Batten disease or the Neuronal Ceroid Lipofuscinoses (NCLss) are each the result of inherited mutations that result in lysosomal dysfunction. Some of these disorders are due to deficiencies in lysosomal enzymes, while several others are the result of deficiencies in transmembrane proteins that are either directly or indirectly important for lysosomal function. An important step towards devising therapies for these fatal disorders is the characterization of animal models of NCL. These have been generated via gene manipulation or by identifying naturally occurring mutants that bear disease-causing mutations. These models have proved invaluable both for investigating disease mechanisms and testing how to deliver experimental therapies, and for assessing their efficacy. The majority of this work has been done in mice, but larger animal species with their more brains have proved especially important. We have been characterizing the onset and progression of neuropathological changes in multiple forms of NCL. This work has included identifying which brain regions and cell types are most affected, and their contribution to disease progression. Recently we have discovered that glia become dysfunctional in multiple forms of NCL, to the extent that they appear to harm neurons. However, how this happens differs markedly between forms of NCL. We have also recently identified spinal pathology in several NCLs, which contributes to disease outcome and also needs to be targeted therapeutically. Larger animal species are proving especially well suited for translating our work, with pre-clinical enzyme replacement studies in CLN2 deficient dogs in collaboration with BioMarin leading to a successful clinical trial, and the FDA approval of Brineura being the first treatment for any form of NCL. These studies highlight the importance of defining progressive neuropathological changes in informing the effective targeting of therapeutic approaches for the NCLs.
Medical Laboratory Technician50%