November 12, 2001

Society for Neuroscience Convention
San Diego, California

Participants

NCLRA Members: Liz Aurelio,
Andrew Henery,
Phil Milto,
Ricky Bennett (not able to attend),
Russelle Rankin (not able to attend),
Caroline Wright (not able to attend)

Attendees:
Johan Holmberg - Karolinska Institute, Stockholm, Sweden
Mark Kirk - University of Missouri
Elizabeth Kriscenski - University of Rochester
Karen Mellodew - Kings College
Dinos Meletis - Karolinska Institute, Stockholm, Sweden
Jason Meyer - University of Missouri
David Pearce - University of Rochester
Evan Snyder - Harvard
Greg Stewart - Genzyme
Charles Stiles - Dana - Farber Cancer Institute Harvard
Clive Svendsen - University of Madison-Wisconsin
Stan Tamaki - StemCells Inc.
Nabuko Uchida - StemCells Inc.
Dafe Uwanogho - Kings College
Su-Chun Zhang - University of Madison-Wisconsin

NIH: Giovanna Spinella - NCL Project Coordinator (not able to attend)

Interested invitees not able to attend:
David Archer - Emory University
Fred Gage - The Salk Institute, La Jolla, CA, USA
Stephen Goldman - Cornell University
Harley Koanblum - UCLA
Georg Kuhn, University of Regensburg, Regensburg, Germany
Jeffrey Macklis - Harvard Medical School
Freda Miller - Montreal Neurological Institute
William Mobley - Stanford University
Mahendra Rao - Section Chief - StemCell, LNS, GRC National Institute of Aging
Rosalind Segal - Dana-Farber Cancer Institute, Harvard
Yi Sun - UCLA
Henriette van Praag - The Salk Institute, La Jolla, CA, USA
Irving Weissman - Stanford University

About This Document

The information that is contained in this document is to be used for reference only and should not be construed as absolute information. The information has been compiled from various sources and represents opinions of those who attended. All information should be used in a constructive nature.

The aim of this document is to summarize the discussions of the information presented during the “NCL Stem Cell Initiative” event. Discrepancies and inaccuracies may exist and it is advised to contact conference attendees to obtain detailed information regarding the subject matter. A conference contact list is attached to assist in gaining additional clarity on specific information.

Event Objectives

The objectives of the event were:

· To introduce the NCLRA and NCLs to scientists key in their field of stem cell research.
· To present to leaders in stem cell research a high level NCL overview in hope to gain interest in these diseases of children and foster some direction and collaborations for the future
· To generate interest in cell mediated approaches to treat NCL disorders through open collaboration with researchers in the field.
· To stimulate thought of potential cell mediated strategies to develop treatment for the NCLs

The NCLRA

The Neuronal Ceroid Lipofuscinoses Research Alliance (NCLRA) is a united group of foundations whose purpose is to aid in the coordination of bringing potential therapies to clinical trials for the three major forms of NCL (INCL, LINCL, JNCL). Through this united effort the alliance can provide the following:

Established network of relevant research information and collaborations with NCL scientists for knowledge transfer
Facilitate the obtainment of necessary NCL tools (data, model access, cDNA, enzymatic assays, cell lines, antibodies, and other reagents…)
Advocate voice to regulatory bodies and agencies
Patient population representation
Strong relationships politically and with governmental agencies (NIH and FDA)
Well funded foundations ready to support therapy development projects
Clinical program experience: pre-clinical study design, protocol development, tox. study design, regulatory requirements, detailed feasibility study, work plans…

NCLRA Achievements

The NCLRA is a proven result driven alliance with many achievements and accomplishments:

Identified, developed, initiated and is funding a multi-million-dollar gene transfer therapy program with the Weill Medical College of Cornell University.
The NCLRA has developed a network of relevant research information and has fostered collaboration between academic groups and private sector biotech companies.
Developed and implemented a not-for-profit therapy development model designed to leverage platform technologies to advance the therapy development process for rare diseases.
The NCLRA has initiated and is sponsoring a small molecule drug-screening program.
Developed a multi-faceted approach to propel therapy development utilizing science, business, awareness, fundraising, politics, and the regulatory bodies of the NIH and FDA to advance therapy development.
Developed business plan to illustrate the large impact of therapy development for NCL target disorders by leveraging learned technologies to other related disorders.
Organized and have held multiple NCL therapy focused workshops with research professionals, private industry biotech organizations, regulatory agencies of the FDA and NIH, clinicians and neurosurgeons driving therapy development for the NCLs.
NCLRA members are nationally recognized by the NIH as NCL authorities.
NCLRA members are regularly invited to NIH sponsored workshops for rare disease therapy development.
Achieved national notoriety of efforts from being featured on CBS national news program 48 Hours.

As you can see from the above, the NCLRA has not only pioneered new methodologies in creating unity amongst the scientific community and private foundations, but have taken the basic research and made it reality.

NCL Scientific Overview
The main goal of this event was to introduce the NCLs and the NCLRA to leaders in stem cell research. The purpose of this introduction was to generate interest from these leading scientists, foster collaborations, and identify cell-mediated approaches for future clinical applications. Dr. David Pearce, University of Rochester, presented a scientific NCL overview. The overview highlighted the following facts about the NCLs:

The NCLs are Lysosomal Storage Disorders with known genetic defects.

LSDs have a relatively high prevalence as a group.

NCLs are attractive targets for therapy:
Known defects
Lack of impact of environmental and outside genetic factors on phenotype
Potential cross correction
Regulation not essential
Much is known about the defective proteins
Biochemical markers/intermediate endpoints

NCLs are autosomal recessive, neurodegenerative disorders and are characterized by accumulation of fluorescent pigment in the lysosome.

NCL incidence of 1:12,500 - High incidence level.

Infantile (CLN1), Late Infantile (CLN2), and Juvenile (CLN3) represent the majority of these disease cases.
Infantile (CLN1) - first signs manifest at 6 months. Progresses rapidly. Failure to thrive.
Microencephaly, myoclonic jerks, delayed psychomotor development, seizures.
Late Infantile (CLN2) - first signs manifest at 2-4 years. Progresses rapidly.
Vision loss, ataxia, seizures, and mental deterioration.
Juvenile (CLN3) - first signs manifest at 5-7 years.
Vision loss, ataxia, seizures, and mental deterioration.

CLN1 and CLN2 are enzyme deficient disorders (PPT and TPP enzymes, respectively) with low therapeutic threshold of 10% CNS enzymatic expression.

Reagents available for the NCLs
CLN1 and CLN3 have available mouse models
Cell lines, antibodies, cDNAs, enzymatic assays, histochemical stains…

NCL scientists available and willing to collaborate on therapeutic approaches.

Everyone in attendance became well informed about the NCLs and each participant asked meaningful and insightful questions. The overall impression from the attending scientists was the tremendous promise for cell-mediated therapies to treat NCL disorders. The event illustrated the validity of cell-mediated therapies for NCL.

NCL and Stem Cell Advantages

Good model disorder to pilot therapy technologies.
Risk/benefit ratio is in favor of therapy.
Orphan disease status.
Currently, no other approved therapies.
Well-funded foundation to readily support therapy development projects.
A subset of the NCLs (INCL/LINCL) are perfect targets for cell mediated therapies because it can benefit from both introduction of cells to produce enzyme and for CNS regeneration.

Notable Event Accomplishments:

Introduced the NCLs and the NCLRA to leading stem cell research organizations.
Generated interest among stem cell researchers to evaluate cell mediated approaches to treat the NCLs.
Established relationships between different stem cell researchers and the NCLRA.
Confirmed cell mediated therapies have tremendous potential for therapeutic benefit for the NCLs and the NCLs are a good disease target for such treatments.
Identified stem cell research groups with interest in working on the NCLs in the near future and received proposals to investigate cell-mediated strategies for the NCLs.

Next steps

The NCLRA is contacting interested stem cell research groups to gain insight into a few basic questions regarding cell-mediated therapies for neurodegenerative disorders. The NCLRA is interested in identifying approaches to move stem cell research toward clinical applications. The answers to these questions will aid in evaluating the most promising NCL strategies. The NCLRA’s objective is to identify and develop these strategies into projects that lead to the clinic. Establishing, defining, developing, and funding these projects will be the focus of the NCLRA’s efforts toward stem cell therapies.

1. Is there potential immunogenicity of the stem cells and maybe the elicitation of an antibody response that may or may not eliminate the implanted stem cells and perhaps even cause harm to the brain? How would you recommend handling any immune response issues?

2. What would be the source of any proposed cells that you would use and why (ES, Spinal Fluid, bone marrow, umbilical cord, olfactory bulb, blood, post mortem neuronal...)?

3. Whether a normalizing (correcting) factor (enzyme or other type of protein) will be secreted from the implanted stem cells and be picked up by non-corrected cells and induce normal function them. What would be your objective of the stem cells (regeneration of neurons or produce missing enzyme or both)?

4. What are the potential scientific and practical barriers that need to be overcome for success? Success being defined as taking basic science to clinic.

5. What would be the "best" theoretical approach to develop cell mediated therapies for the NCLs? How would you propose to proceed in mounting a clinical program?

For example:
To treat CLN2 you would take adult neuronal stem cells and inject into the parenchyma in 4 different locations while immunosuppressing with immunosuppressant drugs. The stem cells should differentiate into neurons and produce the missing enzyme while regenerating neuronal cells. Pre clinical data to support IND would require several rounds of adult neuronal stem cells injected into CLN1, CLN2 (when available) and normal mice. Track enzyme distribution, cell growth, and characterize function gain to support the IND.

6. What will it take for you to become an interested partner in the NCL's as a therapeutic investigator? And how would you proceed or what steps would you take to develop a clinical program?

The NCLRA is interested in funding research that positions the NCLs to move toward the clinic in the future. It is understood that more basic research needs to be performed and a few factors need to be evaluated before a clinical program is mounted. The NCLRA would like to start developing the science that will enable cell-mediated therapies for the NCLs to move toward the clinic (fund projects that lead to the clinic). The alliance is interested in any proposal that researchers might have to develop or support a clinical program.