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Title: Spinal cord pathology in CLN1 disease : a novel therapeutic target
Author: Nelvagal, Hemanth Ramesh
ISNI:       0000 0004 6347 6807
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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The neuronal ceroid lipofuscinoses (NCLs) are a group of up to 14 inherited progressive neurodegenerative lysosomal storage disorders affecting children and young adults. Together, they are the most common pediatric neurodegenerative storage disorders. Symptoms include loss of vision, epileptic seizures and the loss of cognitive and motor function. A lack of any effective therapies means that all forms are fatal. CLN1 disease or Infantile NCL is one of the most rapidly progressing forms of the disease and is caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase – 1 (PPT1). Ppt1 deficient (Ppt1-/-) mice recapitulate features of the human disease and have proved to be a useful tool in characterizing disease progression and pathology in the brain. However, these pathological changes fail to fully explain the sensorimotor deficits seen in this mouse model as well as in human CLN1 disease. Along with the limited success of various brain directed therapies, this led us to analyze the spinal cord. Our analysis revealed unexpectedly profound and rapidly progressing disease pathology in the spinal cords of these mice, which occurs earlier than similar events in the brain. This included regional atrophy, neuroinflammation, and significant neuron loss at all levels of the cord as well as novel phenotypes indicating a postnatal developmental delay and significant white matter pathology. Automated gait analysis also showed novel early phenotypes in these mice including an increased dependence on the forelimbs for locomotion. Similar spinal cord pathology was also demonstrated in human INCL autopsy samples as well as in mouse models of the other major forms of NCL. Targeting the spinal cords of Ppt1-/-mice with enzyme replacement therapy (ERT) and gene therapy significantly improved disease pathology, motor function and lifespan in these mice, demonstrating the clinical significance of spinal cord pathology in these mice. Furthermore, combining intracranial and intrathecal gene therapy showed a synergistic effect, showing the greatest improvements for any CLN1 disease therapy to date. Taken together, these findings highlight the spinal cord as not only being significantly affected in CLN1 disease, but also as a novel and effective therapeutic target.
Supervisor: Thuret, Sandrine ; Cooper, Jonathan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available