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2016 BDSRA Katz & Johnson All NCL types

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Canine Models for NCL Therapy Development

Publié dans : Santé & Médecine
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2016 BDSRA Katz & Johnson All NCL types

  1. 1. All Types of NCL Canine Models for NCL Therapy Development Martin L. Katz and Gary S. Johnson, School of Medicine and College of Veterinary Medicine, University of Missouri Introduction: Dog models for the neuronal ceroid lipofuscinoses (NCLs or Batten disease) will be useful for evaluating the efficacy of potential therapeutic interventions for treating these diseases. The NCLs result from mutations in at least 13 different genes. Different approaches to therapy are going to be required to treat the different forms of NCL. Therefore, it will be important to have suitable animal models for each of the forms of NCL. A dog model for the CLN2 form of Batten disease played a critical role in the development of an effective enzyme replacement therapy currently being used to treat children with this disorder. This has proven the utility of dog models in pre- clinical studies required before approval can be obtained for conducting human clinical trials. Our goal is to develop dog models for each of the forms of NCL that can be used for therapeutic intervention testing in preparation for conducting human clinical trials. Acknowledgements: This work was made possible by the many dog owners who contributed samples from their pets and the veterinarians who collected postmortem tissues. Numerous research personnel contributed to the disease characterizations and mutation identifications. Among them are Tomoyuki Awano, Douglas Sanders, Dennis O’Brien, Liz Hansen, Fabiana Farias, Jenny Guo, Douglas Gilliam, and Ana Kolicheski. Others who contributed to this work are listed on the laboratory website http://medicine.missouri.edu/neurodegenerativediseases/publications.php Support for some of this work was provided by the BDSRA and the American Kennel Club Canine Health Foundation. Establishing Canine NCL Models: Naturally occurring canine NCLs identified to date: Significance: • A Dachshund model for the CLN2 form of NCL was used to demonstrate the efficacy of enzyme replacement therapy that resulted in the recent successful completion of human clinical trials of this treatment in children by BioMarin Pharmaceutical. • Using this same model, gene therapy to the central nervous system was also found to be effective in treating this disease. This method of treatment may be tested in children in the future. • Currently we have preserved canine semen for the CLN2 and CLN5 forms of Batten disease. • We are screening dogs with the other forms of NCL to obtain semen as a resource for breeding affected dogs. • We also continue to search for dogs with different forms of NCL that correspond to the remaining forms of NCL. We have DNA samples from several other dog breeds with NCL for which we are seeking to causative mutation. • We plan to establish a canine NCL models resource center that will be able to generate dogs affected with each of the forms of NCL. • We developed a panel of biomarkers of NCL disease progression in dogs that can be used in testing for the therapeutic efficacy of treatments using the dog models.