Clinical Outcome Measures Florian Eichler, MD and Gerry Cox, MD, PhD

  • Further development of natural history data and outcome measures is imperative.
  • Patient registries, such as NeuroBank, and global unique identifiers of patients allows harmonization of information collected across centers and permits researchers to effectively query, mine, and use patient data for analysis.
  • A patient portal in registries provides a means for patients (or their parents) to prioritize research needs, indicate services that are lacking, or suggest measures that should be utilized in a clinical trial.
  • Potential outcome measures in LOTS patients include assessments such as completing a 9-hole pegboard, drawing of a spiral, and getting out of a chair and walking. Some LOTS patients at the conference contributed to natural history studies, and their participation is greatly appreciated.
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Anxious to get your bike on the road this spring after all the snow? Celebrate the melting and sign up (or make a gift) 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 

or Support Team NTSAD

with a gift in the 

Million Dollar Bike Ride at


Don't forget to select 


on the drop down menu! 


Email Allison Bradbury with registration confirmation or questions at 


Late Onset Focus Groups
Being a Part of Research - A Patient's Perspective at NTSAD's Conference
Chris, John, Phil, Anne and Sean

I thoroughly enjoyed the focus group session for LOTS. It was so nice to share my experience and symptoms, as well as learn about what others are dealing with. I shared some of what I thought only I was dealing with, only to find out that many of the others did too. I also found out a few things that they describe are actually happening to me, but I never really attributed them to LOTS. This session was extremely helpful in teaching me how to deal with this horrible disease. I gained many new friends at the conference and have been in touch with them already and it's only been a couple weeks since I've seen them. I can't wait for Orlando!

Thank you NTSAD! - John P.
Late Onset Focus Groups
What Happens Next? 
An Update by Gerry Cox, MD
Drs. Gerry Cox, Alaa Hamed, Florian Eichler, Swati Sathe, and Medical Science Liaison Julie Kissell were excited about the opportunity to work with the LOTS adults at the Conference.  They have started to analyze the neurological assessment data and focus group transcripts collected to see which measures might be most useful in a future clinical trial.  Once the data is analyzed, this group will reconnect to determine next steps.  They hope to develop remote assessments and online questionnaires in-between seeing people in person at the Family Conferences.
Canavan Natural History
Attention Canavan Families: 
We Need Your Help to Move Forward

Thanks to Team NTSAD, U Penn, and the Million Dollar Bike Ride a grant was made last year to Annette Bley, MD, University Hospital, Hamburg Eppendorf, Germany, for her proposal,  Quantitative description of the clinical course of Canavan disease.  The study will be done in cooperation with Florian Eichler, MD, and others.


Download the questionnaire and letter from Dr. Bley here


To read other articles, publications and progress reports related to Canavan research funded in part by NTSAD, click here.

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