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Spinal cord pathology in CLN1 disease: A novel therapeutic target

Student thesis: Doctoral ThesisDoctor of Philosophy

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.
Original languageEnglish
Awarding Institution
Award date2017


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