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Scientific Effort

Nathan's Battle Foundation's focus is therapy development for LINCL.  NBF's goal is to pursue every and all therapeutic approaches as aggressively and effectively as possible.

The potential therapeutic options for Late Infantile Batten Disease and the NBF's current directions toward these therapies are: 

Gene Transfer, Small Molecule Pharmaceuticals, Cell mediated therapies, and Enzyme Replacement Therapy.  The following is NBF's progress in each area:

NBF's Research Value

·  Established collaborations with NCL  scientists for knowledge transfer
· Facilitate the obtainment of necessary
   CLN2 tools: data, model access,
   cDNA, enzymatic assays, cell lines,
   antibodies, stains, and other reagents
· Advocate voice to regulatory bodies
· Patient population representation
· Leverage clinical program experience:
   pre-clinical study design, protocol
   development, tox. study design,
   regulatory requirements, detailed
   feasibility study...
· Strong relationships politically and with
   governmental agencies (NIH and
   FDA)

The LINCL disease target advantage:

·  Good model disorder to pilot therapy technologies.
·  "Easy" rare disease to solve given that
    it is truly an enzyme deficient disorder.
·  Risk/benefit ratio is in favor of therapy.
·  Orphan disease status.
·  Well-funded foundation to readily
   support therapy development
   projects.
· LINCL can benefit from an increase
  enzyme levels and CNS regeneration.

 Gene Transfer Therapy - This therapy would introduce a functioning gene into the Central Nervous System (CNS) of a LINCL patient. This functioning gene would produce the necessary enzyme that is required by the CNS to remove the harmful storage material. In principle this would be a long-term cure for the disease.

Nathan’s Battle Foundation entered into a formal agreement with Cornell University’s Institute of Genetic Medicine to perform a feasibility study verifying gene therapy is a viable treatment option for this disease and then mount a gene transfer clinical study.  The feasibility study began in October 2000 and concluded that gene therapy is a promising and viable option to treat LINCL.  On March 15, 2001, the pre-clinical studies and drug development process began.  This project has produced more LINCL data than any other known research project.  Over 350 rodent studies, countless in-vitro studies, several new analytical methods, and 45 non human primate studies have been performed verifying this therapy.  The project has achieved numerous milestones all of which continue to support gene therapy as a treatment for LINCL.  Some highlights are:

· Successfully manufactured the drug in clinical grade form for human use.
· Consistently performed successful gene transfer in rodents.
· Demonstrated long term expression of TPP-1 rodents.
· Performed toxicology studies in rodents.
· Received favorable reviews from the FDA to move forward and defined criteria to move to humans.
· Performed primate distribution and dosage studies meeting the FDAs criteria to move to humans.
· Designed and developed NHP toxicology studies.
· Developed clinical protocols including evaluation methods.
· Performed primate toxicology studies
· Received regulatory approvals from all levels
· Begun human clinical trials.

We are treating children but we lack the total necessary FUNDING to cover the clinical trial expenses.  Our foundation entered into a pledge agreement with the University to raise the required funds to pay to treat the children.  We need help in identifying and approaching philanthropist and foundations that want to help save children's lives by contributing funding to our gene therapy clinical trial. The generosity of these types of individual donors can make the difference.


The feasibility study is published by scientific journal. The Journal of the American Medical Association (JAMA) CLICK TO REVIEW

The clinical trial protocol has also been published

Project Overview - This is a high level overview of our project. This can be given to potential funders.

 

Small Molecule Pharmaceuticals-  This therapy would introduce a drug compound into the body that could cross the blood brain barrier into the CNS of a patient to either enhance residual enzyme activity or remove the storage material that is harmful the the patient. This therapy is thought to be viable but more research needs to be performed on the CLN2 gene with high through put screening of drug compounds. Since the CLN2 gene has not been identified for very long, not a lot of research has been performed in this area. The Nathan's Battle Foundation would like to pursue high through put screening on Nathan and P.J.'s mutations to identify possible beneficial compounds.  The Nathan's Battle Foundation is investigating projects to perform high through put screening for CLN2.

In February 2002, NBF entered into an agreement with a biotech company in Massachusetts to greatly expand our drug screening program.  This is a major project to screen several compound libraries (libraries include the FDA-2000 and the GNC libraries).  NBF is the first and currently the only organization performing drug screening for CLN2. This screening will use CLN2 cell-lines to screen drugs against.  This project identified some potential compounds that had affects on the enzyme level.  Validation studies are currently being performed.  If positive these compounds can be move to the clinic quickly. 

The above screen have produced 10 drug "hits" showing potential for increasing TPP-1 enzyme level in CLN2 cells.  The top 3 compounds have been further evaluated to ensure the results.  The scientific group continues to receive the same positive results from these compounds.  In-vivo mouse studies or fast track human trials are potential next steps for these drugs.

 In August 2001, The Nathan's Battle Foundation initiated a small molecule pharmaceutical drug screening project to screen compounds on Nathan's cell lines.  Over 700 compounds are being screened by the leading CLN2 laboratory to evaluate therapeutic effects.  The Nathan's Battle Foundation entered into an agreement with a pharmaceutical company and an academic university to pursue high through put screening on Nathan and P.J.'s mutations to identify possible beneficial compounds.  If a compound is found that proves beneficial the compound could be administered within the year.  Other drug screening proposals are being evaluated.

ADULT Stem Cell Therapy- This therapy would involve injecting adult stem cells into the CNS. These stem cells would produce the enzyme and aid the CNS to regain function. Adult stem cell therapy has tremendous promise for growing neurons in the CNS to "re-build" the brain. This therapy could also be a potential cure for the disorder with an additional advantage of having the patient regain function by stimulating CNS re-growth.  Adult stem cell research is a technology that the Nathan's Battle Foundation is investigating to begin future therapy projects.  Once we stop the disease we will need to regain lost function of the brain.

NBF is currently evaluating stem cell proposals for CLN2 to develop cell mediated therapies for clinical application.  NBF is investigating scientists and companies interested in stem cell technologies for use as therapies for neurodegenerative disorders.

Phil hosted a dinner at the Society for Neuroscience conference in San Diego during November 01.  The dinner was attended by some of the world's leading stem scientists, biotech professionals, and NIH representatives for the purpose of evaluating cell mediated therapy approaches for the NCLs.  Several  proposals from attendees are being reviewed.  
 
Stem Cell Initiative Event Summary

NBF has initiated 3 different cell mediated projects/studies.  Each project is evaluating the most promising approaches / strategies for neurodegenerative disorders.  If a proof of concept is demonstrated in NCL models with any of these approaches, then a clinical program will be pursued. 

Stem Cells Inc. demonstrated a proof of concept using their stem cell technology on a NCL disorder.  They are now in the process of mounting a clinical program to move this technology to human clinical trials.  Stem Cell's Inc.'s technologies could be in human clinical trials by Q1 2005.

Enzyme Replacement Therapy- This therapy would inject the enzyme that the patient is missing into the CNS. This therapy would work well but there are delivery issues with having to continually inject enzyme into a patients CNS.  Delivery issues and continued enzyme production capabilities are being addressed before proceeding with enzyme replacement therapeutic approaches.  NBF is in discussions with academic institutions to evaluate enzyme replacement possibilities.  Coupled with Blood Brain Barrier technologies make this approach a more viable option and NBF is evaluating these technologies.

Blood Brain Barrier technologies.  NBF is evaluating BBB technologies.  New technologies are being discovered that aid compounds/enzymes to cross the BBB by altering the properties of this protective barrier.  Several technologies are being evaluated to aid in delivery of TPP1 (the missing enzyme) to the brains of CLN2 patients.

 

Other links containing information about NBF's scientific efforts:

Business Plan/ Clinical Trial Efforts - This link contains documentation that outline specific efforts for a clinical trial for Late Infantile Batten Disease. Documents such as: a the CLN2 Business Plan, Clinical Trial Initiative Conference Summary, Action for Therapy Conference Summary, and a Non For Profit Therapy Development Model Presentation.

NCLRA - This link contains information about an organization that Phil is a member of focused on aiding in the development therapies for Batten disease. The Neuronal Ceroid Lipofuscinoses Research Alliance (NCLRA) is a united group of international foundations who's purpose is to aid in the coordination of bringing potential therapies to clinical trials for the three major forms of NCL (INCL, LINCL and JNCL). The JNCL Research Fund is associated with the NCLRA and play a very active role in the following. creating a network of relevant research information, combined our monetary resources to achieve greater impact, project one voice for all our children.

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