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. 

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."

WORKSHOPS

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.

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.